Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2. Clinical considerations and new agents

Journal of Medicinal Chemistry

Volumn 46, Issue 7, 2003, Pages 1081-1111

  Jordan, V Craig ^a  

^a NORTHWESTERN UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

11 [4 (2 DIMETHYLAMINOETHOXY)PHENYL]ESTRADIOL; 11 [4 [[5 [(4,4,5,5,5 PENTAFLUOROPENTYL)SULFONYL]PENTYL]OXY]PHENYL]ESTRADIOL; 3 (4 HYDROXYPHENYL) 2 [4 [2 (1 PIPERIDINYL)ETHOXY]PHENYL] 2H 1 BENZOPYRAN 7 OL; 4 (1,2 DIPHENYL 1 BUTENYL)CINNAMIC ACID; 4 [4 METHYL 2 [4 [2 (1 PIPERIDINYL)ETHOXY]PHENYL] 7 PIVALOYLOXY 2H 1 BENZOPYRAN 3 YLPHENYL] PIVALATE; 4 HYDROXYTAMOXIFEN; 6 HYDROXY 2 (4 HYDROXYPHENYL) 3 [4 [2 (1 PYRROLIDINYL)ETHOXY]BENZOYL]BENZO[B]THIOPHENE; ACOLBIFENE; ANASTROZOLE; ANTIESTROGEN; ARZOXIFENE; CLOMIFENE; CONJUGATED ESTROGEN; DIETHYLSTILBESTROL; DROLOXIFENE; ESTROGEN; ESTROGEN RECEPTOR; FULVESTRANT; GOSERELIN; GW 7604; IDOXIFENE; LASOFOXIFENE; LEUPRORELIN; LY 353389; MITOGEN ACTIVATED PROTEIN KINASE; N BUTYL 11 (3,17BETA DIHYDROXYESTRA 1,3,5(10) TRIEN 7ALPHA YL) N METHYLUNDECANAMIDE; NAFOXIDINE; NORTAMOXIFEN; OSPEMIFENE; PIPENDOXIFENE; RALOXIFENE; SCH 57068; TAMOXIFEN; TOREMIFENE; TSE 4247; UNCLASSIFIED DRUG; UNINDEXED DRUG; ZINDOXIFENE;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BINDING AFFINITY; BREAST CANCER; CARCINOGENESIS; CLINICAL TRIAL; CROSS RESISTANCE; DNA ADDUCT; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG RESISTANCE; ENDOMETRIUM CANCER; HOT FLUSH; HUMAN; LIVER CELL CARCINOMA; NONHUMAN; OSTEOPOROSIS; REVIEW; SIGNAL TRANSDUCTION; TUMOR GROWTH;

ANIMALS; ANTINEOPLASTIC AGENTS; DRUG RESISTANCE; ENDOMETRIAL NEOPLASMS; ESTRADIOL CONGENERS; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; ESTROGEN RECEPTOR MODULATORS; FEMALE; HUMANS; MODELS, MOLECULAR; OSTEOPOROSIS, POSTMENOPAUSAL; RALOXIFENE; RECEPTORS, ESTROGEN; SELECTIVE ESTROGEN RECEPTOR MODULATORS; STEROIDS; STRUCTURE-ACTIVITY RELATIONSHIP; TAMOXIFEN;

EID: 0037468902     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm020450x     Document Type: Review

References (414)

1. Furr, B. J.; Jordan, V. C. The pharmacology and clinical uses of tamoxifen. Pharmacol. Ther. 1984, 25, 127-205.
2. Jaiyesimi, I. A.; Buzdar, A. U.; Decker, D. A.; Hortobagyi, G. N. Use of tamoxifen for breast cancer: twenty-eight years later [see comments]. J. Clin. Oncol. 1995, 13, 513-529.
3. Osborne, C. K. Tamoxifen in the treatment of breast cancer. N. Engl. J. Med. 1998, 339, 1609-1618.
4. EBCTCG tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998, 351, 1451-1467.
5. Fisher, B.; Dignam, J.; Bryant, J.; DeCillis, A.; Wickerham, D. L.; Wolmark, N.; Costantino, J.; Redmond, C.; Fisher, E. R.; Bowman, D. M.; Deschenes, L.; Dimitrov, N. V.; Margolese, R. G.; Robidoux, A.; Shibata, H.; Terz, J.; Paterson, A. H.; Feldman, M. I.; Farrar, W.; Evans, J.; Lickley, H. L. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors [see comments]. J. Natl. Cancer Inst. 1996, 88, 1529-1542.
6. Fisher, B.; Dignam, J.; Bryant, J.; Wolmark, N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J. Natl. Cancer Inst. 2001, 93, 684-690.
7. Canney, P. A.; Griffiths, T.; Latief, T. N.; Priestman, T. J. Clinical significance of tamoxifen withdrawal response. Lancet 1987, 1, 36.
8. Howell, A.; Dodwell, D. J.; Anderson, H.; Redford, J. Response after withdrawal of tamoxifen and progestogens in advanced breast cancer [see comments]. Ann. Oncol. 1992, 3, 611-617.
9. Bonte, J.; Ide, P.; Billiet, G.; Wynants, P. Tamoxifen as a possible chemotherapeutic agent in endometrial adenocarcinoma. Gynecol. Oncol. 1981, 11, 140-161.
10. Cohen, C. J. Tamoxifen and endometrial cancer: tamoxifen effects on the human female genital tract. Semin. Oncol. 1997, 24, S1-55 - S51-64.
11. Goldstein, S. R. Unusual ultrasonographic appearance of the uterus in patients receiving tamoxifen [see comments]. Am. J. Obstet. Gynecol. 1994, 170, 447-451.
12. Decensi, A.; Fontana, V.; Bruno, S.; Gustavino, C.; Gatteschi, B.; Costa, A. Effect of tamoxifen on endometrial proliferation. J. Clin. Oncol. 1996, 14, 434-440.
13. Kedar, R. P.; Bourne, T. H.; Powles, T. J.; Collins, W. P.; Ashley, S. E.; Cosgrove, D. O.; Campbell, S. Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial [see comments]. Lancet 1994, 343, 1318-1321.
14. Fornander, T.; Rutqvist, L. E.; Cedermark, B.; Glas, U.; Mattsson, A.; Silfversward, C.; Skoog, L.; Somell, A.; Theve, T.; Wilking, N.; et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989, 1, 117-120.
15. Fisher, B.; Costantino, J. P.; Wickerham, D. L.; Redmond, C. K.; Kavanah, M.; Cronin, W. M.; Vogel, V.; Robidoux, A.; Dimitrov, N.; Atkins, J.; Daly, M.; Wieand, S.; Tan-Chiu, E.; Ford, L.; Wolmark, N. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl. Cancer Inst. 1998, 90, 1371-1388.
16. Fisher, B.; Costantino, J. P.; Redmond, C. K.; Fisher, E. R.; Wickerham, D. L.; Cronin, W. M. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J. Natl. Cancer Inst. 1994, 86, 527-537.
17. Bernstein, L.; Deapen, D.; Cerhan, J. R.; Schwartz, S. M.; Liff, J.; McGann-Maloney, E.; Perlman, J. A.; Ford, L. Tamoxifen therapy for breast cancer and endometrial cancer risk. J. Natl. Cancer Inst. 1999, 91, 1654-1662.
18. Sakai, F.; Cheix, F.; Clavel, M.; Colon, J.; Mayer, M.; Pommatau, E.; Saez, S. Increases in steroid binding globulins induced by tamoxifen in patients with carcinoma of the breast. J. Endocrinol. 1978, 76, 219-226.
19. Jordan, V. C.; Fritz, N. F.; Tormey, D. C. Long-term adjuvant therapy with tamoxifen: effects on sex hormone binding globulin and antithrombin III. Cancer Res. 1987, 47, 4517-4519.
20. Fex, G.; Adielsson, G.; Mattson, W. Oestrogen-like effects of tamoxifen on the concentration of proteins in plasma. Acta Endocrinol. 1981, 97, 109-113.
21. Helgason, S.; Wilking, N.; Carlstrom, K.; Damber, M. G.; von Schoultz, B. A comparative study of the estrogenic effects of tamoxifen and 17 beta-estradiol in postmenopausal women. J. Clin. Endocrinol. Metab. 1982, 54, 404-408.
22. Jordan, V. C.; Fritz, N. F.; Tormey, D. C. Endocrine effects of adjuvant chemotherapy and long-term tamoxifen administration on node-positive patients with breast cancer. Cancer Res. 1987, 47, 624-630.
23. Bertelli, G.; Pronzato, P.; Amoroso, D.; Cusimano, M. P.; Conte, P. F.; Montagna, G.; Bertolini, S.; Rosso, R. Adjuvant tamoxifen in primary breast cancer: influence on plasma lipids and antithrombin III levels. Breast Cancer Res. Treat. 1988, 12, 307-310.
24. Bagdade, J. D.; Wolter, J.; Subbaiah, P. V.; Ryan, W. Effects of tamoxifen treatment on plasma lipids and lipoprotein lipid composition. J. Clin. Endocrinol. Metab. 1990, 70, 1132-1135.
25. Love, R. R.; Newcomb, P. A.; Wiebe, D. A.; Surawicz, T. S.; Jordan, V. C.; Carbone, P. P.; DeMets, D. L. Effects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer [see comments]. J. Natl. Cancer Inst. 1990, 82, 1327-1332.
26. Love, R. R.; Wiebe, D. A.; Newcomb, P. A.; Cameron, L.; Leventhal, H.; Jordan, V. C.; Feyzi, J.; DeMets, D. L. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann. Intern. Med. 1991, 115, 860-864.
27. Love, R. R.; Wiebe, D. A.; Feyzi, J. M.; Newcomb, P. A.; Chappell, R. J. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women after 5 years of treatment. J. Natl. Cancer Inst. 1994, 86, 1534-1539.
28. Shewmon, D. A.; Stock, J. L.; Rosen, C. J.; Heiniluoma, K. M.; Hogue, M. M.; Morrison, A.; Doyle, E. M.; Ukena, T.; Weale, V.; Baker, S. Tamoxifen and estrogen lower circulating lipoprotein- (a) concentrations in healthy postmenopausal women. Arterioscler. Thromb. 1994, 14, 1586-1593.
29. Grey, A. B.; Stapleton, J. P.; Evans, M. C.; Reid, I. R. The effect of the anti-estrogen tamoxifen on cardiovascular risk factors in normal postmenopausal women. J. Clin. Endocrinol. Metab. 1995, 80, 3191-3195.
30. Guetta, V.; Lush, R. M.; Figg, W. D.; Waclawiw, M. A.; Cannon, R. O. 3rd. Effects of the antiestrogen tamoxifen on low-density lipoprotein concentrations and oxidation in postmenopausal women. Am. J. Cardiol. 1995, 76, 1072-1073.
31. Saarto, T.; Blomqvist, C.; Ehnholm, C.; Taskinen, M. R.; Elomaa, I. Antiatherogenic effects of adjuvant antiestrogens: a randomized trial comparing the effects of tamoxifen and toremifene on plasma lipid levels in postmenopausal women with node-positive breast cancer. J. Clin. Oncol. 1996, 14, 429-433.
32. Rutqvist, L. E.; Mattsson, A. Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. The Stockholm Breast Cancer Study Group [see comments]. J. Natl. Cancer Inst. 1993, 85, 1398-1406.
33. Costantino, J. P.; Kuller, L. H.; Ives, D. G.; Fisher, B.; Dignam, J. Coronary heart disease mortality and adjuvant tamoxifen therapy [see comments]. J. Natl. Cancer Inst. 1997, 89, 776- 782.
34. Reis, S. E.; Costantino, J. P.; Wickerham, D. L.; Tan-Chiu, E.; Wang, J.; Kavanah, M. Cardiovascular effects of tamoxifen in women with and without heart disease: breast cancer prevention trial. National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial Investigators. J. Natl. Cancer Inst. 2001, 93, 16-21.
35. McDonald, C. C.; Stewart, H. J. Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. The Scottish Breast Cancer Committee [see comments]. Br. Med. J. 1991, 303, 435-437.
36. McDonald, C. C.; Alexander, F. E.; Whyte, B. W.; Forrest, A. P.; Stewart, H. J. Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial. The Scottish Cancer Trials Breast Group. Br. Med. J. 1995, 311, 977-980.
37. Turken, S.; Siris, E.; Seldin, D.; Flaster, E.; Hyman, G.; Lindsay, R. Effects of tamoxifen on spinal bone density in women with breast cancer. J. Natl. Cancer Inst. 1989, 81, 1086-1088.
38. Love, R. R.; Mazess, R. B.; Barden, H. S.; Epstein, S.; Newcomb, P. A.; Jordan, V. C.; Carbone, P. P.; Demets, D. L. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer [see comments]. N. Engl. J. Med. 1992, 326, 852-856.
39. Wright, C. D.; Garrahan, N. J.; Stanton, M.; Gazet, J. C.; Mansell, R. E., Compston, J. E. Effect of long-term tamoxifen therapy on cancellous bone remodeling and structure in women with breast cancer. J. Bone Miner. Res. 1994, 9, 153-159.
40. Love, R. R.; Barden, H. S.; Mazess, R. B.; Epstein, S.; Chappell, R. J. Effect of tamoxifen on lumbar spine bone mineral density in postmenopausal women after 5 years. Arch. Intern. Med. 1994, 154, 2585-2588.
41. Kristensen, B.; Ejlertsen, B.; Dalgaard, P.; Larsen, L.; Holmegaard, S. N.; Transbol, I.; Mouridsen, H. T. Tamoxifen and bone metabolism in postmenopausal low-risk breast cancer patients: a randomized study. J. Clin. Oncol. 1994, 12, 992-997.
42. Kenny, A. M.; Prestwood, K. M.; Pilbeam, C. C.; Raisz, L. G. The short term effects of tamoxifen on bone turnover in older women. J. Clin. Endocrinol. Metab. 1995, 80, 3287-3291.
43. Powles, T. J.; Hickish, T.; Kanis, J. A.; Tidy, A.; Ashley, S. Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J. Clin. Oncol. 1996, 14, 78-84.
44. The ATAC Trialist Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomized trial. Lancet 2002, 359, 2131-2139.
45. The-Women's-Health-Initiative-Study-Group. Design of the Women's Health Initiative clinical trial and observational study. Controlled Clin. Trials 1998, 19, 61-109.
46. Fisher, B.; Costantino, J.; Redmond, C.; Poisson, R.; Bowman, D.; Couture, J.; Dimitrov, N. V.; Wolmark, N.; Wickerham, D. L.; Fisher, E. R.; et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N. Engl. J. Med. 1989, 320, 479-484.
47. Powles, T. J.; Hardy, J. R.; Ashley, S. E.; Farrington, G. M.; Cosgrove, D.; Davey, J. B.; Dowsett, M.; McKinna, J. A.; Nash, A. G.; Sinnett, H. D.; et al. A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br. J. Cancer 1989, 60, 126-131.
48. Williams, G. M.; Iatropoulos, M. J.; Djordjevic, M. V.; Kaltenberg, O. P. The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat. Carcinogenesis 1993, 14, 315-317.
49. Greaves, P.; Goonetilleke, R.; Nunn, G.; Topham, J.; Orton, T. Two-year carcinogenicity study of tamoxifen in Alderley Park Wistar-derived rats. Cancer Res. 1993, 53, 3919-3924.
50. Hard, G. C.; Iatropoulos, M. J.; Jordan, K.; Radi, L.; Kaltenberg, O. P.; Imondi, A. R.; Williams, G. M. Major difference in the hepatocarcinogenicity and DNA adduct forming ability between toremifene and tamoxifen in female Crl:CD(BR) rats. Cancer Res. 1993, 53, 4534-4541.
51. Dragan, Y. P.; Fahey, S.; Street, K.; Vaughan, J.; Jordan, V. C.; Pitot, H. C. Studies of tamoxifen as a promoter of hepatocarcinogenesis in female Fischer F344 rats. Breast Cancer Res. Treat. 1994, 31, 11-25.
52. Dragan, V. P.; Vaughan, J.; Jordan, V. C.; Pitot, H. C. Comparison of the effects of tamoxifen and toremifene on liver and kidney tumor promotion in female rats. Carcinogenesis 1995, 16, 2733-2741.
53. Dragan, Y. P.; Fahey, S.; Nuwaysir, E.; Sattler, C.; Babcock, K.; Vaughan, J.; McCague, R.; Jordan, V. C.; Pitot, H. C. The effect of tamoxifen and two of its non-isomerizable fixed-ring analogs on multistage rat hepatocarcinogenesis. Carcinogenesis 1996,17, 585-594.
54. Jordan, V. C.; Assikis, V. J. Endometrial carcinoma and tamoxifen: clearing up a controversy [see comments]. Clin. Cancer Res. 1995, 1, 467-472.
55. Rutqvist, L. E.; Johansson, H.; Signomklao, T.; Johansson, U.; Fornander, T.; Wilking, N. Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. Stockholm Breast Cancer Study Group. J. Natl. Cancer Inst. 1995, 87, 645- 651.
56. Jordan, V. C. Tamoxifen and tumorigenicity: a predictable concern [editorial; comment]. J. Natl. Cancer Inst. 1995, 87, 623-626.
57. Jordan, V. C. What if tamoxifen (ICI 46,474) had been found to produce rat liver tumors in 1973? A personal perspective. Ann. Oncol. 1995, 6, 29-34.
58. Mani, C.; Kupfer, D. Cytochrome P-450-mediated activation and irreversible binding of the antiestrogen tamoxifen to proteins in rat and human liver: possible involvement of flavin-containing monooxygenases in tamoxifen activation. Cancer Res. 1991, 51, 6052-6058.
59. Mani, C.; Gelboin, H. V.; Park, S. S.; Pearce, R.; Parkinson, A.; Kupfer, D. Metabolism of the antimammary cancer antiestrogenic agent tamoxifen. I. Cytochrome P-450-catalyzed N-demethylation and 4-hydroxylation [published erratum appears in Drug Metab. Dispos. 1993, 21 (6, November-December), 11174]. Drug Metab. Dispos. 1993, 21, 645-656.
60. Mani, C.; Hodgson, E.; Kupfer, D. Metabolism of the antimammary cancer antiestrogenic agent tamoxifen. II. Flavin-containing monooxygenase-mediated N-oxidation. Drug Metab. Dispos. 1993, 21, 657-661.
61. Mani, C.; Pearce, R.; Parkinson, A.; Kupfer, D. Involvement of cytochrome P4503A in catalysis of tamoxifen activation and covalent binding to rat and human liver microsomes. Carcinogenesis 1994, 15, 2715-2720.
62. Dehal, S. S.; Kupfer, D. Cytochrome P-450 3A and 2D6 catalyze ortho hydroxylation of 4-hydroxytamoxifen and 3-hydroxytamoxifen (droloxifene) yielding tamoxifen catechol: involvement of catechols in covalent binding to hepatic proteins. Drug Metab. Dispos. 1999, 27, 681-688.
63. Zhang, F.; Fan, P. W.; Liu, X.; Shen, L.; van Breeman, R. B.; Bolton, J. L. Synthesis and reactivity of a potential carcinogenic metabolite of tamoxifen: 3,4-dihydroxytamoxifen-o-quinone. Chem. Res. Toxicol. 2000, 13, 53-62.
64. Han, X. L.; Liehr, J. G. Induction of covalent DNA adducts in rodents by tamoxifen. Cancer Res. 1992, 52, 1360-1363.
65. Phillips, D. H.; Hewer, A.; White, I. N.; Farmer, P. B. Cochromatography of a tamoxifen epoxide - deoxyguanylic acid adduct with a major DNA adduct formed in the livers of tamoxifen-treated rats. Carcinogenesis 1994, 15, 793-795.
66. Styles, J. A.; Davies, A.; Lim, C. K.; De Matteis, F.; Stanley, L. A.; White, I. N.; Yuan, Z. X.; Smith, L. L. Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. Carcinogenesis 1994, 15, 5-9.
67. Randerath, K.; Bi, J.; Mabon, N.; Sriram, P.; Moorthy, B. Strong intensification of mouse hepatic tamoxifen DNA adduct formation by pretreatment with the sulfotransferase inhibitor and ubiquitous environmental pollutant pentachlorophenol. Carcinogenesis 1994, 15, 797-800.
68. Randerath, K.; Moorthy, B.; Mabon, N.; Sriram, P. Tamoxifen: evidence by 32P-postlabeling and use of metabolic inhibitors for two distinct pathways leading to mouse hepatic DNA adduct formation and identification of 4-hydroxytamoxifen as a proximate metabolite. Carcinogenesis 1994, 15, 2087-2094.
69. Moorthy, B.; Sriram, P.; Pathak, D. N.; Bodell, W. J.; Randerath, K. Tamoxifen metabolic activation: comparison of DNA adducts formed by microsomal and chemical activation of tamoxifen and 4-hydroxytamoxifen with DNA adducts formed in vivo. Cancer Res. 1996, 56, 53-57.
70. Pongracz, K.; Pathak, D. N.; Nakamura, T.; Burlingame, A. L.; Bodell, W. J. Activation of the tamoxifen derivative metabolite E to form DNA adducts: comparison with the adducts formed by microsomal activation of tamoxifen. Cancer Res. 1995, 55, 3012-3015.
71. Phillips, D. H.; Carmichael, P. L.; Hewer, A.; Cole, K. J.; Poon, G. K. alpha-Hydroxytamoxifen, a metabolite of tamoxifen with exceptionally high DNA-binding activity in rat hepatocytes. Cancer Res. 1994, 54, 5518-5522.
72. Phillips, D. H.; Potter, G. A.; Horton, M. N.; Hewer, A.; Crofton-Sleigh, C.; Jarman, M.; Venitt, S. Reduced genotoxicity of [D5-ethyl]-tamoxifen implicates alpha-hydroxylation of the ethyl group as a major pathway of tamoxifen activation to a liver carcinogen. Carcinogenesis 1994, 15, 1487-1492.
73. Potter, G. A.; McCague, R.; Jarman, M. A mechanistic hypothesis for DNA adduct formation by tamoxifen following hepatic oxidative metabolism. Carcinogenesis 1994, 15, 439-442.
74. Boocock, D. J.; Maggs, J. L.; White, I. N.; Park, B. K. Alpha-hydroxytamoxifen, a genotoxic metabolite of tamoxifen in the rat: identification and quantification in vivo and in vitro. Carcinogenesis 1999, 20, 153-160.
75. Brown, K.; Heydon, R. T.; Jukes, R.; White, I. N.; Martin, E. A. Further characterization of the DNA adducts formed in rat liver after the administration of tamoxifen, N-desmethyltamoxifen or N,N-didesmethyltamoxifen. Carcinogenesis 1999, 20, 2011-2016.
76. Osborne, M. R.; Hewer, A.; Hardcastle, I. R.; Carmichael, P. L.; Phillips, D. H. Identification of the major tamoxifen - deoxyguanosine adduct formed in the liver DNA of rats treated with tamoxifen. Cancer Res. 1996, 56, 66-71.
77. Osborne, M. R.; Davis, W.; Hewer, A. J.; Hardcastle, I. R.; Phillips, D. H. 4-Hydroxytamoxifen gives DNA adducts by chemical activation, but not in rat liver cells. Chem. Res. Toxicol. 1999, 12, 151-158.
78. Sauvez, F.; Drouin, D. S.; Attia, M.; Bertheux, H.; Forster, R. Cutaneously applied 4-hydroxytamoxifen is not carcinogenic in female rats. Carcinogenesis 1999, 20, 843-850.
79. Umemoto, A.; Monden, Y.; Komaki, K.; Suwa, M.; Kanno, Y.; Suzuki, M.; Lin, C. X.; Ueyama, Y.; Momen, M. A.; Ravindernath, A.; Shibutani, S. Tamoxifen - DNA adducts formed by α-acetoxytamoxifen N-oxide. Chem. Res. Toxicol. 1999, 12, 1083-1089.
80. Phillips, D. H.; Hewer, A.; Horton, M. N.; Cole, K. J.; Carmichael, P. L.; Davis, W.; Osborne, M. R. N-demethylation accompanies alpha-hydroxylation in the metabolic activation of tamoxifen in rat liver cells. Carcinogenesis 1999, 20, 2003-2009.
81. Gamboa da Costa, G.; Hamilton, L. P.; Beland, F. A.; Marques, M. M. Characterization of the major DNA adduct formed by α-hydroxy-N-desmethyltamoxifen in vitro and in vivo. Chem. Res. Toxicol. 2000, 13, 200-207.
82. Rajaniemi, H.; Rasanen, I.; Koivisto, P.; Peltonen, K.; Hemminki, K. Identification of the major tamoxifen - DNA adducts in rat liver by mass spectroscopy. Carcinogenesis 1999, 20, 305-309.
83. Phillips, D. H.; Carmichael, P. L.; Hewer, A.; Cole, K. J.; Hardcastle, I. R.; Poon, G. K.; Keogh, A.; Strain, A. J. Activation of tamoxifen and its metabolite alpha-hydroxytamoxifen to DNA- binding products: comparisons between human, rat and mouse hepatocytes. Carcinogenesis 1996, 17, 89-94.
84. Martin, E. A.; Rich, K. J.; White, I. N.; Woods, K. L.; Powles, T. J.; Smith, L. L. 32P-postlabelled DNA adducts in liver obtained from women treated with tamoxifen. Carcinogenesis 1995, 16, 1651-1654.
85. Carmichael, P. L.; Ugwumadu, A. H.; Neven, P.; Hewer, A. J.; Poon, G. K.; Phillips, D. H. Lack of genotoxicity of tamoxifen in human endometrium. Cancer Res. 1996, 56, 1475-1479.
86. Bartsch, H.; Phillips, D. H.; Nair, J.; Hewer, A.; Meyberg-Solomeyer, G.; Grischke, E. M. Lack of evidence for tamoxifen- and toremifene - DNA adducts in lymphocytes of treated patients. Carcinogenesis 2000, 21, 845-847.
87. Hemminki, K.; Rajaniemi, H.; Lindahl, B.; Moberger, B. Tamoxifen-induced DNA adducts in endometrial samples from breast cancer patients [see comments]. Cancer Res. 1996, 56, 4374- 4377.
88. Hemminki, K.; Rajaniemi, H.; Koskinen, M.; Hansson, J. Tamoxifen-induced DNA adducts in leucocytes of breast cancer patients. Carcinogenesis 1997, 18, 9-13.
89. Shibutani, S.; Shaw, P. M.; Suzuki, N.; Dasaradhi, L.; Duffel, M. W.; Terashima, I. Sulfation of alpha-hydroxytamoxifen catalyzed by human hydroxysteroid sulfotransferase results in tamoxifen - DNA adducts. Carcinogenesis 1998, 19, 2007-2011.
90. Terashima, I.; Suzuki, N.; Shibutani, S. Mutagenic potential of alpha-(N2-deoxyguanosinyl)tamoxifen lesions, the major DNA adducts detected in endometrial tissues of patients treated with tamoxifen. Cancer Res. 1999, 59, 2091-2095.
91. Glatt, H.; Davis, W.; Meinl, W.; Hermersdorfer, H.; Venitt, S.; Phillips, D. H. Rat, but not human, sulfotransferase activates a tamoxifen metabolite to produce DNA adducts and gene mutations in bacteria and mammalian cells in culture. Carcinogenesis 1998, 19, 1709-1713.
92. Boocock, D. J.; Maggs, J. L.; Brown, K.; White, I. N.; Park, B. K. Major inter-species differences in the rates of O-sulphonation and O-glucuronylation of alpha-hydroxytamoxifen in vitro: a metabolic disparity protecting human liver from the formation of tamoxifen - DNA adducts. Carcinogenesis 2000, 21, 1851-1858.
93. Comoglio, A.; Gibbs, A. H.; White, I. N.; Gant, T.; Martin, E. A.; Smith, L. L.; Gamalero, S. R.; DeMatteis, F. Effect of tamoxifen feeding on metabolic activation of tamoxifen by the liver of the rhesus monkey: does liver accumulation of inhibitory metabolites protect from tamoxifen-dependent genotoxicity and cancer? Carcinogenesis 1996, 17, 1687-1693.
94. Dal Cin, P.; Timmerman, D.; Van den Berghe, I.; Wanschura, S.; Kazmierczak, B.; Vergote, I.; Deprest, J.; Neven, P.; Moerman, P.; Bullerdiek, J.; Van den Berghe, H. Genomic changes in endometrial polyps associated with tamoxifen show no evidence for its action as an external carcinogen. Cancer Res. 1998, 58, 2278-2281.
95. Phillips, D. H. Understanding the genotoxicity of tamoxifen? Carcinogenesis 2001, 22, 839-849.
96. Satyaswaroop, P. G.; Zaino, R. J.; Mortel, R. Estrogen-like effects of tamoxifen on human endometrial carcinoma transplanted into nude mice. Cancer Res. 1984, 44, 4006-4010.
97. Gottardis, M. M.; Robinson, S. P.; Satyaswaroop, P. G.; Jordan, V. C. Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res. 1988, 48, 812-815.
98. Killackey, M. A.; Hakes, T. B.; Pierce, V. K. Endometrial adenocarcinoma in breast cancer patients receiving antiestrogens. Cancer Treat. Rep. 1985, 69, 237-238.
99. Hardell, L. Tamoxifen as risk factor for carcinoma of corpus uteri [letter]. Lancet 1988, 2, 563.
100. Assikis, V. J.; Neven, P.; Jordan, V. C.; Vergote, I. A realistic clinical perspective of tamoxifen and endometrial carcinogenesis. Eur. J. Cancer 1996, 32A, 1464-1476.
101. Franchi, M.; Ghezzi, F.; Donadello, N.; Zanaboni, F.; Beretta, P.; Bolis, P. Endometrial thickness in tamoxifen-treated patients: an independent predictor of endometrial disease. Obstet. Gynecol. 1999, 93, 1004-1008.
102. Nahari, C.; Tepper, R.; Beyth, Y.; Flex, D.; Figer, A.; Cohen, I. Long-term transvaginal ultrasonographic endometrial follow-up in postmenopausal breast cancer patients with tamoxifen treatment. Gynecol. Oncol. 1999, 74, 222-226.
103. Cohen, I.; Perel, E.; Tepper, R.; Flex, D.; Figer, A.; Shapira, J.; Altaras, M. M.; Fishman, A.; Bernheim, J.; Cordoba, M.; Yigael, D.; Beyth, Y. Dose-dependent effect of tamoxifen therapy on endometrial pathologies in postmenopausal breast cancer patients. Breast Cancer Res. Treat. 1999, 53, 255-262.
104. Seoud, M.; Shamseddine, A.; Khalil, A.; Salem, Z.; Saghir, N.; Bikhazi, K.; Bitar, N.; Azar, G.; Kaspar, H. Tamoxifen and endometrial pathologies: a prospective study. Gynecol. Oncol. 1999, 75, 15-19.
105. Ramondetta, L. M.; Sherwood, J. B.; Dunton, C. J.; Palazzo, J. P. Endometrial cancer in polyps associated with tamoxifen use. Am. J. Obstet. Gynecol. 1999, 180, 340-341.
106. Cohen, I.; Bernheim, J.; Azaria, R.; Tepper, R.; Sharony, R.; Beyth, Y. Malignant endometrial polyps in postmenopausal breast cancer tamoxifen-treated patients. Gynecol. Oncol. 1999, 75, 136-141.
107. Tesoro, M. R.; Borgida, A. F.; MacLaurin, N. A.; Asuncion, C. M. Transvaginal endometrial sonography in postmenopausal women taking tamoxifen. Obstet. Gynecol. 1999, 93, 363-366.
108. Elhelw, B.; Ghorab, M. N.; Farrag, S. H. Saline sonohysterography for monitoring asymptomatic postmenopausal breast cancer patients taking tamoxifen. Int. J. Gynaecol. Obstet. 1999, 67, 81-86.
109. Cohen, I.; Azaria, R.; Aviram, R.; Bernheim, J.; Tepper, R.; Cordoba, M.; Beyth, Y. Postmenopausal endometrial pathologies with tamoxifen treatment: comparison between hysteroscopic and hysterectomy findings. Gynecol. Obstet. Invest. 1999, 48, 187-192.
110. Mourits, M. J.; Van der Zee, A. G.; Willemse, P. H.; Ten Hoor, K. A.; Hollema, H.; de Vries, E. Descrepancy between utrasonography and hysteroscopy and histology of endometrium in postmenopausal breast cancer patients using tamoxifen. Gynecol. Oncol. 1999, 73, 21-26.
111. Love, C. D.; Muir, B. B.; Scrimgeour, J. B.; Leonard, R. C.; Dillon, P.; Dixon, J. M. Investigation of endometrial abnormalities in asymptomatic women treated with tamoxifen and an evaluation of the role of endometrial screening [see comments]. J. Clin. Oncol. 1999, 17, 2050-2054.
112. Goncalves, M. A.; Goncalves, W. J.; Matias, M. M.; Nazario, A. C.; de Lima, G. R.; Baracat, E. C. Hysteroscopic evaluation of the endometrium of postmenopausal patients with breast cancer before and after tamoxifen use. Int. J. Gynaecol. Obstet. 1999, 66, 273-279.
113. Neven, P.; Vernaeve, H. Guidelines for monitoring patients taking tamoxifen treatment. Drug Saf. 2000, 22, 1-11.
114. Suh-Burgmann, E. J.; Goodman, A. Surveillance for endometrial cancer in women receiving tamoxifen. Ann. Intern. Med. 1999, 131, 127-135.
115. Cohen, I.; Perel, E.; Flex, D.; Tepper, R.; Altaras, M. M.; Cordoba, M.; Beyth, Y. Endometrial pathology in postmenopausal tamoxifen treatment: comparison between gynaecologically symptomatic and asymptomatic breast cancer patients. J. Clin. Pathol. 1999, 52, 278-282.
116. Buzdar, A. U.; Marcus, C.; Holmes, F.; Hug, V.; Hortobagyi, G. Phase II evaluation of Ly156758 in metastatic breast cancer. Oncology 1988, 45, 344-345.
117. Gradishar, W.; Glusman, J.; Lu, Y.; Vogel, C.; Cohen, F. J.; Sledge, G. W., Jr. Effects of high dose raloxifene in selected patients with advanced breast carcinoma. Cancer 2000, 88, 2047-2053.
118. Clemens, J. A.; Bennett, D. R.; Black, L. J.; Jones, C. D. Effects of a new antiestrogen, keoxifene (LY156758), on growth of carcinogen-induced mammary tumors and on LH and prolactin levels. Life Sci. 1983, 32, 2869-2875.
119. Gottardis, M. M.; Jordan, V. C. Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. Cancer Res. 1987, 47, 4020-4024.
120. Snyder, K. R.; Sparano, N.; Malinowski, J. M. Raloxifene hydrochloride. Am. J. Health-Syst. Pharm. 2000, 57, 1669-1675, 1676-1668.
121. Lerner, L. J.; Jordan, V. C. The development of antiestrogens for the treatment of breast cancer. Cancer Res. 1990, 50, 4177- 4189.
122. Cummings, S. R.; Eckert, S.; Krueger, K. A.; Grady, D.; Powles, T. J.; Cauley, J. A.; Norton, L.; Nickelsen, T.; Bjarnason, N. H.; Morrow, M.; Lippman, M. E.; Black, D.; Glusman, J. E.; Costa, A.; Jordan, V. C. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA, J. Am. Med. Assoc. 1999, 281, 2189-2197.
123. Cauley, J. A.; Norton, L.; Lippman, M. E.; Eckert, S.; Krueger, K. A.; Purdie, D. W.; Farrerons, J.; Karasik, A.; Mellstrom, D.; Ng, K. W.; Stephan, J. J.; Powles, T. J.; Morrow, M.; Costa, A.; Silfen, S. L.; Walls, E. L.; Schmitt, H.; Muchmore, D. B.; Jordan, V. C. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Breast Cancer Res. Treat. 2001, 65 (2), 125-134.
124. Jordan, V. C.; Glusman, J. E.; Powles, T. J.; Costa, A.; Morrow, M.; Norton, L. Incident primary breast cancer are reduced by raloxifene: integrated data from multicenter, double blind, randomized trials in 12,000 postmenopausal women (abstract). American Society of Clinical Oncology: New York, 1998; pp 122a, 466.
125. Jordan, V. C.; Glusman, J. E.; Eckert, S.; Lippman, M. E.; Powles, T. J.; Costa, A.; Morrow, M.; Norton, L. Raloxifene reduces incident primary breast cancer: integrated data from multicenter double blind placebo controlled, randomized trials in postmenopausal women. Breast Cancer Res. Treat. 1998, 50, 227.
126. Delmas, P. D.; Bjarnason, N. H.; Mitlak, B. H.; Ravoux, A. C.; Shah, A. S.; Huster, W. J.; Draper, M.; Christiansen, C. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women [see comments]. N. Engl. J. Med. 1997, 337, 1641-1647.
127. Boss, S. M.; Huster, W. J.; Neild, J. A.; Glant, M. D.; Eisenhut, C. C.; Draper, M. W. Effects of raloxifene hydrochloride on the endometrium of postmenopausal women. Am. J. Obstet. Gynecol. 1997, 177, 1458-1464.
128. Goldstein, S. R.; Scheele, W. H.; Rajagopalan, S. K.; Wilkie, J. L.; Walsh, B. W.; Parsons, A. K. A 12-month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium. Obstet. Gynecol. 2000, 95, 95-103.
129. Fugere, P.; Scheele, W. H.; Shah, A.; Strack, T. R.; Glant, M. D.; Jolly, E. Uterine effects of raloxifene in comparison with continuous-combined hormone replacement therapy in postmenopausal women. Am. J. Obstet. Gynecol. 2000, 182, 568-574.
130. Cohen, F. J.; Watts, S.; Shah, A.; Akers, R.; Plouffe, L., Jr. Uterine effects of 3-year raloxifene therapy in postmenopausal women younger than age 60. Obstet. Gynecol. 2000, 95, 104-110.
131. Gottardis, M. M.; Jiang, S. Y.; Jeng, M. H.; Jordan, V. C. Inhibition of tamoxifen-stimulated growth of an MCF-7 tumor variant in athymic mice by novel steroidal antiestrogens. Cancer Res. 1989, 49, 4090-4093.
132. O'Regan, R. M.; Gajdos, C.; Dardes, R. C.; De Los Reyes, A.; Park, W.; Rademaker, A. W.; Jordan, V. C. Effects of raloxifene after tamoxifen on breast and endometrial tumor growth in athymic mice. J. Natl. Cancer Inst. 2002, 94, 274-283.
133. O'Regan, R. M.; Cisneros, A.; England, G. M.; MacGregor, J. I.; Muenzner, H. D.; Assikis, V. J.; Bilimoria, M. M.; Piette, M.; Dragan, Y. P.; Pitot, H. C.; Chatterton, R.; Jordan, V. C. Effects of the antiestrogens tamoxifen, toremifene, and ICI 182,780 on endometrial cancer growth [see comments]. J. Natl. Cancer Inst. 1998, 90, 1552-1558.
134. Glusman, J. E.; Huster, W. J.; Paul, S. Raloxifene effects on vasomotor and other climacteric symptoms in postmenopausal women. Ob. Gyns. 1998, 5, 166.
135. Davies, G. C.; Huster, W. J.; Plouffe, L., Jr.; Lakshmanan, M. Adverse events reported by postmenopausal women in controlled trials with raloxifene. Obstet. Gynecol. 1999, 93, 558-565.
136. Johnston, C. C., Jr.; Bjarnason, N. H.; Cohen, F. J.; Shah, A.; Lindsay, R.; Mitlak, B. H.; Huster, W.; Draper, M. W.; Harper, K. D.; Heath, H., 3rd; Gennari, C.; Christiansen, C.; Arnaud, C. D.; Delmas, P. D. Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipid levels in early postmenopausal women: three-year data from 2 double-blind, randomized, placebo-controlled trials. Arch. Intern. Med. 2000, 160, 3444-3450.
137. Draper, M. W.; Flowers, D. E.; Huster, W. J.; Neild, J. A. Effects of raloxifene (LY139,481 HCl) on biochemical markers of bone and lipid matabolism in healthy postmenopausal women. Proceeding of the 4th Interantional Symposium on Osteoporosis and Consensus Development Conference; Handelstrykkeriet, Aalborg ApS: Aalbourg, Denmark, 1993; pp 119-121.
138. Heaney, R. P.; Draper, M. W. Raloxifene and estrogen: comparative bone-remodeling kinetics. J. Clin. Endocrinol. Metab. 1997, 82, 3425-3429.
139. Ettinger, B.; Black, D. M.; Mitlak, B. H.; Knickerbocker, R. K.; Nickelsen, T.; Genant, H. K.; Christiansen, C.; Delmas, P. D.; Zanchetta, J. R.; Stakkestad, J.; Gluer, C. C.; Krueger, K.; Cohen, F. J.; Eckert, S.; Ensrud, K. E.; Avioli, L. V.; Lips, P.; Cummings, S. R. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators [see comments]. JAMA, J. Am. Med. Assoc. 1999, 282, 637-645.
140. Walsh, B. W.; Paul, S.; Wild, R. A.; Dean, R. A.; Tracy, R. P.; Cox, D. A.; Anderson, P. W. The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial. J. Clin. Endocrinol. Metab. 2000, 85, 214-218.
141. Walsh, B. W.; Kuller, L. H.; Wild, R. A.; Paul, S.; Farmer, M.; Lawrence, J. B.; Shah, A. S.; Anderson, P. W. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA, J. Am. Med. Assoc. 1998, 279, 1445-1451.
142. Barrett-Conner, E.; Grady, D.; Sashegyi, A.; Anderson, P. W.; Cox, D. A.; Hoszowski, K.; Rautaharju, P.; Harper, K. D. Raloxifene and cardiovascular events in osteoporotic postmenopausal women. JAMA, J. Am. Med. Assoc. 2992, 287, 847-857.
143. Mosca, L.; Barrett-Connor, E.; Wenger, N. K.; Collins, P.; Grady, D.; Kornitzer, M.; Moscarelli, E.; Paul, S.; Wright, T. J.; Helterbrand, J. D.; Anderson, P. W. Design and methods of the raloxifene use for the heart (RUTH) study. Am. J. Cardiol. 2001, 88, 392-395.
144. Holli, K.; Valavaara, R.; Blanco, G.; Kataja, V.; Hietanen, P.; Flander, M.; Pukkala, E.; Joensuu, H. Safety and efficacy results of a randomized trial comparing adjuvant toremifene and tamoxifen in postmenopausal patients with node-positive breast cancer. Finnish Breast Cancer Group. J. Clin. Oncol. 2000, 18, 3487-3494.
145. Kangas, L.; Gronroos, M. Antitumor effects of combination toremifene and medroxyprogesterone acetate (MPA) in vitro and in vivo. J. Steroid Biochem. 1990, 36, 253-257.
146. Kangas, L.; Cantell, K.; Schellekens, H. Additive and synergistic antitumor effects with toremifene and interferons. J. Steroid Biochem. 1990, 36, 259-262.
147. Kangas, L. Review of the pharmacological properties of toremifene. J. Steroid Biochem. 1990, 36, 191-195.
148. Kangas, L.; Nieminen, A. L.; Blanco, G.; Gronroos, M.; Kallio, S.; Karjalainen, A.; Perila, M.; Sodervall, M.; Toivola, R. A new triphenylethylene compound, Fc-1157a. II. Antitumor effects. Cancer Chemother. Pharmacol. 1986, 17, 109-113.
149. Robinson, S. P.; Mauel, D. A.; Jordan, V. C. Antitumor actions of toremifene in the 7,12-dimethylbenzanthracene (DMBA)-induced rat mammary tumor model. Eur. J. Cancer Clin. Oncol. 1988, 24, 1817-1821.
150. di Salle, E.; Zaccheo, T.; Ornati, G. Antiestrogenic and antitumor properties of the new triphenylethylene derivative toremifene in the rat. J. Steroid Biochem. 1990, 36, 203-206.
151. Robinson, S. P.; Jordan, V. C. Antiestrogenic action of toremifene on hormone-dependent, -independent, and heterogeneous breast tumor growth in the athymic mouse. Cancer Res. 1989, 49, 1758-1762.
152. Valavaara, R.; Pyrhonen, S.; Heikkinen, M.; Rissanen, P.; Blanco, G.; Tholix, E.; Nordman, E.; Taskinen, P.; Holsti, L.; Hajba, A. Toremifene, a new antiestrogenic compound, for treatment of advanced breast cancer. Phase II study. Eur. J. Cancer Clin. Oncol. 1988, 24, 785-790.
153. Wiebe, V. J.; Benz, C. C.; Shemano, I.; Cadman, T. B.; DeGregorio, M. W. Pharmacokinetics of toremifene and its metabolites in patients with advanced breast cancer. Cancer Chemother. Pharmacol. 1990, 25, 247-251.
154. Hamm, J. T.; Tormey, D. C.; Kohler, P. C.; Haller, D.; Green, M.; Shemano, I. Phase I study of toremifene in patients with advanced cancer [published erratum appears in J. Clin. Oncol. 1992, 10 (4), 674]. J. Clin. Oncol. 1991, 9, 2036-2041.
155. Hayes, D. F.; Van Zyl, J. A.; Hacking, A.; Goedhals, L.; Bezwoda, W. R.; Mailliard, J. A.; Jones, S. E.; Vogel, C. L.; Berris, R. F.; Shemano, I.; et al. Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J. Clin. Oncol. 1995, 13, 2556-2566.
156. Osborne, C. K.; Jarman, M.; McCague, R.; Coronado, E. B.; Hilsenbeck, S. G.; Wakeling, A. E. The importance of tamoxifen metabolism in tamoxifen-stimulated breast tumor growth. Cancer Chemother. Pharmacol. 1994, 34, 89-95.
157. Lee, E.-S.; MacGregor Schafer, J.; Yao, K.; England, G.; O'Regan, R. M.; de los Reyes, A.; Jordan, V. C. Cross resistance of triphenylethylene-type antiestrogen but not ICI 182,780 in tamoxifen-stimulated breast tumors grown in athymic mice. Clin. Cancer Res. 2000, 6, 4893-4899.
158. Vogel, C. L.; Shemano, I.; Schoenfelder, J.; Gams, R. A.; Green, M. R. Multicenter phase II efficacy trial of toremifene in tamoxifen-refractory patients with advanced breast cancer. J. Clin. Oncol. 1993, 11, 345-350.
159. Stenbygaard, L. E.; Herrstedt, J.; Thomsen, J. F.; Svendsen, K. R.; Engelholm, S. A.; Dombernowsky, P. Toremifene and tamoxifen in advanced breast cancer - a double-blind cross-over trial. Breast Cancer Res. Treat. 1993, 25, 57-63.
160. Hirsimaki, P.; Hirsimaki, Y.; Nieminen, L.; Payne, B. J, Tamoxifen induces hepatocellular carcinoma in rat liver: a 1-year study with two antiestrogens. Arch. Toxicol. 1993, 67, 49-54.
161. Sargent, L. M.; Dragan, Y. P.; Sattler, C.; Bahnub, N.; Sattler, G.; Martin, P.; Cisneros, A.; Mann, J.; Thorgeirsson, S.; Jordan, V. C.; Pitot, H. C. Induction of hepatic aneuploidy in vivo by tamoxifen, toremifene and idoxifene in female Sprague-Dawley rats [published erratum appears in Carcinogenesis 1996, 17 (6), 1393]. Carcinogenesis 1996, 17, 1051-1056.
162. Tomas, E.; Kauppila, A.; Blanco, G.; Apaja-Sarkkinen, M.; Laatikainen, T. Comparison between the effects of tamoxifen and toremifene on the uterus in postmenopausal breast cancer patients. Gynecol. Oncol. 1995, 59, 261-266.
163. McCague, R.; Leclercq, G.; Legros, N.; Goodman, J.; Blackburn, G. M.; Jarman, M.; Foster, A. B. Derivatives of tamoxifen. Dependence of antiestrogenicity on the 4-substituent. J. Med. Chem. 1989, 32, 2527-2533.
164. McCague, R.; Parr, I. B.; Leclercq, G.; Leung, O. T.; Jarman, M. Metabolism of tamoxifen by isolated rat hepatocytes. Identification of the glucuronide of 4-hydroxytamoxifen. Biochem. Pharmacol. 1990, 39, 1459-1465.
165. McCague, R.; Parr, I. B.; Haynes, B. P. Metabolism of the 4-iodo derivative of tamoxifen by isolated rat hepatocytes. Demonstration that the iodine atom reduces metabolic conversion and identification of four metabolites. Biochem. Pharmacol. 1990, 40, 2277-2283.
166. Allen, K. E.; Clark, E. R.; Jordan, V. C. Evidence for the metabolic activation of non-steroidal antioestrogens: a study of structure - activity relationships. Br. J. Pharmacol. 1980, 71, 83-91.
167. Chander, S. K.; McCague, R.; Luqmani, Y.; Newton, C.; Dowsett, M.; Jarman, M.; Coombes, R. C. Pyrrolidino-4-iodotamoxifen and 4-iodotamoxifen, new analogues of the antiestrogen tamoxifen for the treatment of breast cancer. Cancer Res. 1991, 51, 5851- 5858.
168. Johnston, S. R.; Riddler, S.; Haynes, B. P.; A'Hern, R.; Smith, I. E.; Jarman, M.; Dowsett, M. The novel anti-oestrogen idoxifene inhibits the growth of human MCF-7 breast cancer xenografts and reduces the frequency of acquired anti-oestrogen resistance. Br. J. Cancer 1997, 75, 804-809.
169. Johnston, S. R.; Boeddinghaus, I. M.; Riddler, S.; Haynes, B. P.; Hardcastle, I. R.; Rowlands, M.; Grimshaw, R.; Jarman, M.; Dowsett, M. Idoxifene antagonizes estradiol-dependent MCF-7 breast cancer xenograft growth through sustained induction of apoptosis. Cancer Res. 1999, 59, 3646-3651.
170. Coombes, R. C.; Haynes, B. P.; Dowsett, M.; Quigley, M.; English, J.; Judson, I. R.; Griggs, L. J.; Potter, G. A.; McCague, R.; Jarman, M. Idoxifene: report of a phase I study in patients with metastatic breast cancer. Cancer Res. 1995, 55, 1070-1074.
171. Dowsett, M.; Dixon, J. M.; Horgan, K.; Salter, J.; Hills, M.; Harvey, E. Antiproliferative effects of idoxifene in a placebo-controlled trial in primary human breast cancer. Clin. Cancer Res. 2000, 6, 2260-2267.
172. Jordan, V. C.; Dix, C. J.; Naylor, K. E.; Prestwich, G.; Rowsby, L. Nonsteroidal antiestrogens: their biological effects and potential mechanisms of action. J. Toxicol. Environ. Health 1978, 4, 363-390.
173. Jordan, V. C.; Collins, M. M.; Rowsby, L.; Prestwich, G. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J. Endocrinol. 1977, 75, 305-316.
174. Hasmann, M.; Rattel, B.; Loser, R. Preclinical data for Droloxifene. Cancer Lett. 1994, 84, 101-116.
175. White, I. N.; de Matteis, F.; Davies, A.; Smith, L. L.; Crofton-Sleigh, C.; Venitt, S.; Hewer, A.; Phillips, D. H. Genotoxic potential of tamoxifen and analogues in female Fischer F344/n rats, DBA/2 and C57BL/6 mice and in human MCL-5 cells. Carcinogenesis 1992, 13, 2197-2203.
176. Rauschning, W.; Pritchard, K. I. Droloxifene, a new antiestrogen: its role in metastatic breast cancer. Breast Cancer Res. Treat. 1994, 31, 83-94.
177. Grill, H. J.; Pollow, K. Pharmacokinetics of droloxifene and its metabolites in breast cancer patients. Am. J. Clin. Oncol. 1991, 14, S21-S29.
178. Lien, E. A.; Anker, G.; Lonning, P. E.; Ueland, P. M. Determination of droloxifene and two metabolites in serum by high-pressure liquid chromatography. Ther. Drug Monit. 1995, 17, 259-265.
179. Chen, H. K.; Ke, H. Z.; Lin, C. H.; Ma, Y. F.; Qi, H.; Crawford, D. T.; Pirie, C. M.; Simmons, H. A.; Jee, W. S.; Thompson, D. D. Droloxifene inhibits cortical bone turnover associated with estrogen deficiency in rats. Bone 1995, 17, 175S-179S.
180. Ke, H. Z.; Chen, H. K.; Qi, H.; Pirie, C. M.; Simmons, H. A.; Ma, Y. F.; Jee, W. S.; Thompson, D. D. Effects of droloxifene on prevention of cancellous bone loss and bone turnover in the axial skeleton of aged, ovariectomized rats. Bone 1995, 17, 491-496.
181. Ke, H. Z.; Simmons, H. A.; Pirie, C. M.; Crawford, D. T.; Thompson, D. D. Droloxifene, a new estrogen antagonist/agonist, prevents bone loss in ovariectomized rats. Endocrinology 1995, 136, 2435-2441.
182. Herrington, D. M.; Pusser, B. E.; Riley, W. A.; Thuren, T. Y.; Brosnihan, K. B.; Brinton, E. A.; MacLean, D. B. Cardiovascular effects of droloxifene, a new selective estrogen receptor modulator, in healthy postmenopausal women. Arterioscler, Thromb., Vasc. Biol. 2000, 20, 1606-1612.
183. Jones, C. D.; Suarez, T.; Massey, E. H.; Black, L. J.; Tinsley, F. C. Synthesis and antiestrogenic activity of [3,4-dihydro-2-(4- methoxyphenyl)-1-naphthalenyl][4-[2-(1-pyrrolidinyl)ethoxy]- phenyl]methanone, methanesulfonic acid salt. J. Med. Chem. 1979, 22, 962-966.
184. Jones, C. D.; Jevnikar, M. G.; Pike, A. J.; Peters, M. K.; Black, L. J.; Thompson, A. R.; Falcone, J. F.; Clemens, J. A. Antiestrogens. 2. Structure - activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4- hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]- phenyl]methanone hydrochloride (LY156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity. J. Med. Chem. 1984, 27, 1057-1066.
185. Jones, C. D.; Blaszczak, L. C.; Goettel, M. E.; Suarez, T.; Crowell, T. A.; Mabry, T. E.; Ruenitz, P. C.; Srivatsan, V. Antiestrogens. 3. Estrogen receptor affinities and antiproliferative effects in MCF-7 cells of phenolic analogues of trioxifene, [3,4-dihydro-2- (4-methoxyphenyl)-1-naphthalenyl][4-[2-(1-pyrrolidinyl)ethoxy]- phenyl]methanone. J. Med. Chem. 1992, 35, 931-938.
186. Grese, T. A.; Cho, S.; Finley, D. R.; Godfrey, A. G.; Jones, C. D.; Lugar, C. W., 3rd; Martin, M. J.; Matsumoto, K.; Pennington, L. D.; Winter, M. A.; Adrian, M. D.; Cole, H. W.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.; Short, L. L.; Glasebrook, A. L.; Bryant, H. U. Structure - activity relationships of selective estrogen receptor modulators: modifications to the 2-arylbenzothiophene core of raloxifene. J. Med. Chem. 1997, 40, 146-167.
187. Grese, T. A.; Pennington, L. D.; Sluka, J. P.; Adrian, M. D.; Cole, H. W.; Fuson, T. R.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.; Shetler, P. K.; Short, L. L.; Venugopalan, M.; Yang, N. N.; Sato, M.; Glasebrook, A. L.; Bryant, H. U. Synthesis and pharmacology of conformationally restricted raloxifene analogues: highly potent selective estrogen receptor modulators. J. Med. Chem. 1998, 41, 1272-1283.
188. Palkowitz, A. D.; Glasebrook, A. L.; Thrasher, K. J.; Hauser, K. L.; Short, L. L.; Phillips, D. L.; Muehl, B. S.; Sato, M.; Shetler, P. K.; Cullinan, G. J.; Pell, T. R.; Bryant, H. U. Discovery and synthesis of [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]- 2-(4-hydroxyphenyl)]benzo[b]thiophene: a novel, highly potent, selective estrogen receptor modulator. J. Med. Chem. 1997, 40, 1407-1416.
189. Sato, M.; Turner, C. H.; Wang, T.; Adrian, M. D.; Rowley, E.; Bryant, H. U. LY353381.HCl: a novel raloxifene analog with improved SERM potency and efficacy in vivo. J. Pharmacol. Exp. Ther. 1998, 287, 1-7.
190. Munster, P. N.; Buzdar, A.; Dhingra, K.; Enas, N.; Ni, L.; Major, M.; Melemed, A.; Seidman, A.; Booser, D.; Theriault, R.; Norton, L.; Hudis, C. Phase I study of a third-generation selective estrogen receptor modulator, LY353381.HCL, in metastatic breast cancer. J. Clin. Oncol. 2001, 19, 2002-2009.
191. Dardes, R. C.; Bentrem, D.; O'Regan, R. M.; Schafer, J. M.; Jordan, V. C. Effects of the New Selective Estrogen Receptor Modulator LY353381.HCl (Arzoxifene) on Human Endometrial Cancer Growth in Athymic Mice. Clin. Cancer Res. 2001, 7, 4149-4155.
192. MacGregor, S.; Lee, E.-S.; Dardes, R. C.; Bentrem, D. J.; O'Regan, R. M.; de los Reyes, A.; Jordan, V. C. Analysis of cross-resistance of the selective estrogen receptor modulators arzoxifene (LY353381) and LY117018 in tamoxifen-stimulated breast cancer xenografts. Clin. Cancer Res. 2001, 7, 2505-2512.
193. Suh, N.; Glasebrook, A. L.; Palkowitz, A. D.; Bryant, H. U.; Burris, L. L.; Starling, J. J.; Pearce, H. L.; Williams, C.; Peer, C.; Wang, Y.; Sporn, M. B. Arzoxifene, a new selective estrogen receptor modulator for chemoprevention of experimental breast cancer. Cancer Res. 2001, 61, 8412-8415.
194. Gauthier, S.; Caron, B.; Cloutier, J.; Dory, Y. L.; Favre, A.; Larouche, D.; Mailhot, J.; Ouellet, C.; Schwerdtfeger, A.; Leblanc, G.; Martel, C.; Simard, J.; Merand, Y.; Belanger, A.; Labrie, C.; Labrie, F. (S)-(+)-4-[7-(2,2-Dimethyl-1-oxopropoxy)-4-methyl- 2-[4-[2-(1-piperidinyl)-ethoxy]phenyl]-2H-1-benzopyran-3-yl]- phenyl 2,2-dimethylpropanoate (EM-800): a highly potent, specific, and orally active nonsteroidal antiestrogen. J. Med. Chem. 1997, 40, 2117-2122.
195. Sharma, A. P.; Saeed, A.; Durani, S.; Kapil, R. S. Structure-activity relationship of antiestrogens. Effect of the side chain and its position on the activity of 2,3-diaryl-2H-1-benzopyrans. J. Med. Chem. 1990, 33, 3216-3222.
196. Luo, S.; Labrie, C.; Belanger, A.; Candas, B.; Labrie, F. Prevention of development of dimethylbenz[]anthracene (DMBA)-induced mammary tumors in the rat by the new nonsteroidal antiestrogen EM-800 (SCH57050). Breast Cancer Res. Treat. 1998, 49, 1-11.
197. Luo, S.; Stojanovic, M.; Labrie, C.; Labrie, F. Inhibitory effect of the novel anti-estrogen EM-800 and medroxyprogesterone acetate on estrone-stimulated growth of dimethylbenz[a]anthracene-induced mammary carcinoma in rats. Int. J. Cancer 1997, 73, 580-586.
198. Luo, S.; Sourla, A.; Labrie, C.; Gauthier, S.; Merand, Y.; Belanger, A.; Labrie, F. Effect of twenty-four-week treatment with the antiestrogen EM-800 on estrogen-sensitive parameters in intact and ovariectomized mice. Endocrinology 1998, 139, 2645-2656.
199. Martel, C.; Labrie, C.; Belanger, A.; Gauthier, S.; Merand, Y.; Li, X.; Provencher, L.; Candas, B.; Labrie, F. Comparison of the effects of the new orally active antiestrogen EM-800 with ICI 182 780 and toremifene on estrogen-sensitive parameters in the ovariectomized mouse. Endocrinology 1998, 139, 2486-2492.
200. Sourla, A.; Luo, S.; Labrie, C.; Belanger, A.; Labrie, F. Morphological changes induced by 6-month treatment of intact and ovariectomized mice with tamoxifen and the pure antiestrogen EM-800. Endocrinology 1997, 138, 5605-5617.
201. Simard, J.; Labrie, C.; Belanger, A.; Gauthier, S.; Singh, S. M.; Merand, Y.; Labrie, F. Characterization of the effects of the novel non-steroidal antiestrogen EM-800 on basal and estrogen- induced proliferation of T-47D, ZR-75-1 and MCF-7 human breast cancer cells in vitro. Int. J. Cancer 1997, 73, 104-112.
202. Simard, J.; Sanchez, R.; Poirier, D.; Gauthier, S.; Singh, S. M.; Merand, Y.; Belanger, A.; Labrie, C.; Labrie, F. Blockade of the stimulatory effect of estrogens, OH-tamoxifen, OH-toremifene, droloxifene, and raloxifene on alkaline phosphatase activity by the antiestrogen EM-800 in human endometrial adenocarcinoma Ishikawa cells. Cancer Res. 1997, 57, 3494-3497.
203. Couillard, S.; Gutman, M.; Labrie, C.; Belanger, A.; Candas, B.; Labrie, F. Comparison of the effects of the antiestrogens EM-800 and tamoxifen on the growth of human breast ZR-75-1 cancer xenografts in nude mice. Cancer Res. 1998, 58, 60-64.
204. Gallagher, A.; Chambers, T. J.; Tobias, J. H. The estrogen antagonist ICI 182,780 reduces cancellous bone volume in female rats. Endocrinology 1993, 133, 2787-2791.
205. Luo, S.; Labrie, C.; Belanger, A.; Labrie, F. Effect of dehydroepiandrosterone on bone mass, serum lipids, and dimethylbenz-[a]anthracene-induced mammary carcinoma in the rat. Endocrinology 1997, 138, 3387-3394.
206. Tremblay, A.; Tremblay, G. B.; Labrie, C.; Labrie, F.; Giguere, V. EM-800, a novel antiestrogen, acts as a pure antagonist of the transcriptional functions of estrogen receptors alpha and beta. Endocrinology 1998, 139, 111-118.
207. Labrie, F.; Labrie, C.; Belanger, A.; Simard, J.; Gauthier, S.; Luu-The, V.; Merand, Y.; Giguere, V.; Candas, B.; Luo, S.; Martel, C.; Singh, S. M.; Fournier, M.; Coquet, A.; Richard, V.; Charbonneau, R.; Charpenet, G.; Tremblay, A.; Tremblay, G.; Cusan, L.; Veilleux, R. EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium. J. Steroid Biochem. Mol. Biol. 1999, 69, 51-84.
208. Bowler, J.; Lilley, T. J.; Pittam, J. D.; Wakeling, A. E. Novel steroidal pure antiestrogens. Steroids 1989, 54, 71-99.
209. MacGregor Schafer, J. I.; Liu, H.; Tonetti, D. A.; Jordan, V. C. The interaction of raloxifene and the active metabolite of the antiestrogen EM-800 (SC 5705) with the human estrogen receptor. Cancer Res. 1999, 59, 4308-4313.
210. Martel, C.; Picard, S.; Richard, V.; Belanger, A.; Labrie, C.; Labrie, F. Prevention of bone loss by EM-800 and raloxifene in the ovariectomized rat. J. Steroid Biochem. Mol. Biol. 2000, 74, 45-56.
211. von Angerer, E.; Strohmeier, J. 2-Phenylindoles. Effect of N-benzylation on estrogen receptor affinity, estrogenic properties, and mammary tumor inhibiting activity. J. Med. Chem. 1987, 30, 131-136.
212. Schneider, M. R.; von Angerer, E.; Hohn, W.; Sinowatz, F. Antitumor activity of antiestrogenic phenylindoles on experimental prostate tumors. Eur. J. Cancer Clin. Oncol. 1987, 23, 1005-1015.
213. Stein, R. C.; Dowsett, M.; Cunningham, D. C.; Davenport, J.; Ford, H. T.; Gazet, J. C.; von Angerer, E.; Coombes, R. C. Phase I/II study of the anti-oestrogen zindoxifene (D16726) in the treatment of advanced breast cancer. A Cancer Research Campaign Phase I/II Clinical Trials Committee study. Br. J. Cancer 1990, 61, 451-453.
214. Robinson, S. P.; Koch, R.; Jordan, V. C. In vitro estrogenic actions in rat and human cells of hydroxylated derivatives of D16726 (zindoxifene), an agent with known antimammary cancer activity in vivo. Cancer Res. 1988, 48, 784-787.
215. von Angerer, E.; Knebel, N.; Kager, M.; Ganss, B. 1-(Aminoalkyl)-2-phenylindoles as novel pure estrogen antagonists. J. Med. Chem. 1990, 33, 2635-2640.
216. Nishino, Y.; Schneider, M. R.; Michna, H.; von Angerer, E. Pharmacological characterization of a novel oestrogen antagonist, ZK 119010, in rats and mice. J. Endocrinol. 1991, 130, 409-414.
217. Miller, C. P.; Collini, M. D.; Tran, B. D.; Harris, H. A.; Kharode, Y. P.; Marzolf, J. T.; Moran, R. A.; Henderson, R. A.; Bender, R. H.; Unwalla, R. J.; Greenberger, L. M.; Yardley, J. P.; Abou-Gharbia, M. A.; Lyttle, C. R.; Komm, B. S. Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens. J. Med. Chem. 2001, 44, 1654-1657.
218. Greenberger, L. M.; Annable, T.; Collins, K. I.; Komm, B. S.; Lyttle, C. R.; Miller, C. P.; Satyaswaroop, P. G.; Zhang, Y.; Frost, P. A new antiestrogen, 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2- piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride (ERA- 923), inhibits the growth of tamoxifen-sensitive and -resistant tumors and is devoid of uterotropic effects in mice and rats. Clin. Cancer Res. 2001, 7, 3166-3177.
219. Rosati, R. L.; Da Silva Jardine, P.; Cameron, K. O.; Thompson, D. D.; Ke, H. Z.; Toler, S. M.; Brown, T. A.; Pan, L. C.; Ebbinghaus, C. F.; Reinhold, A. R.; Elliott, N. C.; Newhouse, B. N.; Tjoa, C. M.; Sweetnam, P. M.; Cole, M. J.; Arriola, M. W.; Gauthier, J. W.; Crawford, D. T.; Nickerson, D. F.; Pirie, C. M.; Qi, H.; Simmons, H. A.; Tkalcevic, G. T. Discovery and preclinical pharmacology of a novel, potent, nonsteroidal estrogen receptor agonist/antagonist, CP-336156, a diaryltetrahydronaphthalene. J. Med. Chem. 1998, 41, 2928-2931.
220. Ke, H. Z.; Paralkar, V. M.; Grasser, W. A.; Crawford, D. T.; Qi, H.; Simmons, H. A.; Pirie, C. M.; Chidsey-Frink, K. L.; Owen, T. A.; Smock, S. L.; Chen, H. K.; Jee, W. S.; Cameron, K. O.; Rosati, R. L.; Brown, T. A.; Dasilva-Jardine, P.; Thompson, D. D. Effects of CP-336,156, a new, nonsteroidal estrogen agonist/antagonist, on bone, serum cholesterol, uterus and body composition in rat models. Endocrinology 1998, 139, 2068-2076.
221. Ke, H. Z.; Qi, H.; Crawford, D. T.; Chidsey-Frink, K. L.; Simmons, H. A.; Thompson, D. D. Lasofoxifene (CP-336,156), a selective estrogen receptor modulator, prevents bone loss induced by aging and orchidectomy in the adult rat. Endocrinology 2000, 141, 1338-1344.
222. Cohen, L. A.; Pittman, B.; Wang, C. X.; Aliaga, C.; Yu, L.; Moyer, J. D. LAS, a novel selective estrogen receptor modulator with chemopreventive and therapeutic activity in the N-nitroso-N-methylurea-induced rat mammary tumor model. Cancer Res. 2001, 61, 8683-8688.
223. Willson, T. M.; Henke, B. R.; Momtahen, T. M.; Charifson, P. S.; Batchelor, K. W.; Lubahn, D. B.; Moore, L. B.; Oliver, B. B.; Sauls, H. R.; Triantafillou, J. A.; et al. 3-[4-(1,2-Diphenylbut-1-enyl)phenyl] acrylic acid: a non-steroidal estrogen with functional selectivity for bone over uterus in rats. J. Med. Chem. 1994, 37, 1550-1552.
224. Willson, T. M.; Norris, J. D.; Wagner, B. L.; Asplin, I.; Baer, P.; Brown, H. R.; Jones, S. A.; Henke, B.; Sauls, H.; Wolfe, S.; Morris, D. C.; McDonnell, D. P. Dissection of the molecular mechanism of action of GW5638, a novel estrogen receptor ligand, provides insights into the role of estrogen receptor in bone. Endocrinology 1997, 138, 3901-3911.
225. Wijayaratne, A. L.; Nagel, S. C.; Paige, L. A.; Christensen, D. J.; Norris, J. D.; Fowlkes, D. M.; McDonnell, D. P. Comparative analyses of mechanistic differences among antiestrogens. Endocrinology 1999, 140, 5828-5840.
226. Bentrem, D.; Dardes, R.; Liu, H.; MacGregor-Schafer, J.; Zapf, J.; Jordan, V. Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen. Endocrinology 2001, 142, 838-846.
227. Connor, C. E.; Norris, J. D.; Broadwater, G.; Willson, T. M.; Gottardis, M. M.; Dewhirst, M. W.; McDonnell, D. P. Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor. Cancer Res. 2001, 61, 2917-2922.
228. Dardes, R.; O'Regan, R.; Gajdos, C.; Robinson, S. P.; Bentrem, D.; de los Reyes, A.; Jordan, V. C. Effects of a new clinically relevant antiestrogen (GW5638) related to tamoixfen on breast and endometrial cancer growth in vivo. Clin. Cancer Res., in press.
229. Wijayaratne, A. L.; McDonnell, D. P. The human estrogen receptor-alpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators. J. Biol. Chem. 2001, 276, 35684- 35692.
230. Jordan, V. C.; Bain, R. R.; Brown, R. R.; Gosden, B.; Santos, M. A. Determination and pharmacology of a new hydroxylated metabolite of tamoxifen observed in patient sera during therapy for advanced breast cancer. Cancer Res. 1983, 43, 1446-1450.
231. Robertson, D. W.; Katzenellenbogen, J. A.; Hayes, J. R.; Katzenellenbogen, B. S. Antiestrogen basicity - activity relationships: a comparison of the estrogen receptor binding and antiuterotrophic potencies of several analogues of (Z)-1,2-diphenyl-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-butene (tamoxifen, Nolvadex) having altered basicity. J. Med. Chem. 1982, 25, 167-171.
232. Qu, Q.; Zheng, H.; Dahllund, J.; Laine, A.; Cockcroft, N.; Peng, Z.; Koskinen, M.; Hemminki, K.; Kangas, L.; Vaananen, K.; Harkonen, P. Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats. Endocrinology 2000, 141, 809-820.
233. DeGregorio, M. W.; Wurz, G. T.; Taras, T. L.; Erkkola, R. U.; Halonen, K. H.; Huupponen, R. K. Pharmacokinetics of (deaminohydroxy)toremifene in humans: a new, selective estrogen-receptor modulator. Eur. J. Clin. Pharmacol. 2000, 56, 469-475.
234. Grese, T. A.; Adrian, M. D.; Phillips, D. L.; Shetler, P. K.; Short, L. L.; Glasebrook, A. L.; Bryant, H. U. Photochemical synthesis of N-arylbenzophenanthridine selective estrogen receptor modulators (serms). J. Med. Chem. 2001, 44, 2857-2860.
235. Wakeling, A. E.; Bowler, J. Steroidal pure antioestrogens. J. Endocrinol. 1987, 112, R7-R10.
236. Howell, A.; Robertson, J. F. R.; Quaresma Albano, J.; Aschermannova, A.; Mauriac, L.; Kleeberg, U. R.; Vergot, I.; Erikstein, B.; Webster, A.; Morris, C. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J. Clin. Oncol. 2002, 20, 3396-3403.
237. Osborne, C. K.; Pippen, J.; Jones, S. E.; Parker, L. M.; Ellis, M.; Come, S.; Gertler, S. Z.; May, J. T.; Burton, G.; Dimery, I.; Webster, A.; Morris, C.; Elledge, R.; Buzdar, A. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J. Clin. Oncol. 2002, 20, 3386-3395.
238. Jordan, V. C.; Fritz, N. F.; Langan-Fahey, S.; Thompson, M.; Tormey, D. C. Alteration of endocrine parameters in premenopausal women with breast cancer during long-term adjuvant therapy with tamoxifen as the single agent. J. Natl. Cancer Inst. 1991, 83, 1488-1491.
239. Ravdin, P. M.; Fritz, N. F.; Tormey, D. C.; Jordan, V. C. Endocrine status of premenopausal node-positive breast cancer patients following adjuvant chemotherapy and long-term tamoxifen. Cancer Res. 1988, 48, 1026-1029.
240. Klijn, J. G.; Blamey, R. W.; Boccardo, F.; Tominaga, T.; Duchateau, L.; Sylvester, R. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J. Clin. Oncol. 2001, 19, 343353.
241. Boccardo, F.; Rubagotti, A.; Amoroso, D.; Mesiti, M.; Romeo, D.; Sismondi, P.; Giai, M.; Genta, F.; Pacini, P.; Distante, V.; Bolognesi, A.; Aldrighetti, D.; Farris, A. Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. boccardo@hp380.ist.unige.it. J. Clin. Oncol. 2000, 18, 2718-2727.
242. Lerner, L. J.; Holthaus, J. F.; Thompson, C. R. A non-steroidal estrogen antagonist 1-(p-2-diethylaminoethoxyphenyl)-1-phenyl-2-p-methoxyphenylethanol. Endocrinology 1958, 63, 295-318.
243. Gee, A. C.; Carlson, K. E.; Martini, P. G.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Coactivator peptides have a differential stabilizing effect on the binding of estrogens and antiestrogens with the estrogen receptor. Mol. Endocrinol. 1999, 13, 1912-1923.
244. Wakeling, A. E.; Bowler, J. Novel antioestrogens without partial agonist activity. J. Steroid Biochem. 1988, 31, 645-653.
245. Jordan, V. C.; Fenuik, L.; Allen, K. E.; Cotton, R. C.; Richardson, D.; Walpole, A. L.; Bowler, J. Structural derivatives of tamoxifen and oestradiol 3-methyl ether as potential alkylating antioestrogens. Eur. J. Cancer 1981, 17, 193-200.
246. Bucourt, R.; Vignau, M.; Torelli, V.; Richard-Roytt Geynet, C.; Secco-Millet, C.; Redcailh, G.; Baulieu, E. E New biospecific adsorbents for the purification of estradiol receptor. J. Biol. Chem. 1978, 253, 8221-8228.
247. Wakeling, A. E.; Dukes, M.; Bowler, J. A potent specific pure antiestrogen with clinical potential. Cancer Res. 1991, 51, 3867-3873.
248. Fawell, S. E.; White, R.; Hoare, S.; Sydenham, M.; Page, M.; Parker, M. G. Inhibition of estrogen receptor-DNA binding by the "pure" antiestrogen ICI 164,384 appears to be mediated by impaired receptor dimerization. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 6883-6887.
249. Sabbah, M.; Gouilleux, F.; Sola, B.; Redeuilh, G.; Baulieu, E. E. Structural differences between the hormone and antihormone estrogen receptor complexes bound to the hormone response element. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 390-394.
250. Pham, T. A.; Elliston, J. F.; Nawaz, Z.; McDonnell, D. P.; Tsai, M. J.; O'Malley, B. W. Antiestrogen can establish nonproductive receptor complexes and alter chromatin structure at target enhancers. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 3125-3129.
251. Dauvois, S.; Danielian, P. S.; White, R.; Parker, M. G. Antiestrogen ICI 164,384 reduces cellular estrogen receptor content by increasing its turnover. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 4037-4041.
252. Gibson, M. K.; Nemmers, L. A.; Beckman, W. C., Jr.; Davis, V. L.; Curtis, S. W.; Korach, K. S. The mechanism of ICI 164,384 antiestrogenicity involves rapid loss of estrogen receptor in uterine tissue. Endocrinology 1991, 129, 2000-2010.
253. DeFriend, D. J.; Howell, A.; Nicholson, R. I.; Anderson, E.; Dowsett, M.; Mansel, R. E.; Blamey, R. W.; Bundred, N. J.; Robertson, J. F.; Saunders, C.; et al. Investigation of a new pure antiestrogen (ICI 182780) in women with primary breast cancer. Cancer Res. 1994, 54, 408-414.
254. Dauvois, S.; White, R.; Parker, M. G. The antiestrogen ICI 182780 disrupts estrogen receptor nucleocytoplasmic shuttling. J. Cell Sci. 1993, 106, 1377-1388.
255. Alarid, E. T.; Bakopoulos, N.; Solodin, N. Proteasome-mediated proteolysis of estrogen receptor: a novel component in autologous down-regulation. Mol. Endocrinol. 1999, 13, 1522-1534.
256. Osborne, C. K.; Coronado-Heinsohn, E. B.; Hilsenbeck, S. G.; McCue, B. L.; Wakeling, A. E.; McClelland, R. A.; Manning, D. L.; Nicholson, R. I. Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J. Natl. Cancer Inst. 1995, 87, 746-750.
257. Gottardis, M. M.; Ricchio, M. E.; Satyaswaroop, P. G.; Jordan, V. C. Effect of steroidal and nonsteroidal antiestrogens on the growth of a tamoxifen-stimulated human endometrial carcinoma (EnCa101) in athymic mice. Cancer Res. 1990, 50, 3189-3192.
258. Lykkesfeldt, A. E.; Larsen, S. S.; Briand, P. Human breast cancer cell lines resistant to pure antiestrogens are sensitive to tamoxifen treatment. Int. J. Cancer 1995, 61, 529-534.
259. Howell, A.; DeFriend, D.; Robertson, J.; Blamey, R.; Walton, P. Response to a specific antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer [see comments]. Lancet 1995, 345, 29-30.
260. Howell, A.; DeFriend, D. J.; Robertson, J. F.; Blamey, R. W.; Anderson, L.; Anderson, E.; Sutcliffe, F. A.; Walton, P. Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer. Br. J. Cancer 1996, 74, 300-308.
261. Van de Velde, P.; Nique, F.; Bouchoux, F.; Bremaud, J.; Hameau, M. C.; Lucas, D.; Moratille, C.; Viet, S.; Philibert, D.; Teutsch, G. RU 58,668, a new pure antiestrogen inducing a regression of human mammary carcinoma implanted in nude mice. J. Steroid Biochem. Mol. Biol. 1994, 48, 187-196.
262. Van de Velde, P.; Nique, F.; Planchon, P.; Prevost, G.; Bremaud, J.; Hameau, M. C.; Magnien, V.; Philibert, D.; Teutsch, G. RU 58668: further in vitro and in vivo pharmacological data related to its antitumoral activity. Mol. Biol. 1996, 59, 449-457.
263. Devin-Leclerc, J.; Meng, X.; Delahaye, F.; Leclerc, P.; Baulieu, E.; Catelli, M. Interaction and dissociation by ligands of estrogen receptor and hsp90: the antiestrogen RU 58668 induces a protein synthesis-dependent clustering of the receptor in the cytoplasm. Mol. Endocrinol. 1998, 12, 842-854.
264. Li, S.; Levesque, C.; Geng, C. S.; Yan, X.; Labrie, F. Inhibitory effects of medroxyprogesterone acetate (MPA) and the pure antiestrogen EM-219 on estrone (E1)-stimulated growth of dimethylbenz[a]anthracene (DMBA)-induced mammary carcinoma in the rat. Breast Cancer Res. Treat. 1995, 34, 147-159.
265. Levesque, C.; Merand, Y.; Dufour, J. M.; Labrie, C.; Labrie, F. Synthesis and biological activity of new halo-steroidal antiestrogens. J. Med. Chem. 1991, 34, 1624-1630.
266. de Launoit, Y.; Dauvois, S.; Dufour, M.; Simard, J.; Labrie, F. Inhibition of cell cycle kinetics and proliferation by androgen 5 alpha-dihydrotestosterone and antiestrogen N,N-butyl-N-methyl-11-[16′ alpha-chloro-3′,17 beta-dihydroxy-estra-1′,3′,5′-(10)-triene-7′ alpha-y1]undecanamide in human breast cancer ZR75-1 cells. Cancer Res. 1991, 51, 2797-2802.
267. Labrie, C.; Martel, C.; Dufour, J. M.; Levesque, C.; Merand, Y.; Labrie, F. Novel compounds inhibit estrogen formation and action. Cancer Res. 1992, 52, 610-615.
268. Pike, A. C.; Brzozowski, A. M.; Walton, J.; Hubbard, R. E.; Thorsell, A.; Li, Y.; Gustafsson, J.; Carlquist, M. Structural insights into the mode of action of a pure antiestrogen. Structure 2001, 9 (February), 145-153.
269. Brzozowski, A. M.; Pike, A. C.; Dauter, Z.; Hubbard, R. E.; Bonn, T.; Engstrom, O.; Ohman, L.; Greene, G. L.; Gustafsson, J. A.; Carlquist, M. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997, 389, 753-758.
270. Pike, A. C.; Brzozowski, A. M.; Hubbard, R. E.; Bonn, T.; Thorsell, A. G.; Engstrom, O.; Ljunggren, J.; Gustafsson, J. A.; Carlquist, M. Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J. 1999, 18, 4608-4618.
271. Jordan, V. C.; Koch, R. Regulation of prolactin synthesis in vitro by estrogenic and antiestrogenic derivatives of estradiol and estrone. Endocrinology 1989, 124, 1717-1726.
272. Lubahn, D. B.; Moyer, J. S.; Golding, T. S.; Couse, J. F.; Korach, K. S.; Smithies, O. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 11162-11166.
273. Couse, J. F.; Lindzey, J.; Grandien, K.; Gustafsson, J. A.; Korach, K. S. Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse. Endocrinology 1997, 138, 4613-4621.
274. Rosenfeld, C. S.; Ganjam, V. K.; Taylor, J. A.; Yuan, X.; Stiehr, J. R.; Hardy, M. P.; Lubahn, D. B. Transcription and translation of estrogen receptor-beta in the male reproductive tract of estrogen receptor-alpha knock-out and wild-type mice. Endocrinology 1998, 139, 2982-2987.
275. Shughrue, P.; Scrimo, P.; Lane, M.; Askew, R.; Merchenthaler, I. The distribution of estrogen receptor-beta mRNA in forebrain regions of the estrogen receptor-alpha knockout mouse. Endocrinology 1997, 138, 5649-5652.
276. Krege, J. H.; Hodgin, J. B.; Couse, J. F.; Enmark, E.; Warner, M.; Mahler, J. F.; Sar, M.; Korach, K. S.; Gustafsson, J. A.; Smithies, O. Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 15677-15682.
277. McInerney, E. M.; Weis, K. E.; Sun, J.; Mosselman, S.; Katzenellenbogen, B. S. Transcription activation by the human estrogen receptor subtype beta (ER beta) studied with ER beta and ER alpha receptor chimeras. Endocrinology 1998, 139, 4513-4522.
278. McCague, R.; Kuroda, R.; Leclercq, G.; Stoessel, S. Synthesis and estrogen receptor binding of 6,7-dihydro-8-phenyl-9-[4-[2(dimethylamino)ethoxy]phenyl]-5H- benzocycloheptene, a nonisomerizable analogue of tamoxifen. X-ray crystallographic studies. J. Med. Chem. 1986, 29, 2053-2059.
279. Jordan, V. C.; MacGregor Schafer, J. I.; Levenson, A. S.; Liu, H.; Pease, K. M.; Simons, L. A.; Zapf, J. W. Molecular classification of estrogens. Cancer Res. 2001, 61, 6619-6623.
280. Gust, R.; Keilitz, R.; Schmidt, K. Investigations of new lead structures for the design of selective estrogen receptor modulators. J. Med. Chem. 2001, 44, 1963-1970.
281. Liu, H.; Lee, E. S.; De Los Reyes, A.; Zapf, J. W.; Jordan, V. C. Silencing and reactivation of the selective estrogen receptor modulator-estrogen receptor alpha complex. Cancer Res. 2001, 61, 3632-3639.
282. Gaido, K. W.; Leonard, L. S.; Maness, S. C.; Hall, J. M.; McDonnell, D. P.; Saville, B.; Safe, S. Differential interaction of the methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane with estrogen receptors alpha and beta [in process citation]. Endocrinology 1999, 140, 5746-5753.
283. Webb, P.; Nguyen, P.; Valentine, C.; Weatherman, R. V.; Scanlan, T. S.; Kushner, P. J. An antiestrogen-responsive estrogen receptor-alpha mutant (D351Y) shows weak AF-2 activity in the presence of tamoxifen. J. Biol. Chem. 2000, 275, 37552-37558.
284. Pento, J. T.; Magarian, R. A.; King, M. M. A comparison of the efficacy for antitumor activity of the non-steroidal antiestrogens analog II and tamoxifen in 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors. Cancer Lett. 1982, 15, 261-269.
285. Pento, J. T.; Magarian, R. A.; Wright, R. J.; King, M. M.; Benjamin, E. J. Nonsteroidal estrogens and antiestrogens: biological activity of cyclopropyl analogs of stilbene and stilbenediol. J. Pharm. Sci. 1981, 70, 399-403.
286. Day, B. W.; Magarian, R. A.; Jain, P. T.; Pento, J. T.; Mousissian, G. K.; Meyer, K. L. Synthesis and biological evaluation of a series of 1,1-dichloro-2,2,3-triarylcyclopropanes as pure antiestrogens. J. Med. Chem. 1991, 34, 842-851.
287. Sun, J.; Meyers, M. J.; Fink, B. E.; Rajendran, R.; Katzenellenbogen, J. A.; Katzenellenbogen, B. S. Novel ligands that function as selective estrogens or antiestrogens for estrogen receptor-alpha or estrogen receptor-beta. Endocrinology 1999, 140, 800-804.
288. Shiau, A. K.; Barstad, D.; Radek, J. T.; Meyers, M. J.; Nettles, K. W.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A.; Agard, D. A.; Greene, G. L. Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism. Nat. Struct. Biol. 2002, 9, 359-364.
289. Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Synthesis and biological evaluation of a novel series of furans: ligands selective for estrogen receptor α. J. Med. Chem. 2001, 44, 3838-3848.
290. Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Pyrazole ligands: structure - affinity/activity relationships and estrogen receptor-α-selective agonists. J. Med. Chem. 2000, 43, 4934-4947.
291. Fink, B. E.; Mortensen, D. S.; Stauffer, S. R.; Aron, Z. D.; Kastzenellbogen, J. A. Novel structural templates for estrogen - receptor ligands and prespects for combinatorial synthesis of estrogens. Chem. Biol. 1999, 6, 205-219.
292. Meyers, M. J.; Sun, J.; Carlson, K. E.; Marriner, G. A.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Estrogen receptor-β potency-selective ligands: structure - activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J. Med. Chem. 2001, 44, 4230-4251.
293. Speirs, V.; Parkes, A. T.; Kerin, M. J.; Walton, D. S.; Carleton, P. J.; Fox, J. N.; Atkin, S. L. Coexpression of estrogen receptor alpha and beta: poor prognostic factors in human breast cancer? Cancer Res. 1999, 59, 525-528.
294. Dotzlaw, H.; Leygue, E.; Watson, P. H.; Murphy, L. C. Estrogen receptor-beta messenger RNA expression in human breast tumor biopsies: relationship to steroid receptor status and regulation by progestins. Cancer Res. 1999, 59, 529-532.
295. Speirs, V.; Malone, C.; Walton, D. S.; Kerin, M. J.; Atkin, S. L. Increased expression of estrogen receptor beta mRNA in tamoxifen-resistant breast cancer patients. Cancer Res. 1999, 59, 5421-5424.
296. Arteaga, C. L. The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J. Clin. Oncol. 2001, 19, 32S-40S.
297. Houston, S. J.; Plunkett, T. A.; Barnes, D. M.; Smith, P.; Rubens, R. D.; Miles, D. W. Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer. Br. J. Cancer 1999, 79, 1220-1226.
298. Sjogren, S.; Inganas, M.; Lindgren, A.; Holmberg, L.; Bergh, J. Prognostic and predictive value of c-erbB-2 overexpression in primary breast cancer, alone and in combination with other prognostic markers. J. Clin. Oncol. 1998, 16, 462-469.
299. Berns, E. M.; Foekens, J. A.; van Staveren, I. L.; van Putten, W. L.; de Koning, H. Y.; Portengen, H.; Klijn, J. G. Oncogene amplification and prognosis in breast cancer: relationship with systemic treatment. Gene 1995, 159, 11-18.
300. Leitzel, K.; Teramoto, Y.; Konrad, K.; Chinchilli, V. M.; Volas, G.; Grossberg, H.; Harvey, H.; Demers, L.; Lipton, A. Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of breast cancer. J. Clin. Oncol. 1995, 13, 1129-1135.
301. Borg, A.; Baldetorp, B.; Ferno, M.; Killander, D.; Olsson, H.; Ryden, S.; Sigurdsson, H. ERBB2 amplification is associated with tamoxifen resistance in steroid-receptor positive breast cancer. Cancer Lett. 1994, 81, 137-144.
302. Archer, S. G.; Eliopoulos, A.; Spandidos, D.; Barnes, D.; Ellis, I. O., Blamey, R. W.; Nicholson, R. I.; Robertson, J. F. Expression of ras p21, p53 and c-erbB-2 in advanced breast cancer and response to first line hormonal therapy. Br. J. Cancer 1995, 72, 1259-1266.
303. Wright, C.; Nicholson, S.; Angus, B.; Sainsbury, J. R.; Farndon, J.; Cairns, J.; Harris, A. L.; Horne, C. H. Relationship between c-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer. Br. J. Cancer 1992, 65, 118-121.
304. Stal, O.; Borg, A.; Ferno, M.; Kallstrom, A. C.; Malmstrom, P.; Nordenskjold, B. ErbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer. Ann. Oncol. 2000, 11, 1545-1550.
305. Berry, D.; Muss, H. B.; Thor, A. D.; Dressler, L.; Liu, E. T.; Broadwater, G.; Budman, D. R.; Henderson, I. C.; Barcos, M.; Hayes, D.; Norton, L. HER-2/neu and p53 expression versus tamoxifen resistance in estrogen receptor-positive, node-positive breast cacner. J. Clin. Oncol. 2000, 18, 3471-3479.
306. Elledge, R. M.; Green, S.; Ciocca, D.; Pugh, R.; Allred, D. C.; Clark, G. M.; Hill, J.; Ravdin, P.; O'Sullivan, J.; Martino, S.; Osborne, C. K. HER-2 expression and response to tamoxifen in estrogen receptor-positive breast cancer: a Southwest Oncology Group Study. Clin. Cancer Res. 1998, 4, 7-12.
307. Nicholson, R. I.; McClelland, R. A.; Gee, J. M.; Manning, D. L.; Cannon, P.; Robertson, J. F.; Ellis, I. O.; Blamey R. W. Epidermal growth factor recptor expression in breast cancer: association with response to endocrine therapy. Breast Cancer Res. Treat. 1994, 29, 117-125.
308. Knoop, A. S.; Bentzen, S. M.; Nielsen, M. M.; Rasmussen, B. B.; Rose, C. Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients. J. Clin. Oncol. 2001, 19, 3376-3384.
309. Hu, J. C.; Mokbel, K. Does c-erbB2/HER2 overexpression predict adjuvant tamoxifen failure in patients with early breast cancer? Eur. J. Surg. Oncol. 2001, 27, 335-337.
310. Benz, C. C.; Scott, G. K.; Sarup, J. C.; Johnson, R. M.; Tripathy, D.; Coronado, E.; Shepard, H. M.; Osborne, C. K. Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res. Treat. 1993, 24, 85-95.
311. Kurokawa, H.; Lenferink, A. E.; Simpson, J. F.; Pisacane, P. I.; Sliwkowski, M. X.; Forbes, J. T.; Arteaga, C. L. Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res. 2000, 60, 5887-5894.
312. Robertson, J. F. Oestrogen receptor: a stable phenotype in breast cancer. Br. J. Cancer 1996, 73, 5-12.
313. Goss, P.; Strasser, K. Aromatase inhibitors in the treatment and prevention of breast cancer. J. Clin. Oncol. 2001, 19, 881-894.
314. Nawata, H.; Bronzert, D.; Lippman, M. E. Isolation and characterization of a tamoxifen-resistant cell line derived from MCF-7 human breast cancer cells. J. Biol. Chem. 1981, 256, 5016-5021.
315. Miller, M. A.; Lippman, M. E.; Katzenellenbogen, B. S. Antiestrogen binding in antiestrogen growth-resistant estrogen-responsive clonal variants of MCF-7 human breast cancer cells. Cancer Res. 1984, 44, 5038-5045.
316. Bronzert, D. A.; Greene, G. L.; Lippman, M. E. Selection and characterization of a breast cancer cell line resistant to the antiestrogen LY 117018. Endocrinology 1985, 117, 1409-1417.
317. van den Berg, H. W.; Lynch, M.; Martin, J.; Nelson, J.; Dickson, G. R.; Crockard, A. D. Characterisation of a tamoxifen-resistant variant of the ZR-75-1 human breast cancer cell line (ZR-75-9a1) and ability of the resistant phenotype. Br. J. Cancer 1989, 59, 522-526.
318. Lykkesfeldt, A. E.; Sorensen, E. K. Effect of estrogen and antiestrogens on cell proliferation and synthesis of secreted proteins in the human breast cancer cell line MCF-7 and a tamoxifen resistant variant subline, AL-1. Acta Oncol. 1992, 31, 131-138,
319. Wiseman, L. R.; Johnson, M. D.; Wakeling, A. E.; Lykkesfeldt, A. E.; May, F. E.; Westley, B. R. Type I IGF receptor and acquired tamoxifen resistance in oestrogen-responsive human breast cancer cells. Eur. J. Cancer 1993, 16, 2256-2264.
320. Brunner, N.; Frandsen, T. L.; Holst-Hansen, C.; Bei, M.; Thompson, E. W.; Wakeling, A. E.; Lippman, M. E.; Clarke, R. MCF7/LCC2: a 4-hydroxytamoxifen resistant human breast cancer variant that retains sensitivity to the steroidal antiestrogen ICI 182,780. Cancer Res. 1993, 53, 3229-3232.
321. Lykkesfeldt, A. E.; Madsen, M. W.; Briand, P. Altered expression of estrogen-regulated genes in a tamoxifen-resistant and ICI 164,384 and ICI 182,780 sensitive human breast cancer cell line, MCF-7/TAMR-1. Cancer Res. 1994, 54, 1587-1595.
322. Borras, M.; Jin, L.; Bouhoute, A.; Legros, N.; Leclercq, G. Evaluation of estrogen receptor, antiestrogen binding sites and calmodulin for antiestrogen resistance of two clones derived from the MCF-7 breast cancer cell line. Biochem. Pharmacol. 1994, 48, 2015-2024.
323. Brunner, N.; Boysen, B.; Jirus, S.; Skaar, T. C.; Holst-Hansen, C.; Lippman, J.; Frandsen, T.; Spang-Thomsen, M.; Fuqua, S. A.; Clarke, R. MCF7/LCC9: an antiestrogen-resistant MCF-7 variant in which acquired resistance to the steroidal antiestrogen ICI 182,780 confers an early cross-resistance to the nonsteroidal antiestrogen tamoxifen. Cancer Res. 1997, 57, 3486-3493.
324. Larsen, S. S.; Madsen, M. W.; Jensen, B. L.; Lykkesfeldt, A. E. Resistance of human breast-cancer cells to the pure steroidal anti-estrogen ICI 182,780 is not associated with a general loss of estrogen-receptor expression or lack of estrogen responsiveness. Int. J. Cancer 1997, 72, 1129-1136.
325. Parisot, J. P.; Leeding, K. S.; Hu, X. F.; DeLuise, M.; Zalcberg, J. R.; Bach, L. A. Induction of insulin-like growth factor binding protein expression by ICI 182,780 in a tamoxifen-resistant human breast cancer cell line. Breast Cancer Res. Treat. 1999, 55, 231-242.
326. Chan, C. M.; Lykkesfeldt, A. E.; Parker, M. G.; Dowsett, M. Expression of nuclear receptor interacting proteins TIF-1, SUG-1, receptor interacting protein 140, and corepressor SMRT in tamoxifen- resistant breast cancer. Clin. Cancer Res. 1999, 5, 3460-3467.
327. Zajchowski, D. A.; Kauser, K.; Zhu, D.; Webster, L.; Aberle, S.; White, F. A., 3rd; Liu, H. L.; Humm, R.; MacRobbie, J.; Ponte, P.; Hegele-Hartung, C.; Knauthe, R.; Fritzemeier, K. H.; Vergona, R.; Rubanyi, G. M. Identification of selective estrogen receptor modulators by their gene expression fingerprints. J. Biol. Chem. 2000, 275, 15885-15894.
328. Hyder, S. M.; Nawaz, Z.; Chiappetta, C.; Stancel, G. M. Identification of functional estrogen response elements in the gene coding for the potent angiogenic factor vascular endothelial growth factor. Cancer Res. 2000, 60, 3183-3190.
329. Hodges, Y. K.; Tung, L.; Yan, X. D.; Graham, J. D.; Horwitz, K. B.; Horwitz, L. D. Estrogen receptors alpha and beta: prevalence of estrogen receptor beta mRNA in human vascular smooth muscle and transcriptional effects. Circulation 2000, 101, 1792-1798.
330. Gagliardi, A.; Collins, D. C. Inhibition of angiogenesis by antiestrogens. Cancer Res. 1993, 53, 533-535.
331. Haran, E. F.; Maretzek, A. F.; Goldberg, I.; Horowitz, A.; Degani, H. Tamoxifen enhances cell death in implanted MCF7 breast cancer by inhibiting endothelium growth. Cancer Res. 1994, 54, 5511-5514.
332. Gagliardi, A. R.; Hennig, B.; Collins, D. C. Antiestrogens inhibit endothelial cell growth stimulated by angiogenic growth factors. Anticancer Res. 1996, 16, 1101-1106.
333. Evans, S. M.; Koch, C. J.; Laughlin, K. M.; Jenkins, W. T.; Van Winkle, T.; Wilson, D. F. Tamoxifen induces hypoxia in MCF-7 xenografts. Cancer Res. 1997, 57, 5155-5161.
334. Lindner, D. J.; Borden, E. C. Effects oftamoxifen and interferon-beta or the combination on tumor-induced angiogenesis. Int. J. Cancer 1997, 71, 456-461.
335. Blackwell, K. L.; Haroon, Z. A.; Shan, S.; Saito, W.; Broadwater, G.; Greenberg, C. S.; Dewhirst, M. W. Tamoxifen inhibits angiogenesis in estrogen receptor-negative animal models. Clin. Cancer Res. 2000, 6, 4359-4364.
336. Satyaswaroop, P. G.; Zaino, R. J.; Mortel, R. Human endometrial adenocarcinoma transplanted into nude mice: growth regulation by estradiol. Science 1983, 219, 58-60.
337. Levenson, A. S.; Jordan, V. C. MCF-7: the first hormone-responsive breast cancer cell line. Cancer Res. 1997, 57, 3071-3078.
338. Osborne, C. K.; Hobbs, K.; Clark, G. M. Effect of estrogens and antiestrogens on growth of human breast cancer cells in athymic nude mice. Cancer Res. 1985, 45, 584-590.
339. Gottardis, M. M.; Robinson, S. P.; Jordan, V. C. Estradiol-stimulated growth of MCF-7 tumors implanted in athymic mice: a model to study the tumoristatic action of tamoxifen. J. Steroid Biochem. 1988, 30, 311-314.
340. Osborne, C. K.; Coronado, E. B.; Robinson, J. P. Human breast cancer in the athymic nude mouse: cytostatic effects of long-term antiestrogen therapy. Eur. J. Cancer Clin. Oncol. 1987, 23, 1189-1196.
341. Gottardis, M. M.; Jordan, V. C. Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res. 1988, 48, 5183-5187.
342. Gottardis, M. M.; Wagner, R. J.; Borden, E. C.; Jordan, V. C. Differential ability of antiestrogens to stimulate breast cancer cell (MCF-7) growth in vivo and in vitro. Cancer Res. 1989, 49, 4765-4769.
343. Murphy, C. S.; Meisner, L. F.; Wu, S. Q.; Jordan, V. C. Short-and long-term estrogen deprivation of T47D human breast cancer cells in culture. Eur. J. Cancer Clin. Oncol. 1989, 25, 1777-1788.
344. Murphy, C. S.; Pink, J. J.; Jordan, V. C. Characterization of a receptor-negative, hormone-nonresponsive clone derived from a T47D human breast cancer cell line kept under estrogen-free conditions. Cancer Res. 1990, 50, 7285-7292.
345. Murphy, C. S.; Jordan, V. C. Structural components necessary for the antiestrogenic activity of tamoxifen. J. Steroid Biochem. 1989, 34, 407-411.
346. Murphy, C. S.; Langan-Fahey, S. M.; McCague, R.; Jordan, V. C. Structure - function relationships ofhydroxylated metabolites of tamoxifen that control the proliferation of estrogen-responsive T47D breast cancer cells in vitro. Mol. Pharmacol. 1990, 38, 737-743.
347. Murphy, C. S.; Parker, C. J.; McCague, R.; Jordan, V. C. Structure - activity relationships of nonisomerizable derivatives of tamoxifen: importance of hydroxyl group and side chain positioning for biological activity. Mol. Pharmacol. 1991, 39, 421-428.
348. Pink, J. J.; Bilimoria, M. M.; Assikis, J.; Jordan, V. C. Irreversible loss of the oestrogen receptor in T47D breast cancer cells following prolonged oestrogen deprivation [published erratum appears in Br. J. Cancer 1997, 75 (10), 1557]. Br. J. Cancer 1996, 74, 1227-1236.
349. MacGregor Schafer, J. I.; Lee, E.-S.; O'Regan, R. M.; de los Reyes, A.; Jordan, V. C. Rapid development of tamoxifen stimulated mutat p53 tumors (T47D) in athymic mice. Clin. Cancer Res. 2000, 6, 4373-4380.
350. Dardes, R. C.; Liu, H.; Gajdos, C.; O'Regan, R.; de los Reyes, A.; Jordan, V. C. Raloxifene stimulated endometrial cancer grown in athymic mice: cross resistance with ICI 172,780 and antitumor action of estradiol. Breast Cancer Res. Treat. 2001, 69, 288 (Abstract 447).
351. Liu, H.; Lee, E. S.; de los reyes, A.; Jordan, V. C. Antitumor action of estradiol on estrogen-deprived or raloxifene-resistant humna breast cancer cells. Breast Cancer Res. Treat. 2000, 64, 134 (Abstract 573).
352. Wolf, D. M.; Langan-Fahey, S. M.; Parker, C. J.; McCague, R.; Jordan, V. C. Investigation of the mechanism of tamoxifen-stimulated breast tumor growth with nonisomerizable analogues of tamoxifen and metabolites. J. Natl. Cancer Inst. 1993, 85, 806-812.
353. Brockdorff, B. L.; Skouv, J.; Reiter, B. E.; Lykkesfeldt, A. E. Increased expression of cytochrome p450 1A1 and 1B1 genes in anti-estrogen-resistant human breast cancer cell lines. Int. J. Cancer 2000, 88, 902-906.
354. Xu, J.; Qiu, Y.; DeMayo, F. J.; Tsai, S. Y.; Tsai, M. J.; O'Malley, B. W. Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. Science 1998, 279, 1922-1925.
355. Webb, P.; Nguyen, P.; Valentine, C.; Lopez, G. N.; Kwok, G. R.; McInerney, E.; Katzenellenbogen, B. S.; Enmark, E.; Gustafsson, J. A.; Nilsson, S.; Kushner, P. J. The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. Mol. Endocrinol. 1999, 13, 1672-1685.
356. Pettersson, K.; Delaunay, F.; Gustafsson, J. A. Estrogen receptor beta acts as a dominant regulator of estrogen signaling. Oncogene 2000, 19, 4970-4978.
357. Schiff, R.; Reddy, P.; Ahotupa, M.; Coronado-Heinsohn, E.; Grim, M.; Hilsenbeck, S. G.; Lawrence, R.; Deneke, S.; Herrera, R.; Chamness, G. C.; Fuqua, S. A.; Brown, P. H.; Osborne, C. K. Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo. J. Natl. Cancer Inst. 2000, 92, 1926-1934.
358. Weatherman, R. V.; Scanlan, T. S. Unique protein determinants of the subtype-selective ligand responses of the estrogen receptors (ERalpha and ERbeta) at AP-1 sites. J. Biol. Chem. 2001, 276, 3827-3832.
359. Montano, M. M.; Katzenellenbogen, B. S. The quinone reductase gene: a unique estrogen receptor-regulated gene that is activated by antiestrogens. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 2581-2586.
360. Montano, M. M.; Jaiswal, A. K.; Katzenellenbogen, B. S. Transcriptional regulation of the human quinone reductase gene by antiestrogen-liganded estrogen receptor-alpha and estrogen receptor-beta. J. Biol. Chem. 1998, 273, 25443-25449.
361. Herman, M. E.; Katzenellenbogen, B. S. Response-specific antiestrogen resistance in a newly characterized MCF-7 human breast cancer cell line resulting from long-term exposure to trans-hydroxytamoxifen. J. Steroid Biochem. Mol. Biol. 1996, 59, 121-134.
362. Chen, B.; Jordan, V. C. Role of estrogen receptor (ER) beta in modulating ER alpha SERM complexes in MDA-MB-231 breast cancer cells. Breast Cancer Res. Treat. 2001, 69, 293.
363. Fournier, B.; Gutzwiller, S.; Dittmar, T.; Matthias, G.; Steenbergh, P.; Matthias, P. Estrogen receptor (ER)-alpha, but not ER-beta, mediates regulation of the insulin-like growth factor I gene by antiestrogens. J. Biol. Chem. 2001, 276, 35444-35449.
364. Sutherland, R. L.; Hall, R. E.; Taylor, I. W. Cell proliferation kinetics of MCF-7 human mammary carcinoma cells in culture and effects of tamoxifen on exponentially growing and plateau-phase cells. Cancer Res. 1983, 43, 3998-4006.
365. Sutherland, R. L.; Reddel, R. R.; Green, M. D. Effects of oestrogens on cell proliferation and cell cycle kinetics. A hypothesis on the cell cycle effects of antioestrogens. Eur. J. Cancer Clin. Oncol. 1983, 19, 307-318.
366. Musgrove, E. A.; Lee, C. S.; Buckley, M. F.; Sutherland, R. L. Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 8022-8026.
367. Watts, C. K.; Brady, A.; Sarcevic, B.; deFazio, A.; Musgrove, E. A.; Sutherland, R. L. Antiestrogen inhibition of cell cycle progression in breast cancer cells is associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. Unpublished results, 1995.
368. Wilcken, N. R.; Prall, O. W.; Musgrove, E. A.; Sutherland, R. L. Inducible overexpression of cyclin D1 in breast cancer cells reverses the growth-inhibitory effects of antiestrogens. Clin. Cancer Res. 1997, 3, 849-854.
369. Carroll, J. S.; Prall, O. W.; Musgrove, E. A.; Sutherland, R. L. A pure estrogen antagonist inhibits cyclin E-Cdk2 activity in MCF-7 breast cancer cells and induces accumulation of p130-E2F4 complexes characteristic of quiescence. J. Biol. Chem. 2000, 275, 38221-38229.
370. Collett, M. S.; Erikson, R. L. Protein kinase activity associated with the avian sarcoma virus src gene product. Proc. Natl. Acad. Sci. U.S.A. 1978, 75, 2021-2024.
371. Levinson, A. D.; Oppermann, H.; Levintow, L.; Varmus, H. E.; Bishop, J. M. Evidence that the transforming gene of avian sarcoma virus encodes a protein kinase associated with a phosphoprotein. Cell 1978, 15, 561-572.
372. Hunter, T.; Sefton, B. M. Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc. Natl. Acad. Sci. U.S.A. 1980, 77, 1311-1315.
373. Cooper, J. A.; Gould, K. L.; Cartwright, C. A.; Hunter, T. Tyr527 is phosphorylated in pp60c-src: implications for regulation. Science 1986, 231, 1431-1434.
374. Sugimoto, Y.; Whitman, M.; Cantley, L. C.; Erikson, R. L. Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. Proc. Natl. Acad. Sci. U.S.A. 1984, 81, 2117-2121.
375. Jacobs, C.; Rubsamen, H. Expression of pp60c-src protein kinase in adult and fetal human tissue: high activities in some sarcomas and mammary carcinomas. Cancer Res. 1983, 43, 1696-1702.
376. Ottenhoff-Kalff, A. E.; Rijksen, G.; van Beurden, E. A.; Hennipman, A.; Michels, A. A.; Stall, G. E. Characterization of protein tyrosine kinases from human breast cancer: invlvement of the c0src oncogene product. Cancer Res. 1992, 52.
377. Verbeek, B. S.; Vroom, T. M.; Adriaansen-Slot, S. S.; Ottenhoff-Kalff, A. E.; Geertzema, J. G.; Hennipman, A.; Rijksen, G. c-Src protein expression is increased in human breast cancer. An immunohistochemical and biochemical analysis. J. Pathol. 1996, 180, 383-388.
378. Feng, W.; Webb, P.; Nguyen, P.; Liu, X.; Li, J.; Karin, M.; Kushner, P. J. Potentiation of estrogen receptor activation function 1 (AF-1) by src/JNK through a serine 118-independent pathway. Mol. Endocrinol. 2001, 15, 32-45.
379. Lee, H.; Jiang, F.; Wang, Q.; Nicosia, S. V.; Yang, J.; Su, B.; Bai, W. MEKK1 activation of human estrogen receptor alpha and stimulation of the agonistic activity of 4-hydroxytamoxifen in endometrial and ovarian cancer cells. Mol. Endocrinol. 2000, 14, 1882-1896.
380. Kousteni, S.; Bellido, T.; Plotkin, L. I.; O'Brien, C. A.; Bodenner, D. L.; Han, L.; Han, K.; DiGregorio, G. B.; Katzenellenbogen, J. A.; Katzenellenbogen, B. S.; Roberson, P. K.; Weinstein, R. S.; Jilka, R. L.; Manolagas, S. C. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 2001, 104, 719-730.
381. Migliaccio, A.; Di Domenico, M.; Castoria, G.; de Falco, A.; Bontempo, P.; Nola, E.; Auricchio, F. Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol - receptor complex in MCF-7 cells. EMBO J. 1996, 15, 1292-1300.
382. Singer, C. A.; Figueroa-Masot, X. A.; Batchelor, R. H.; Dorsa, D. M. The mitogen-activated protein kinase pathway mediates estrogen neuroprotection after glutamate toxicity in primary cortical neurons. J. Neurosci. 1999, 19, 2455-2463.
383. Razandi, M.; Pedram, A.; Greene, G. L.; Levin, E. R. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells. Mol. Endocrinol. 1999, 13, 307-319.
384. Wade, C. B.; Robinson, S.; Shapiro, R. A.; Dorsa, D. M. Estrogen receptor (ER)alpha and ERbeta exhibit unique pharmacologic properties when coupled to activation of the mitogen-activated protein kinase pathway. Endocrinology 2001, 142, 2336-2342.
385. Simoncini, T.; Hafezi-Moghadam, A.; Brazil, D. P.; Ley, K.; Chin, W. W.; Liao, J. K. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000, 407, 538-541.
386. Campbell, R. A.; Bhat-Nakshatri, P.; Patel, N. M.; Constantinidou, D.; Ali, S.; Nakshatri, H. Phosphatidylinositol 3-kinase/ AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J. Biol. Chem. 2001, 276, 9817-9824.
387. Xia, Z.; Dickens, M.; Raingeaud, J.; Davis, R. J.; Greenberg, M. E. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 2001, 276, 9817-9824.
388. Paul, A.; Wilson, S.; Belham, C. M.; Robinson, C. J.; Scott, P. H.; Gould, G. W.; Plevin, R. Stress-activated protein kinases: activation, regulation and function. Cell. Signalling 1997, 9, 403-410.
389. Huang, C.; Ma, W. Y.; Maxiner, A.; Sun, Y.; Dong, Z. p38 kinase mediates UV-induced phosphorylation of p53 protein at serine 389. J. Biol. Chem. 1999, 274, 12229-12235.
390. Zhang, C. C. a. S. Activation of the p38 mitogen-activated protein kinase pathway by estrogen or by 4-hydroxytamoxifen is coupled to estrogen receptor-induced apoptosis. J. Biol. Chem. 2000, 275, 479-486.
391. Tomizawa, M.; Kumar, A.; Perrot, V.; Nakae, J.; Accili, D.; Rechler, M. M.; Kumaro, A. Insulin inhibits the activation of transcription by a C-terminal fragment of the forkhead transcription factor FKHR. A mechanism for insulin inhibition of insulin-like growth factor-binding protein-1 transcription. J. Biol. Chem. 2000, 275, 7289-7295.
392. Biggs, W. H., 3rd; Meisenhelder, J.; Hunter, T.; Cavenee, W. K.; Arden, K. C. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 7421-7426.
393. Zhao, H. H.; Herrera, R. E.; Coronado-Heinsohn, E.; Yang, M. D.; Ludes-Meyers, J. H.; Seybold-Tilson, K. J.; Nawaz, Z.; Yee, D.; Barr, F. G.; Diab, S. G.; Brown, P. H.; Fuqua, S. A.; Osborne, C. K. Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions. J. Biol. Chem. 2001, 276, 27907-27912.
394. Schuur, E. R.; Loktev, A. V.; Sharma, M.; Sun, Z.; Roth, R. A.; Weigel, R. J. Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family. J. Biol. Chem. 2001, 276, 33554-33560.
395. Janes, P. W.; Daly, R. J.; deFazio, A.; Sutherland, R. L. Activation of the Ras signalling pathway in human breast cancer cells overexpressing erbB-2. Oncogene 1994, 9, 3601-3608.
396. Qian, X.; Dougall, W. C.; Fei, Z.; Greene, M. I. Intermolecular association and trans-phosphorylation of different neu-kinase forms permit SH2-dependent signaling and oncogenic transformation. Oncogene 1995, 10, 211-219.
397. Muthuswamy, S. K.; Siegel, P. M.; Dankort, D. L.; Webster, M. A.; Muller, W. J. Mammary tumors expressing the neu protooncogene possess elevated c-Src tyrosine kinase activity. Mol. Cell. Biol. 1994, 14, 735-743.
398. Lee, R. J.; Albanese, C.; Fu, M.; D'Amico, M.; Lin, B.; Watanabe, G.; Haines, G. K., 3rd; Siegel, P. M.; Hung, M. C.; Yarden, Y.; Horowitz, J. M.; Muller, W. J.; Pestell, R. G. Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol. Cell. Biol. 2000, 20, 672-683.
399. Newman, S. P.; Bates, N. P.; Vernimmen, D.; Parker, M. G.; Hurst, H. C. Cofactor competition between the ligand-bound oestrogen receptor and an intron 1 enhancer leads to oestrogen repression of ERBB2 expression in breast cancer. Oncogene 2000, 19, 490-497.
400. Jordan, V. C.; Allen, K. E.; Dix, C. J. Pharmacology of tamoxifen in laboratory animals. Cancer Treat. Rep. 1980, 64, 745-759.
401. Skidmore, J. R.; Walpole, A. L.; Woodburn, J. Effect of some triphenylethylenes on oestradiol binding in vitro to macromolecules from uterus and anterior pituitary. J. Endocrinol. 1972, 52, 289-298.
402. Wolf, D. M.; Jordan, V. C. A laboratory model to explain the survival advantage observed in patients taking adjuvant tamoxifen therapy. Recent Results Cancer Res. 1993, 127, 23-33.
403. Yao, K.; Lee, E. S.; Bentrem, D. J.; England, G.; Schafer, J. I.; O'Regan, R. M.; Jordan, V. C. Antitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice [in process citation]. Clin Cancer Res. 2000, 6, 2028-2036.
404. Soto, A. M.; Sonnenschein, C. The two faces ofjanus: sex steroids as mediators of both cell proliferation and cell death. J. Natl. Cancer Inst. 2001, 93, 1673-1675.
405. Boyer, M. J.; Tattersall, M. H. Diethylstilbestrol revisited in advanced breast cancer management. Med. Pediatr. Oncol. 1990, 18, 317-320.
406. Lonning, P. E.; Taylor, P. D.; Anker, G.; Iddon, J.; Wie, L.; Jorgensen, L. M.; Mella, O.; Howell, A. High-dose estrogen treatment in postmenopausal breast cancer patients heavily exposed to endocrine therapy. Breast Cancer Res. Treat. 2001, 67, 111-116.
407. Song, R. X.; Mor, G.; Naftolin, F.; McPherson, R. A.; Song, J.; Zhang, Z.; Yue, W.; Wang, J.; Santen, R. J. Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J. Natl. Cancer Inst. 2001, 93, 1714-1723.
408. Szelei, J.; Soto, A. M.; Geck, P.; Desronvil, M.; Prechtl, N. V.; Weill, B. C.; Sonnenschein, C. Identification of human estrogen-inducible transcripts that potentially mediate the apoptotic response in breast cancer. J. Steroid Biochem. Mol. Biol. 2000, 72, 89-102.
409. Chisamore, M. J.; Ahmed, Y.; Bentrem, D. J.; Jordan, V. C.; Tonetti, D. A. Novel antitumor effect of estradiol in athymic mice injected with a T47D breast cancer cell line overexpressing protein kinase Calpha. Clin. Cancer Res. 2001, 7, 3156-3165.
410. Tonetti, D. A.; Chisamore, M. J.; Grdina, W.; Schurz, H.; Jordan, V. C. Stable transfection of protein kinase C alpha cDNA in hormone-dependent breast cancer cell lines. Br. J. Cancer 2000, 83, 782-791.
411. Sun, J.; Hunahg, Y. R.; Hrrington, W. R.; Sheng, S.; Katzenellenbogen, J. A.; Katzenellenbogen, B. S. Antagonists selective for estrogen receptor alpha. Endocrinology 2002, 143, 941-947.
412. Paech, K.; Webb, P.; Kuiper, G. G.; Nilsson, S.; Gustafsson, J.; Kushner, P. J.; Scanlan, T. S. Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites [see comments]. Science 1997, 277, 1508-1510.
413. Hedden, A.; Muller, V.; Jensen, E. V A new interpretation of antiestrogen action. Ann. N. Y. Acad. Sci. 1995, 761, 109-120.
414. Jordan, V. C. The secrets of selective estrogen receptor modulation: cell specific coregulation. Cancer Cell 2002, 1, 215-217.