Development and assessment of conventional and targeted drug combinations for use in the treatment of aggressive breast cancers

Current Cancer Drug Targets

Volumn 6, Issue 6, 2006, Pages 455-489

  Waterhouse, D N ^a   Gelmon, K A ^a   Klasa, R ^a   Chi, K ^a   Huntsman, D ^a   Ramsay, E ^a   Wasan, E ^a   Edwards, L ^a   Tucker, C ^a   Zastre, J ^a   Zhang, Y Z ^a   Yapp, D ^a   Dragowska, W ^a   Dunn, S ^a   Dedhar, S ^a   Bally, M B ^a  

^a BRITISH COLUMBIA CANCER AGENCY   (Canada)

Author keywords

Cancer; Chemotherapy; Combination treatment; Preclinical development; Targeted agents

Indexed keywords

ANASTROZOLE; CANERTINIB; CAPECITABINE; CARBOPLATIN; CISPLATIN; CYCLOPHOSPHAMIDE; DOCETAXEL; DOXORUBICIN; EPIRUBICIN; ERLOTINIB; EVEROLIMUS; EXEMESTANE; FLUOROURACIL; GEFITINIB; GEMCITABINE; IDARUBICIN; IMATINIB; IRINOTECAN; LAPATINIB; LETROZOLE; METHOTREXATE; NAVELBINE; OCTREOTIDE; PACLITAXEL; PERTUZUMAB; TAMOXIFEN; TEMSIROLIMUS; TIPIFARNIB; TRASTUZUMAB; UNINDEXED DRUG;

ABNORMALLY HIGH SUBSTRATE CONCENTRATION IN BLOOD; ALOPECIA; ANEMIA; ANGIOGENESIS; APOPTOSIS; ARTHRALGIA; ASTHENIA; BLOOD CLOTTING DISORDER; BLOOD TOXICITY; BONE MARROW SUPPRESSION; BRADYCARDIA; BREAST CANCER; BREAST METASTASIS; CANCER CELL; CANCER COMBINATION CHEMOTHERAPY; CANCER GROWTH; CANCER INVASION; CANCER RISK; CARDIOTOXICITY; CELL CYCLE; CELL POPULATION; CELL SURVIVAL; CELL TRANSFORMATION; CHILL; CLINICAL EFFECTIVENESS; CLINICAL TRIAL; CONGESTIVE HEART FAILURE; DIARRHEA; DIZZINESS; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENTIATION; DRUG SCREENING; DRUG TARGETING; ECG ABNORMALITY; EDEMA; ELECTROLYTE DISTURBANCE; ENDOMETRIUM CANCER; EYE DISEASE; FATIGUE; FEVER; FLU LIKE SYNDROME; FLUID RETENTION; FRACTURE; GASTROINTESTINAL DISEASE; HAND FOOT SYNDROME; HEART DISEASE; HEMORRHAGIC CYSTITIS; HOT FLUSH; HUMAN; HYPERPIGMENTATION; HYPOXIA; IMMUNE DEFICIENCY; IN VITRO STUDY; IN VIVO STUDY; INFECTION; INJECTION SITE IRRITATION; INJECTION SITE REACTION; INSOMNIA; KIDNEY DISEASE; LEUKOPENIA; LIVER DISEASE; LUNG DISEASE; METASTASIS; MULTIDRUG RESISTANCE; MYALGIA; NAUSEA; NEPHROTOXICITY; NEUROPATHY; NEUROTOXICITY; NEUTROPENIA; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; ONCOGENE NEU; OTOTOXICITY; PAIN; PERIPHERAL EDEMA; PERIPHERAL NEUROPATHY; POSITRON EMISSION TOMOGRAPHY; PROTEIN EXPRESSION; RASH; REPRODUCTIVE TOXICITY; REVIEW; SENSORY NEUROPATHY; SIDE EFFECT; SKIN MANIFESTATION; STOMATITIS; THROMBOCYTOPENIA; THROMBOEMBOLISM; TRANSGENIC MOUSE; TREATMENT OUTCOME; UNSPECIFIED SIDE EFFECT; VISUAL DISORDER; VOMITING;

ANIMALS; ANTINEOPLASTIC AGENTS; BREAST NEOPLASMS; DRUG DELIVERY SYSTEMS; DRUG THERAPY, COMBINATION; HUMANS; NEOPLASM INVASIVENESS;

EID: 33748578982     PISSN: 15680096     EISSN: None     Source Type: Journal    
DOI: 10.2174/156800906778194586     Document Type: Review

References (296)

1. Bonadonna, G.; Zambetti, M.; Moliterni, A.; Gianni, L.; Valagussa, P. Clinical relevance of different sequencing of doxorubicin and cyclophosphamide, methotrexate and fluorouracil in operable breast cancer. J. Clin. Oncol. 2004, 22, 1614-1620.
2. Goldhirsch, A.; Wood, W. C.; Gelber, R. D.; Coates, A. S.; Thurlimann, B.; Senn, H. J. Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer. J. Clin. Oncol. 2003, 21, 3357-3365.
3. Chabner, B. A.; Myers, C. E. Clinical pharmacology of cancer chemotherapy. In: Cancer: principles and practice of oncology; DeVita, V. T.; Hellman, S.; Rosenberg, S. A., Eds.; 3rd ed. J. B. Lippincott Co.: Philadelphia, 1989, pp. 365-367.
4. Haskell, C. M., Ed.; Cancer Treatment; 3rd ed., W. B. Saunders Co.: Philadelphia, 1990.
5. Page, T.; Takimoto, C. Principles of Chemotherapy. In Cancer Management: A Multidisciplinary Approach; Foundation for Thymic Cancer Research: Longport, NJ, 2005. http://www. thymic.org/03chemoprinc.pdf (accessed June 2005).
6. Piccart-Gebhart, M. J.; Procter, M.; Leyland-Jones, B.; Goldhirsch, A.; Untch, M.; Smith, I.; Gianni, L.; Baselga, J.; Bell, R.; Jackisch, C.; Cameron, D.; Dowsett, M.; Barrios, C. H.; Steger, G.; Huang, C. S.; Andersson, M.; Inbar, M.; Lichinitser, M.; Lang, I.; Nitz, U.; Iwata, H.; Thomssen, C.; Lohrisch, C.; Suter, T. M.; Ruschoff, J.; Suto, T.; Greatorex, V.; Ward, C.; Straehle, C.; McFadden, E.; Dolci, M. S.; Gelber, R. D. Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 2005, 353, 1659-1672.
7. Romond, E. H.; Perez, E. A.; Bryant, J.; Suman, V. J.; Geyer, C. E. Jr.; Davidson, N. E.; Tan-Chiu, E.; Martino, S.; Paik, S.; Kaufman, P. A.; Swain, S. M.; Pisansky, T. M.; Fehrenbacher, L.; Kutteh, L. A.; Vogel, V. G.; Visscher, D. W.; Yothers, G.; Jenkins, R. B.; Brown, A. M.; Dakhil, S. R.; Mamounas, E. P.; Lingle, W. L.; Klein, P. M.; Ingle, J. N.; Wolmark, N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 2005, 353, 1673-1684.
8. Beatson, C. T. On treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet 1896, 2, 104-107.
9. Agus, D. B.; Gordon, M. S.; Taylor, C.; Natale, R. B.; Karlan, B.; Mendelson, D. S.; Press, M. F.; Allison, D. E.; Sliwkowski, M. X.; Lieberman, G.; Kelsey, S. M.; Fyfe, G. Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J. Clin. Oncol. 2005, 23, 2534-2543.
10. Chu, I.; Blackwell, K.; Chen, S.; Slingerland, J. The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer. Cancer Res. 2005, 65, 18-25.
11. Spector, N. L.; Xia, W.; Burris, H. 3rd; Hurwitz, H.; Dees, E. C.; Dowlati, A.; O'Neil, B.; Overmoyer, B.; Marcom, P. K.; Blackwell, K. L.; Smith, D. A.; Koch, K. M.; Stead, A.; Mangum, S.; Ellis, M. J.; Liu, L.; Man, A. K.; Bremer, T. M.; Harris, J.; Bacus, S. Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J. Clin. Oncol. 2005, 23, 2502-2512.
12. rd; Hurwitz, H. I.; Dees, E. C.; Dowlati, A.; Blackwell, K. L.; O'Neil, B.; Marcom, P. K.; Ellis, M. J.; Overmoyer, B.; Jones, S. F.; Harris, J. L.; Smith, D. A.; Koch, K. M.; Stead, A.; Mangum, S.; Spector, N. L. Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J. Clin. Oncol. 2005, 23, 5305-5313.
13. Yatscoff, R. W.; Aspeslet, L. J. The monitoring of immunosuppressive drugs: a pharmacodynamic approach. Ther. Drug Monit. 1998, 20, 459-463.
14. ATAC Trial Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005, 365, 60-62.
15. Baum, M.; Buzdar, A.; Cuzick, J.; Forbes, J.; Houghton, J.; Howell, A.; Sahmoud, T. The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003, 98, 1802-1810.
16. Goss, P. E.; Ingle, J. N.; Martino, S.; Robert, N. J.; Muss, H. B.; Piccart, M. J.; Castiglione, M.; Tu, D.; Shepherd, L. E.; Pritchard, K. I.; Livingston, R. B.; Davidson, N. E.; Norton, L.; Perez, E. A.; Abrams, J. S.; Therasse, P.; Palmer, M. J.; Pater, J. L. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N. Engl. J. Med. 2003, 349, 1793-1802.
17. Kunz-Schughart, L. A.; Kreutz, M.; Knuechel, R. Multicellular spheroids: a three-dimensional in vitro culture system to study tumour biology. Int. J. Exp. Pathol. 1998, 79, 1-23.
18. Kunz-Schughart, L. A.; Freyer, J. P.; Hofstaedter, F.; Ebner, R. The Use of 3-D Cultures for High-Throughput Screening: The Multicellular Spheroid Model. J. Biomol. Screen. 2004, 9, 273-285.
19. Agre, P.; Williams, T. E. The human tumor cloning assay in cancer drug development. A review. Invest. New Drugs 1983, 1, 33-45.
20. von Hoff, D. D. Human tumor cloning assays: applications in clinical oncology and new antineoplastic agent development. Cancer Met. Rev. 1988, 7, 357-371.
21. Nielsen, T. O.; Andrews, H. N.; Cheang, M.; Kucab, J. E.; Hsu, F. D.; Ragaz, J.; Gilks, C. B.; Makretsov, N.; Bajdik, C. D.; Brookes, C.; Neckers, L. M.; Evdokimova, V.; Huntsman, D. G.; Dunn, S. E. Expression of the insulin-like growth factor I receptor and urokinase plasminogen activator in breast cancer is associated with poor survival: potential for intervention with 17-allylamino geldanamycin. Cancer Res. 2004, 64, 286-91.
22. Chou, J.; Chou, T. -C.; Talalay, P. Computer simulations of drug effects: Quantitation of synergism, summation and antagonism of multiple drugs. Pharmacologist 1983, 25, 175-184.
23. Chou, T. -C.; Talalay, P. Quantitative Analysis of Dose-Effect Relationships: The Combined Effects of Multiple Drugs or Enzyme Inhibitors in Analysis of Multiple Drug Effects. Adv. Enzyme Regul. 1984, 22, 27-55.
24. Redpath, J. L. Mechanisms in combination therapy: isobologram analysis and sequencing. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 1980, 38, 355-356.
25. Ling, V. Multidrug resistance: molecular mechanisms and clinical relevance. Cancer Chemother. Pharmacol. 1997, 40, S3-S8.
26. Lage, H.; Dietel, M. Effect of the breast-cancer resistance protein on atypical multidrug resistance. Lancet Oncol. 2000, 1, 169-175.
27. Dorssers, L. C.; Van der Flier, S.; Brinkman, A.; van Agthoven, T.; Veldscholte, J.; Berns, E. M.; Klijn, J. G.; Beex, L. V.; Foekens, J. A. Tamoxifen resistance in breast cancer: elucidating mechanisms. Drugs 2001, 61, 1721-1733.
28. Geisler, S.; Lonning, P. E.; Aas, T.; Johnsen, H.; Fluge, O.; Haugen, D. F.; Lillehaug, J. R.; Akslen, L. A.; Borresen-Dale, A. L. Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer. Cancer Res. 2001, 61, 2505-2512.
29. Anelli, A.; Brentani, R. R.; Gadelha, A. P.; Amorim De Albuquerque, A.; Soares, F. Correlation of p53 status with outcome of neoadjuvant chemotherapy using paclitaxel and doxorubicin in stage IIIB breast cancer. Ann. Oncol. 2003, 14, 428-432.
30. Elmore, L. W.; Rehder, C. W.; Di, X.; McChesney, P. A.; Jackson-Cook, C. K.; Gewirtz, D. A.; Holt, S. E. Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction. J. Biol. Chem. 2002, 277, 35509-35515.
31. Taucher, S.; Rudas, M.; Mader, R. M.; Gnant, M.; Sporn, E.; Dubsky, P.; Roka, S.; Bachleitner, T.; Fitzal, F.; Kandioler, D.; Wenzel, C.; Steger, G. G.; Mittlbock, M.; Jakesz, R. Influence of neoadjuvant therapy with epirubicin and docetaxel in the expression of HER2/neu in patients with breast cancer. Breast Cancer Res. Treat. 2003, 82, 207-213.
32. Vargas-Roig, L. M.; Gago, F. E.; Tello, O.; Martin de Civetta, M. T.; Ciocca, D. R. c-erbB-2 (HER2/neu) protein and drug resistance in breast cancer patients treated with induction chemotherapy. Int. J. Cancer 1999, 84, 129-134.
33. Yu, D.; Hung, M. C. Role of erbB2 in breast cancer chemosensitivity. Bioessays 2000, 22, 673-680.
34. Pegram, M. D.; Konecny, G. E.; O'Callaghan, C.; Beryt, M.; Pietras, R.; Slamon, D. J. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J. Natl. Cancer Inst. 2004, 96, 739-749.
35. Atlas, E.; Cardillo, M.; Mehmi, I.; Zahedkargaran, H.; Tang, C.; Lupu, R. Heregulin is sufficient for the promotion of tumorigenicity and metastasis of breast cancer cells in vivo. Mol. Cancer Res. 2003, 1, 165-175.
36. Anido, J.; Matar, P.; Albanell, J.; Guzman, M.; Rojo, F.; Arribas, J.; Averbuch, S.; Baselga, J. ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells. Clin. Cancer Res. 2003, 9, 1274-1283.
37. Molina, M. A.; Codony-Servat, J.; Albanell, J.; Rojo, F.; Arribas, J.; Baselga, J. Trastuzumab (Herceptin), a humanized anti-Her2 receptor monoclonal antibody inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res. 2001, 61, 4744-4749.
38. Sliwkowski, M. X.; Lofgren, J. A.; Lewis, G. D.; Hotaling, T. E.; Fendly, B. M.; Fox, J. A. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin. Oncol. 1999, 26, 60-70.
39. Lewis, G. D.; Figari, I.; Fendly, B.; Wong, W. L.; Carter, P.; Gorman, C.; Shepard, H. M. Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol. Immunother. 1993, 37, 255-263.
40. Pegram, M.; Hsu, S.; Lewis, G.; Pietras, R.; Beryt, M.; Sliwkowski, M.; Coombs, D.; Baly, D.; Kabbinavar, F.; Slamon, D. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 1999, 18, 2241-2251.
41. Pietras, R. J.; Fendly, B. M.; Chazin, V. R.; Pegram, M. D.; Howell, S. B.; Slamon, D. J. Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 1994, 9, 1829-1838.
42. Nagata, Y.; Lan, K. H.; Zhou, X.; Tan, M.; Esteva, F. J.; Sahin, A. A.; Klos, K. S.; Li, P.; Monia, B. P.; Nguyen, N. T.; Hortobagyi, G. N.; Hung, M. C.; Yu, D. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004, 6, 117-127.
43. Miles, D.; von Minckwitz, G.; Seidman, A. D. Combination versus sequential single-agent therapy in metastatic breast cancer. Oncologist 2002, 7, 13-19.
44. Albanell, J.; Codony-Servat, J.; Rojo, F.; Del Campo, J. M.; Sauleda, S.; Anido, J.; Raspall, G.; Giralt, J.; Rosello, J.; Nicholson, R. I.; Mendelsohn, J.; Baselga, J. Activated Extracellular Signal-Regulated Kinases: Association With Epidermal Growth Factor Receptor/Transforming Growth Factor Alpha Expression in Head and Neck Squamous Carcinoma and Inhibition by Anti- Epidermal Growth Factor Receptor Treatments. Cancer Res. 2001, 61, 6500-6510.
45. Slamon, D. J.; Leyland-Jones, B.; Shak, S.; Fuchs, H.; Paton, V.; Bajamonde, A.; Fleming, T.; Eiermann, W.; Wolter, J.; Pegram, M.; Baselga, J.; Norton, L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. NEJM 2001, 344, 783-792.
46. Cook-Bruns, N. Retrospective analysis of the safety of Herceptin immunotherapy in metastatic breast cancer. Oncology 2001, 61, 58-66.
47. Seidman, A.; Hudis, C.; Pierri, M. K.; Shak, S.; Paton, V.; Ashby, M.; Murphy, M.; Stewart S. J.; Keefe, D. Cardiac dysfunction in the trastuzumab clinical trials experience. J. Clin. Oncol. 2002, 20, 1215-1221.
48. Schimmel, K. J. M.; Richel, D. J.; van den Brink, R. B. A.; Guchelaar, H. J. Cardiotoxicity of cytotoxic drugs. Cancer Treat. Rev. 2004, 30, 181-191.
49. Untch, M.; Eidtmann, H.; du Bois, A.; Meerpohl, H. G.; Thomssen, C.; Ebert, A.; Harbeck, N.; Jackisch, C.; Heilman, V.; Emons, G.; Wallwiener, D.; Wiese, W.; Blohmer, J. -U.; Hoffken, K.; Kuhn, W.; Reichardt, P.; Muscholl, M.; Pauschinger, M.; Langer, B.; Luck, H. J. Cardiac safety of trastuzumab in combination with epirubicin and cyclophosphamide in women with metastatic breast cancer results of a phase I trial. Eur. J. Cancer 2004, 40, 988-997.
50. Zhao, Y. -Y.; Sawyer, D. R.; Baliga, R. R.; Opel, D. J.; Han, X.; Marchionni, M. A.; Kelly, R. A. Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J. Biol. Chem. 1998, 273, 10261-10269.
51. Qiu, Y.; Ravi, L.; Kung, H. J. Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells. Nature 1998, 393, 83-85.
52. Chien, K. R. Stress pathways and heart failure. Cell 1999, 98, 555-558.
53. Hirota, H.; Chen, J.; Betz, U. A. K.; Rajewsky, K.; Gu, Y.; Ross, J. Jr.; Muller, W.; Chien, K. R. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell 1999, 97, 189-198.
54. Ewer, M. S.; Gibbs, H. R.; Swafford, J.; Benjamin, R. S. Cardiotoxicity in patients receiving trastuzumab (Herceptin): Primary toxicity, synergistic or sequential stress, or surveillance artifact? Semin. Oncol. 1999, 26, 96-101.
55. Woodburn, J. R. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol. Therapeut. 1999, 82, 241-250.
56. Moasser, M. M.; Basso, A.; Averbuch, S. D.; Rosen, N. The tyrosine kinase inhibitor ZD1839 ("Iressa") inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res. 2001, 61, 7184-7188.
57. Moulder, S. L.; Yakes, F. M.; Muthuswamy, S. K.; Bianco, R.; Simpson, J. F.; Arteaga, C. L. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res. 2001, 61, 8887-8895.
58. Graus-Porta, D.; Beerli, R. R.; Daly, J. M.; Hynes, N. E. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997, 16, 1647-1655.
59. Warburton, C.; Dragowska, W. H.; Gelmon, K.; Chia, S.; Yan, H.; Masin, D.; Denyssevych, T.; Wallis, A. E.; Bally, M. B. Treatment of HER2/neu Overexpressing Breast Cancer Xenograft Models with Trastuzumab (Herceptin) and Gefitinib (ZD1839): Drug Combination Effects on Tumor Growth, HER2/neu and Epidermal Growth Factor Receptor Expression, and Viable Hypoxic Cell Fraction. Clin. Cancer Res. 2004, 10, 2512-2524.
60. Noramanno, N.; Campiglio, M.; De Luca, A.; Somenzi, G.; Maiello, M.; Ciardiello, F.; Gianni, L.; Salomon, D. S.; Menard, S. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. Ann. Oncol. 2002, 13, 65-72.
61. Moulder, S. L.; Arteaga, C. L. A phase I/II trial of trastuzumab and gefitinib in patients with metastatic breast cancer that overexpresses HER2/neu (ErbB-2). Clin. Breast Cancer 2003, 4, 142-145.
62. Schneeweiss, A.; Kolay, S.; Aulmann, S.; Von Minckwitz, G.; Torode, J.; Koehler, M.; Bastert, G. Induction of remission in a patient with metastatic breast cancer refractory to trastuzumab and chemotherapy following treatment with gefitinib ("Iressa", ZD1839). Anti-Cancer Drugs 2004, 15, 235-238.
63. Baselga, J.; Norton, L.; Albanell, J.; Kim, Y. -M.; Mendelsohn, J. Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 1998, 58, 2825-2831.
64. Leyland-Jones, B.; Gelmon, K.; Ayoub, J. -P.; Arnold, A.; Verma, S.; Dias, R.; Ghahramani, P. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J. Clin. Oncol. 2003, 21, 3965-3971.
65. Yu, D.; Jing, T.; Liu, B.; Yao, J.; Tan, M.; McDonnell, T. J.; Hung, M. -C. Overexpression of ErbB2 blocks Taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase. Mol. Cell. 1998, 2, 581-591.
66. Yu, D.; Liu, B.; Jing, T.; Sun, D.; Price, J. E.; Singletary, S. E.; Ibrahim, N.; Hortobagyi, G. N.; Hung, M. -C. Overexpression of both p185c-ebB2 and p170mdr-1 renders breast cancer cells highly resistant to taxol. Oncogene 1998b, 16, 2087-2094.
67. Lee, S.; Yang, W.; Lan, K. -H.; Sellappan, S.; Klos, K.; Hortobagyi, G.; Hung, M. -C.; Yu, D. Enhanced sensitization to taxol-induced apoptosis by herceptin pretreatment in ErbB2-overexpressing breast cancer cells. Cancer Res. 2002, 62, 5703-5710.
68. Izumi, Y.; Xu, L.; di Tomaso, E.; Fukumura, D.; Jain, R. K. Tumor biology: Herceptin acts as an anti-angiogenic cocktail. Nature 2002, 416, 279-280.
69. Belotti, D.; Vergani, V.; Drudis, T.; Borsotti, P.; Pitelli, M. R.; Viale, G.; Giavazzi, R.; Taraboletti, G. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin. Cancer Res. 1996, 2, 1843-1849.
70. Klos, K. S.; Zhou, X.; Lee, S.; Zhang, L.; Yang, W.; Nagata, Y.; Yu, D. Combined trastuzumab and paclitaxel treatment better inhibits ErbB-2-mediated angiogenesis in breast carcinoma through a more effective inhibition of Akt than either treatment alone. Cancer 2003, 98, 1377-1385.
71. 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. J. Natl. Cancer Inst. 1996, 88, 1529-1542.
72. Budzer, A. U. Advances in endocrine treatments for postmenopausal women with metastatic and early breast cancer. Oncologist 2003, 8, 335-341.
73. Coombes, R. C.; Hall, E.; Gibson, L. J.; Paridaens, R.; Jassem, J.; Delozier, T.; Jones, S. E.; Alvarez, I.; Bertelli, G.; Ortmann, O.; Coates, A. S.; Bajetta, E.; Dodwell, D.; Coleman, R. E.; Fallowfield, L. J.; Mickiewicz, E.; Andersen, J.; Lonning, P. E.; Cocconi, G.; Stewart, A.; Stuart, N.; Snowdon, C. F.; Carpentieri, M.; Massimini, G.; Bliss, J. M. Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. New Engl. J. Med. 2004, 350, 1081-1092.
74. Boeddinghaus, I. M.; Dowsett, M. Comparative clinical pharmacology and pharmacokinetic interactions of aromatase inhibitors. J. Steroid Biochem. Mol. Biol. 2001, 79, 85-91.
75. Dowsett, M.; Cuzick, J.; Howell, A.; Jackson, I.; ATAC Trialists' Group. Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during adjuvant endocrine therapy for early breast cancer in postmenopausal women: a sub-protocol of the 'Arimidex and tamoxifen alone or in combination' (ATAC) trial. Br. J. Cancer 2001, 85, 317-324.
76. Ellis, M. Overcoming endocrine therapy resistance with signal transduction inhibition. Oncologist 2004, 9, 20-26.
77. Kelland, L. R. Farnesyl transferase inhibitors in the treatment of breast cancer. Exp. Opin. Investig. Drugs 2003, 12, 413-241.
78. Hidalgo, M.; Rowinsky, E. K. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 2000, 19, 6680-6686.
79. Chen, J.; Fang, Y. A novel pathway regulating the mammalian target of rapamycin (mTOR) signaling. Biochem. Pharmacol. 2002, 64, 1071-1077.
80. Carraway, H. M.; Hidalgo, M. Mammalian target of rapamycin (mTOR) antagonists. Br. Cancer Res. 2004, 6, 219-224.
81. Zhou, X.; Tan, M.; Stone Hawthorne, V.; Klos, K. S.; Lan, K. H.; Yang, Y.; Yang, W.; Smith, T. L.; Shi, D.; Yu, D. Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin. Cancer Res. 2004, 10, 6779-6788.
82. Yu, K.; Toral-Barza, L.; Discafani, C.; Zhang, W. -G.; Skotnicki, J.; Frost, P.; Gibbons, J. J. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr.-Relat. Cancer 2001, 8, 249-258.
83. Mondesire, W. H.; Jian, W.; Zhang, H.; Ensor, J.; Hung, M. C.; Mills, G. B.; Meric-Bernstam, F. Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin. Cancer Res. 2004, 10, 7031-7042.
84. Witton, C. J. Determining sensitivity to rapamycin and its analogues in breast cancer patients. Br. Cancer Res. 2005, 7, 41-42.
85. Chan, S. Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br. J. Cancer 2004, 91, 1420-1424.
86. Darnell, J. E., Jr. STATs and gene regulation. Science 1997, 277, 1630-1635.
87. Horvath, C. M. STAT proteins and transcriptional responses to extracellular signals. Trends Biochem. Sci. 2000, 25, 496-502.
88. Song, J. I.; Grandis, J. R. STAT signaling in head and neck cancer. Oncogene 2000, 19, 2489-95.
89. Garcia, R.; Yu, C. L.; Hudnall, A.; Catlett, R.; Nelson, K. L.; Smithgall, T.; Fujita, D. J.; Ethier, S. P.; Jove, R. Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell. Growth. Differ. 1997, 8, 1267-1276.
90. Schaefer, L. K.; Ren, Z.; Fuller, G. N.; Schaefer, T. S. Constitutive activation of Stat3alpha in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2). Oncogene 2002, 21, 2058-2065.
91. Coffer, P. J.; Koenderman, L.; de Groot, R. P. The role of STATs in myeloid differentiation and leukemia. Oncogene 2000, 19, 2511-2522.
92. Garcia, R.; Jove, R. Activation of STAT transcription factors in oncogenic tyrosine kinase signalling. J. Biomed. Sci. 1998, 5, 79-85.
93. Watson, C. J.; Miller, W. R. Elevated levels of members of the STAT family of transcription factors in breast carcinoma nuclear extracts. Br. J. Cancer 1995, 71, 840-844.
94. Bromberg, J. F.; Wrzeszczynska, M. H.; Devgan, G.; Zhao, Y.; Pestell, R. G.; Albanese, C.; Darnell, J. E., Jr. Stat3 as an oncogene. Cell 1999, 98, 295-303.
95. Kumar, A.; Commane, M.; Flickinger, T. W.; Horvath, C. M.; Stark, G. R. Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science 1997, 278, 1630-1632.
96. Burke, W. M.; Jin, X.; Lin, H. J.; Huang, M.; Liu, R.; Reynolds, R. K.; Lin, J. Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells. Oncogene 2001, 20, 7925-7934.
97. Dolled-Filhart, M.; Camp, R. L.; Kowalski, D. P.; Smith, B. L.; Rimm, D. L. Tissue Microarray Analysis of Signal Transducers and Activators of Transcription 3 (Stat3) and Phospho-Stat3 (Tyr705) in Node-negative Breast Cancer Shows Nuclear Localization Is Associated with a Better Prognosis. Clin. Cancer Res. 2003, 9, 594-600.
98. Nevalainen, M. T.; Xie, J.; Torhorst, J.; Bubendorf, L.; Haas, P.; Kononen, J.; Sauter, G.; Rui, H. Signal Transducer and Activator of Transcription-5 Activation and Breast Cancer Prognosis. J. Clin. Oncol. 2004, 22, 2053-2060.
99. Calo, V.; Migliavacca, M.; Bazan, V.; Macaluso, M.; Buscemi, M.; Gebbia, N.; Russo, A. STAT proteins: from normal control of cellular events to tumorigenesis. J. Cell Physiol. 2003, 197, 157-168.
100. Garcia, R.; Bowman, T. L.; Niu, G.; Yu, H.; Minton, S.; Muro-Cacho, C. A.; Cox, C. E.; Falcone, R.; Fairclough, R.; Parsons, S.; Laudano, A.; Gazit, A.; Levitzki, A.; Kraker, A.; Jove, R. Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 2001, 20, 2499-2513.
101. Fukada, T.; Ohtani, T.; Yoshida, Y.; Shirogane, T.; Nishida, K.; Nakajima, K.; Hibi, M.; Hirano, T. STAT3 orchestrates contradictory signals in cytokine-induced G1 to S cell-cycle transition. EMBO J. 1998, 17, 6670-6677.
102. Ouchi, T.; Lee, S. W.; Ouchi, M.; Aaronson, S. A.; Horvath, C. M. Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-gamma target genes. Proc. Natl. Acad. Sci. USA 2000, 97, 5208-5213.
103. Bowman, T.; Garcia, R.; Turkson, J.; Jove, R.. STATs in oncogenesis. Oncogene 2000, 19, 2474-2488.
104. Sinibaldi, D.; Wharton, W.; Turkson, J.; Bowman, T.; Pledger, W. J.; Jove, R. Induction of p21WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated STAT3 signaling. Oncogene 2000, 19, 5419-5427.
105. Niu, G.; Wright, K. L.; Huang, M.; Song, L.; Haura, E.; Turkson, J.; Zhang, S.; Wang, T.; Sinibaldi, D.; Coppola, D.; Heller, R.; Ellis, L. M.; Karras, J.; Bromberg, J.; Pardoll, D.; Jove, R.; Yu. H. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 2002, 21, 2000-2008.
106. Baselga, J. Current and planned clinical trials with trastuzumab (Herceptin). Semin. Oncol. 2000, 27, 27-32.
107. Baselga, J. New therapeutic agents targeting the epidermal growth factor receptor. J. Clin. Oncol. 2000, 18, 54S-59S.
108. Real, P. J.; Cao, Y.; Wang, R.; Nikolovska-Coleska, Z.; Sanz-Ortiz, J.; Wang, S.; Fernandez-Luna, J. L. Breast cancer cells can evade apoptosis-mediated selective killing by a novel small molecule inhibitor of Bcl-2. Cancer Res. 2004, 64, 7947-7953.
109. Kaufmann, S. H.; Vaux, D. L. Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene 2003, 22, 7414-7430.
110. Vincent, P. W.; Bridges, A. J.; Dykes, D. J.; Fry, D. W.; Leopold, W. R.; Patmore, S. J.; Roberts, B. J.; Rose, S.; Sherwood, V.; Zhou, H.; Elliott, W. L. Anticancer efficacy of the irreversible EGFr tyrosine kinase inhibitor PD 0169414 against human tumor xenografts. Cancer Chemother. Pharmacol. 2000, 45, 231-238.
111. Meydan, N.; Grunberger, T.; Dadi, H.; Shahar, M.; Arpaia, E.; Lapidot, Z.; Leeder, J. S.; Freedman, M.; Cohen, A.; Gazit, A.; Levitzki, A.; Roifman, C. M. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 1996, 379, 645-648.
112. Holtick, U.; Vockerodt, M.; Pinkert, D.; Schoof, N.; Sturzenhofecker, B.; Kussebi, N.; Lauber, K.; Wesselborg, S.; Loffler, D.; Horn, F.; Trumper, L.; Kube, D. STAT3 is essential for Hodgkin lymphoma cell proliferation and is a target of tyrphostin AG17 which confers sensitization for apoptosis. Leukemia 2005, 19, 936-944.
113. Turkson, J.; Ryan, D.; Kim, J. S.; Zhang, Y.; Chen, Z.; Haura, E.; Laudano, A.; Sebti, S.; Hamilton, A. D.; Jove, R. Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. J. Biol. Chem. 2001, 276, 45443-45455.
114. Grandis, J. R.; Drenning, S. D.; Chakraborty, A.; Zhou, M. Y.; Zeng, Q.; Pitt, A. S.; Tweardy, D. J. Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth In vitro. J. Clin. Invest. 1998, 102, 1385-1392.
115. Barton, B. E.; Murphy, T. F.; Shu, P.; Huang, H. F.; Meyenhofer, M.; Barton, A. Novel single-stranded oligonucleotides that inhibit signal transducer and activator of transcription 3 induce apoptosis in vitro and in vivo in prostate cancer cell lines. Mol. Cancer Ther. 2004, 3, 1183-1191
116. Jing, N.; Tweardy, D. J. Targeting Stat3 in cancer therapy. Anticancer Drugs. 2005, 16, 601-607.
117. Turkson, J.; Jove, R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 2000, 19, 6613-6626.
118. Chambers, A. F.; Matrisian, L. M. Changing views of the role of matrix metalloproteinases in metastasis. J. Natl. Cancer Inst. 1997, 89, 1260-1270.
119. Basset, P.; Bellocq, J. P.; Wolf, C.; Stoll, I.; Hutin, P.; Limacher, J. M.; Podhajcer, O. L.; Chenard, M. P.; Rio, M. C.; Chambon, P. A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature 1990, 348, 699-704.
120. Basset, P.; Wolf, C.; Rouyer, N.; Bellocq, J. P.; Rio, M. C.; Chambon, P. Stromelysin-3 in stromal tissue as a control factor in breast cancer behavior. Cancer 1994, 74, 1045-1049.
121. Hoyhtya, M.; Fridman, R.; Komarek, D.; Porter-Jordan, K.; Stetler-Stevenson, W. G.; Liotta, L. A.; Liang, C. M. Immunohistochemical localization of matrix metalloproteinase 2 and its specific inhibitor TIMP-2 in neoplastic tissues with monoclonal antibodies. Int. J. Cancer 1994, 56, 500-505.
122. Poulsom, R.; Hanby, A. M.; Pignatelli, M.; Jeffery, R. E.; Longcroft, J. M.; Rogers, L.; Stamp, G. W. Expression of gelatinase A and TIMP-2 mRNAs in desmoplastic fibroblasts in both mammary carcinomas and basal cell carcinomas of the skin. J. Clin. Pathol. 1993, 46, 429-436.
123. Mason, J. A.; Yancy, H. F.; Lashley, K.; Jett, M.; Day, A. A. Comparative study of matrix metalloproteinase expression between African American and Caucasian Women. J. Carcinog. 2004, 3, 15-20.
124. Lochter, A.; Srebrow, A.; Sympson, C. J.; Terracio, N.; Werb, Z.; Bissell, M. J. Misregulation of stromelysin-1 expression in mouse mammary tumor cells accompanies acquisition of stromelysin-1 dependent invasive properties. J. Biol. Chem. 1997, 272, 5007-5015.
125. Davies, B.; Brown, P. D.; East, N.; Crimmin, M. J.; Balkwill, F. R. A synthetic matrix maetalloproteinase inhibitor decreases tumor burden and prolongs survival of mice bearing human ovarian carcinoma xenografts [published erratum appears in Cancer Res. 1993, 53, 3652]. Cancer Res. 1993, 53, 2087-2091.
126. Tester, A. M.; Waltham, M.; Oh, S. -J.; Bae, S. -N.; Bills, M. M.; Walker, E. C.; Kern, F. G.; Stetler-Stevenson, W. G.; Lippman, M. E.; Thompson, E. W. Pro-Matrix Metalloproteinase-2 Transfection Increases Orthotopic Primary Growth and Experimental Metastasis of MDA-MB-231 Human Breast Cancer Cells in Nude Mice. Cancer Res. 2004, 64, 652-658.
127. Montel, V.; Kleeman, J.; Agarwal, D.; Spinella, D.; Kawai, K.; Tarin, D. Altered Metastatic Behavior of Human Breast Cancer Cells after Experimental Manipulation of Matrix Metalloproteinase 8. Gene Expr. 2004, 64, 1687-1694.
128. Strongin, A. Y.; Marmer, B. L.; Grant, G. A.; Goldberg, G. I. Plasma membrane-dependent activation of the 72-kDa type IV collagenase is prevented by complex formation with TIMP-2. J. Biol. Chem. 1993, 268, 14033-14039.
129. Strongin, A. Y.; Collier, I.; Bannikov, G.; Marmer, B. L.; Grant, G. A., Goldberg, G. I. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J. Biol. Chem. 1995, 270, 5331-5338.
130. Atkinson, S. J.; Crabbe, T.; Cowell, S.; Ward, R. V.; Butler, M. J.; Sato, H.; Seike, M.; Reynolds, J. J.; Murphy, G. J. Intermolecular autolytic cleavage can contribute to the activation of progelatinase A by cell membranes. Biol. Chem. 1995, 270, 30479-30485.
131. Baramova, E. N.; Bajou, K.; Remacle, A.; L'Hoir, C.; Krell, H. W.; Weidle, U. H.; Noel, A.; Foidart, J. M. Involvement of PA/plasmin system in the processing of pro-MMP-9 and in the second step of pro-MMP-2 activation. FEBS Lett. 1997, 405, 157-162.
132. Giunciuglio, D.; Culty, M.; Fassina, G.; Masiello, L.; Melchiori, A.; Paglialunga, G.; Arand, G.; Ciardiello, F.; Basolo, F.; Thompson, E. W. Invasive phenotype of MCF10A cells overexpressing c-Ha-ras and c-erbB-2 oncogenes. Int. J. Cancer 1995, 63, 815-822.
133. Kaya, M.; Yoshida, K.; Higashino, F.; Mitaka, T.; Ishii, S.; Fujinaga, K. A single ets-related transcription factor, E1AF, confers invasive phenotype on human cancer cells. Oncogene 1996, 12, 221-227.
134. Hsia, D. A.; Mitra, S. K.; Hauck, C. R.; Streblow, D. N.; Nelson, J. A.; Ilic, D.; Huang, S.; Li, E.; Nemerow, G. R.; Leng, J.; Spencer, K. S. R.; Cheresh, D. A.; Schlaepfer, D. D. Differential regulation of cell motility and invasion by FAK. J. Cell Biol. 2003, 160, 753-767.
135. O-charoenrat, P.; Modjtahedi, H.; Rhys-Evans, P.; Court, W. J.; Box, G. M.; Eccles, S. A. Epidermal Growth Factor-like Ligands Differentially Up-regulate Matrix Metalloproteinase 9 in Head and Neck Squamous Carcinoma Cells. Cancer Res. 2000, 60, 1121-1128.
136. Schenk, S.; Hintermann, E.; Bilban, M.; Koshikawa, N.; Hojilla, C.; Khokha, R.; Quaranta, V. Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution. J. Cell Biol. 2003, 161, 197-209.
137. 2 Promotes Matrix Metalloproteinase-2-mediated Cell Migration via the Phosphatidylinositol 3-Kinase and Akt Pathway. J. Biol. Chem. 2004 279, 36579-36585.
138. Razandi, M.; Pedram, A.; Park, S. T.; Levin, E. R. Proximal Events in Signaling by Plasma membrane Estrogen Receptors. J. Biol. Chem. 2003, 278, 2701-2712.
139. Gilles, C.; Bassuk, J. A.; Pulyaeva, H.; Sage, E. H.; Foidart, J. -M.; Thompson, E. W. SPARC/Osteonbectin Induces Matrix Metalloproteinase 2 Activation in Human Breast Cancer Cell Lines. Cancer Res. 1998, 58, 5529-5536.
140. Yu, Q.; Stamenkovic, I. Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Gen. Dev. 1999, 13, 35-48.
141. Sledge, G. W. Jr.; Qulali, M.; Goulet, R.; Bone, E. A.; Fife, R. Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. J. Natl. Cancer Inst. 1995, 18, 1546-1550.
142. Conway, J. G.; Trexler, S. J.; Wakefield, J. A.; Marron, B. E.; Emerson, D. L.; Bickett, D. M.; Deaton, D. N.; Garrison, D.; Elder, M.; McElroy, A.; Willmott, N.; Dockerty, A. J.; McGeehan, G. M. Effect of matrix metalloproteinase inhibitors on tumor growth and spontaneous metastasis. Clin. Exp. Metastas. 1996, 14, 115-124.
143. Anderson, I. C.; Shipp, M. A.; Docherty, A. J.; Teicher, B. A. Combination therapy including a gelatinase inhibitor and cytotoxic agent reduces local invasion and metastasis of murine Lewis lung carcinoma. Cancer Res. 1996, 56, 715-718.
144. Shono, T.; Motoyama, M.; Tatsumi, K.; Ulbrich, N.; Iwamoto, Y.; Kuwano, M.; Ono, M. A new synthetic matrix metalloproteinase inhibitor modulates both angiogenesis and urokinase type plasminogen activator activity. Angiogenesis 1998, 2, 319-329.
145. Duffy, M. J.; McCarthy, K. Matrix metalloproteinases in cancer: prognostic markers and targets for therapy. Int. J. Oncol. 1998, 12, 1343-1348.
146. Henriet, P.; Blavier, L.; DeClerck, Y. A. Tissue inhibitors of metalloproteinases (TIMP) in invasion and proliferation. Acta Path. Micro. Immun. Scand. 1999, 107, 111-119.
147. Khokha, R.; Waterhouse, P.; Yagel, S.; Lala, P. K.; Overall, C. M.; Norton, G.; Denhardt, D. T. Antisense RNA-induced reduction in murine TIMP levels confers oncogenicity on Swiss 3T3 cells. Science 1989, 243, 947-950.
148. Denhardt, D. T.; Khokha, R.; Yagel, S.; Overall, C. M.; Parhar, R. S. Matrix 1992, (Suppl. 1), 281-285.
149. Mohanam, S.; Wang, S. W.; Rayford, A.; Yamamoto, M.; Sawaya, R.; Nakajima, M.; Liotta, L. A.; Nicolson, G. L.; Stetler-Stevenson, W. G.; Rao, J. S. Expression of tissue inhibitors of metalloproteinases: negative regulators of human glioblastoma invasion in vivo. Clin. Exp. Metastas. 1995, 13, 57-62.
150. Tsuchiya, Y.; Sato, H.; Endo, Y.; Okada, Y.; Mai, M.; Sasaki, T.; Seiki, M. Tissue inhibitor of metalloproteinase 1 is a negative regulator of the metastatic ability of a human gastric cancer cell line, KKLS, in the chick embryo. Cancer Res. 1993, 53, 1397-1402
151. Imren, S.; Kohn, D. B.; Shimada, H.; Blavier, L.; DeClerck, Y. A. Overexpression of tissue inhibitor of metalloproteinases-2 retroviral-mediated gene transfer in vivo inhibits tumor growth and invasion. Cancer Res. 1996, 56, 2891-2895.
152. Watanabe, M.; Takahashi, Y.; Ohta, T.; Mai., M.; Sasaki, T.; Seiki, M. Inhibition of metastasis in human gastric cancer cells transfected with tissue inhibitor of metalloproteinase 1 gene in nude mice. Cancer 1996, 77, 1676-1680.
153. Khokha, R. Suppression of the tumorigenic and metastatic abilities of murine B16-F10 melanoma cells in vivo by the overexpression of the tissue inhibitor of the metalloproteinases-1. J. Natl. Cancer Inst. 1994, 86, 299-304.
154. Khokha, R.; Zimmer, M. J.; Wilson, S. M.; Chambers, A. F. Upregulation of TIMP-1 expression in B16-F10 melanoma cells suppresses their metastatic ability in chick embryo. Clin. Exp. Metastas. 1992, 10, 365-370.
155. DeClerck, Y. A.; Perez, N.; Shimada, H.; Boone, T. C.; Langley, K. E.; Taylor, S. M. Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res. 1992, 52, 701-708.
156. Zhao, Y. -G.; Xiao, A. -Z.; Park, H. I.; Newcomer, R.; Yan, M.; Man, Y. -G.; Heffelfinger, S. C.; Sang, Q. -X. A. Endometase/ Matrilysin-2 in Human Breast Ductal Carcinoma in Situ and its Inhibition by Tissue Inhibitors of Metalloproteinases-2 and -4: A Putative Role in the Initiation of Breast Cancer Invasion. Cancer Res. 2004, 64, 590-598.
157. Wang, M.; Liu, Y. E.; Greene, J.; Sheng, S.; Fuchs, A.; Rosen, E. M.; Shi, Y. E. Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4. Oncogene 1997, 14, 2767-2774.
158. Brown, P. Clinical studies with matrix metalloproteinase inhibitors APMIS 1999, 107, 174-180.
159. Talbot, D. C.; Brown P. Experimental and clinical studies on the use of matrix metalloprtoeinases inhibitors for the treatment of cancer. Eur. J. Cancer 1996, 32A, 2528-2533.
160. Sloan, E. K.; Stanley, K. L.; Anderson, R. L. Caveolin-1 inhibits breast cancer growth and metastasis. Oncogene 2004, 23, 7893-7897.
161. Aharinejad, S.; Paulus, P.; Sioud, M.; Hofmann, M.; Zins, K.; Schafer, R.; Stanley, E. R.; Abraham, D. Colony-Stimulating Factor-1 Blockade by Antisense Oligonucleotides and Small Interfering RNAs Suppresses Growth of Human Mammary Tumor Xenografts in Mice. Cancer Res. 2004, 64, 5378-5384.
162. Salatino, M.; Schillaci, R.; Proietti, C. J.; Carnevale, R.; Frahm, I.; Molinolo, A. A.; Iribarren, A.; Charreau, E. H.; Elizalde, P. V. Inhibition of in vivo breast cancer growth by antisense oligodeoxynucleotides to type I insulin-like growth factor receptor mRNA involves inactivation of ErbBs, PI-3K/Akt and p42/p44 MAPK signaling pathways but not modulation of progesterone receptor activity. Oncogene 2004, 23, 5161-5174.
163. Weidner, N.; Semple, J. P.; Welch, W. R.; Folkman, J. Tumor angiogenesis and metastasis - correlation in invasive breast carcinoma. New Eng. J. Med. 1991, 324, 1-8.
164. Staller, P.; Sulitkova, J.; Lisztwan, J.; Moch, H.; Oakeley, E. J.; Krek, W. Chemokine receptor CXCR4 downregulated by von Hippel Lindau tumour suppressor pVHL. Nature 2003, 425, 307-311.
165. Liang, Z.; Wu, T.; Lou, H.; Yu, X.; Taichman, R. S.; Lau, S. K.; Nie, S.; Umbreit, J.; Shim, H. Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4. Cancer Res. 2004, 64, 4302-4308.
166. Sounni, N. E.; Devy, L.; Hajitou, A.; Frankenne, F.; Munaut, C.; Gilles, C.; Deroanne, C.; Thompson, E. W.; Foidhart, J. M.; Noel, A. MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression. FASEB 2002, 16, 555-564.
167. Ferrara, N.; Davis-Smyth, T. The biology of vascular endothelial growth factor. Endocrine Rev. 1997, 18, 4-25.
168. Neufeld, G.; Cohen, T.; Gengrinovitch, S.; Poltorak, Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999, 13, 9-22.
169. Waltenberger, J.; Claesson-Welsh, L.; Siegbahn, A.; Shibuya, M.; Heldin, C. H. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J. Biol. Chem. 1994, 269, 26988-26995.
170. D'Angelo, G.; Struman, I.; Martial, J.; Weiner, R. I. Activation of mitogen-activated protein kinases by vascular endothelial growth factor and basic fibroblast growth factor in capillary endothelial cells is inhibited by the antiangiogenic factor 16-kDa N-terminal fragment of prolactin. Proc. Natl. Acad. Sci. USA 1995, 92, 6374-6378.
171. Landgren, E.; Schiller, P.; Cao, Y.; Claesson-Welsh, L. Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-gamma and migration of endothelial cells expressing Flt 1. Oncogene 1998, 16, 359-367.
172. Heer, K.; Kumar, H.; Read, J. R.; Fox, J. N.; Monson, J. R. T.; Kerin, M. J. Serum Vascular Endothelial Growth Factor in Breast Cancer: Its Relation with Cancer Type and Estrogen Receptor Status. Clin. Cancer Res. 2001, 7, 3491-3494.
173. Lu, H.; Shu, X. O.; Cui, Y.; Kataoka, N.; Wen, W.; Cai, Q.; Ruan, Z. X.; Gao, Y. T.; Zheng, W. Association of genetic polymorphisms in the VEGF gene with breast cancer survival. Cancer Res. 2005, 65, 5015-5019.
174. Davis, S.; Aldrich, T. H.; Jones, P. F.; Acheson, A.; Compton, D. L.; Jain, V.; Ryan, T. E.; Bruno, J.; Radziejewski, C.; Maisonpierre, P. C.; Yancopoulos, G. D. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 1996, 87, 1161-1169.
175. Suri, C.; Jones, P. F.; Patan, S.; Bartunkova, S.; Maisonpierre, P. C.; Davis, S.; Sato, T. N.; Yancopoulos, G. D. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 1996, 87, 1171-1180.
176. Kim, I.; Kim, H. G.; So, J. N.; Kim, J. H.; Kwak, H. J.; Koh, G. Y. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3′-Kinase/Akt signal transduction pathway. Circ. Res. 2000, 86, 24-29.
177. Maisonpierre, P. C.; Suri, C.; Jones, P.; Bartunkova, S.; Wiegand, S. J.; Radziejewski, C.; Compton, D.; McClain, J.; Aldrich, T. H.; Papadopoulos, N.; Daly, T. J.; Davis, S.; Sato, T. N.; Yancopoulos, G.D. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997, 277, 55-60.
178. Suri, C.; McClain, J.; Thurston, G.; McDonald, D. M.; Oldmixon, E. H.; Sato, T. N.; Yancopoulos, G. D. Increased vascularization in mice overexpressing angiopoietin-1. Science 1998, 282, 468-471.
179. Currie, M. J.; Gunningham, S. P.; Han, C.; Scott, P. A. E.; Robinson, B. A.; Harris, A. L.; Fox, S. B. Angiopoietin-1 Is Inversely Related to Thymidine Phosphorylase Expression in Human Breast Cancer, Indicating a Role in Vascular Remodeling. Clin. Cancer Res. 2001, 7, 918-927.
180. Valenzuela, D. M.; Griffiths, J. A.; Rojas, J.; Aldrich, T. H.; Jones, P. F.; Zhou, H.; McClain, J.; Copeland, N. G.; Gilbert, D. J.; Jenkins, N. A.; Huang, T.; Papadopoulos, N.; Maisonpierre. P. C.; Davis, S.; Yancopoulos, G. D. Angiopoietins 3 and 4: diverging gene counterparts in mice and humans. Proc. Natl. Acad. Sci. USA 1999, 96, 1904-1909.
181. Shweiki, D.; Itin, A.; Soffer, D.; Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992, 359, 843-845.
182. Minchenko, A.; Bauer, T.; Salceda, S.; Caro, J. Hypoxic stimulation of vascular endothelial growth factor expression in vitro and in vivo. Lab. Invest. 1994, 71, 374-379.
183. Ryan, H. E.; Poloni, M.; McNulty, W.; Elson, D.; Gassmann, M.; Arbeit, M.; Johnson, R. S. Hypoxia-inducible factor-1α is a positive factor in solid tumour growth. Cancer Res. 2000, 60, 4010-4015.
184. Vaupel, P.; Kallinowski, F.; Okunieff, P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 1989, 49, 6449-6465.
185. Hill, S. A.; Pigott, K. H.; Saunders, M. I.; Powell, M. E. B.; Arnold, S.; Obeid, A.; Ward, G.; Leahy, M.; Hoskin, P. J.; Chaplin, D. J. Microregional blood flow in murine and human tumors assessed using laser Doppler microprobes. Br. J. Cancer 1996, 74, S260-S263.
186. Cohen-Jonathan, E.; Evans, S. M.; Koch, C. J.; Muschel, R. J.; McKenna, G.; Wu, J. M.; Bernhard, E. J. The farnesyltransferase inhibitor L744,832 reduces hypoxia in tumors expressing activated H-ras. Cancer Res. 2001, 61, 2289-2293.
187. Bos, R.; Zhong, H.; Hanrahan, C. F.; Mommers, E. C. M.; Semenza, G. L.; Pinedo, H. M.; Abeloff, M. D.; Simons, J. W.; van Diest, P. J.; van der Wall, E. Levels of hypoxia-inducible factor 1α during breast carcinogenesis. JNCI 2000, 93, 309-314.
188. Jiang, B. -H.; Agani, F.; Passaniti, A.; Semenza, G. L. V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res. 1997, 57, 5328-5335.
189. Maxwell, P. H.; Dachs, F. U.; Gleadle, J. M.; Nicholls, L. G.; Harris, A. L.; Stratford, I. J.; Hankinson, O.; Pugh, C. W.; Ratcliffe, P. J. Hypoxia-inducible factor 1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc. Natl. Acad. Sci. USA 1997, 94, 8104-8109.
190. Ravi, R.; Mookerjee, B.; Bhujwalla, Z. M.; Sutter, C. H.; Artemov, D.; Zeng, Q.; Dillehay, L. E.; Madnan, A.; Semenza, G. L.; Bedi, A. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes Dev. 2000, 14, 34-44.
191. Richard, D. E.; Berra, E.; Pouysseur, J. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1α (HIF-1α) and enhance the transcriptional activity of HIF-1. J. Biol. Chem. 1999, 274, 32631-32637.
192. Salnikow, K.; An, W. G.; Melillo, G.; Blagosklonny, M. V.; Costa, M. Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors. Carcinogenesis 1999, 20, 1819-1823.
193. Salnikow, K.; Costa, M.; Figg, W. D.; Blagosklonny, M. V. Hyperinducibility of hypoxia-responsive genes without p53/p21-dependent check-point in aggressive prostate cancer. Cancer Res. 2000, 60, 5630-5634.
194. Zhong, H.; De Marzo, A. M.; Laughner, E.; Lim, M.; Hilton, D. A.; Zagzag, D.; Buechler, P.; Issacs, W. B.; Semenza, G. L.; Simons, J. W. Overexpression of hypoxia-inducible factor 1α in common human cancers and their muetastases. Cancer Res. 1999, 59, 5830-5835.
195. Zhong, H.; Chiles, K.; Feldser, D.; Laughner, E.; Hanrahan, C.; Georgescu, M. -M.; Simmons, J. W.; Semenza, G. L. Modulation of HIF-1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells:implications for tumor angiogenesis and therapeutics. Cancer Res. 2000, 60, 1541-1545.
196. Zundel, W.; Schindler, C.; Haas-Kogan, D.; Koong, A.; Kaper, F.; Chen, E.; Gottschalk, A. R.; Ryan, H. E.; Johnson, R. S.; Jefferson, A. B.; Stokoe, D.; Giaccia, A. J. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 2000, 14, 391-396.
197. Laughner, E.; Taghavi, P.; Chiles, K.; Mahon, P. C.; Semenza, G. L. HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1α (HIF-1α) Synthesis: Novel Mechanisms for HIF-1 -Mediated Vascular Endothelial Growth Factor Expression. MCB 2001, 21, 3995-4004.
198. Lee, A. V. Location, location, location: regulation of breast cancer progression by the microenvironment. Breast Cancer Res. 2004, 6, 279-280.
199. Ruggeri, B.; Singh, J.; Gingrich, D.; Angles, T.; Albom, M.; Chang, H.; Robinson, C.; Hunter, K.; Dobrzanski, P.; Jones-Bolin, S.; Pritchard, S.; Aimone, L.; Klein-Szanto, A.; Herbert, J. M.; Bono, F.; Schaeffer, P.; Casellas, P.; Bourie, B.; Pili, R.; Isaacs, J.; Ator, M.; Hudkins, R.; Vaught, J.; Mallamo, J.; Dionne, C. CEP-7055: A Novel, Orally Active Pan Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases with Potent Antiangiogenic Activity and Antitumor Efficacy in Preclinical Models. Cancer Res. 2003, 63, 5978-5991.
200. Traxler, P.; Allegrini, P. R.; Brandt, R.; Brueggen, J.; Cozens, R.; Fabbro, D.; Grosios, K.; Lane, H. A.; McSheehy, P.; Mestan, J.; Meyer, T.; Tang, C.; Wartmann, M.; Wood, J.; Caravatti, G. AEE788: A Dual Family Epidermal Growth Factor Receptor/ErbB2 and Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor with Antitumor and Antiangiogenic Activity. Cancer Res. 2004, 64, 4931-4941.
201. Takei, Y.; Kadomatsu, K.; Yuzawa, Y.; Matsuo, S.; Muramatsu, T. A Small Interfering RNA Targeting Vascular Endothelial Growth Factor as Cancer Therapeutics. Cancer Res. 2004, 64, 3365-3370.
202. Wilhelm, S. M.; Carter, C.; Tang, L.; Wilkie, D.; McNabola, A.; Rong, H.; Chen, C.; Zhang, X.; Vincent, P.; McHugh, M.; Cao, Y.; Shujath, J.; Gawlak, S.; Eveleigh, D.; Rowley, B.; Liu, L.; Adnane, L.; Lynch, M.; Auclair, D.; Taylor, I.; Gedrich, R.; Voznesensky, A.; Riedl, B.; Post, L. E.; Bollag, G.; Trail, P. A. BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis. Cancer Res. 2004, 64, 7099-7109.
203. Denny, W. A.; Wilson, W. R. Tirapazamine: a bioreductive anticancer drug that exploits tumour hypoxia. Exp. Opin. Investig. Drugs 2000, 9, 2889-2901.
204. Johnson, C. A.; Kilpatrick, D.; von Roemeling, R.; Langer, C.; Graham, M. A.; Greenslade, D.; Kennedy, G.; Keenan, E.; O'Dwyer, P. J. Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors. J. Clin. Oncol. 1997, 15, 773-780.
205. Gatineau, M.; Rixe, O.; Chevalier, T. L. Tirapazamine with cisplatin and vinorelbine in patients with advanced non-small-cell lung cancer: a phase I/II study. Clin. Lung Cancer 2005, 6, 293-8
206. Patterson, A. V.; Saunders, M.; Chinje, E. C.; Talbot, D. C.; Harris, A. L.; Stratford, I. J. Importance of P450 reductase activity in determining sensitivity of breast tumor cells to the bioreductive drug, tirapazamine (SR4233) and RSU1069. Br. J. Cancer 1997, 76, 1338-1347.
207. Lin, E. Y.; Nguyen, A. V.; Russell, R. G.; Pollard, J. W. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 2001, 193, 727-740.
208. Leek, R. D.; Hunt, N. C.; Landers, R. J.; Lewis, C. E.; Royds, J. A.; Harris, A. L. Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J. Pathol. 2000, 190, 430-436.
209. Salvesen, H. B.; Akslen, L. A. Significance of tumour-associated macrophages, vascular endothelial growth factor and thrombospondin-1 expression for tumour angiogenesis and prognosis in endometrial carcinomas. Int. J. Cancer 1999, 84, 538-543.
210. Leek, R. D.; Landers, R.; Fox, S. B.; Ng, F.; Harris, A. L.; Lewis, C. E. Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma. Br. J. Cancer 1998, 77, 2246-2251.
211. Clark, A. S.; West, K.; Streicher, S.; Dennis, P. A. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol. Cancer Ther. 2002, 1, 707-717.
212. She, Q. B.; Solit, D.; Basso, A.; Moasser, M. M. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3′-kinase/Akt pathway signaling. Clin. Cancer Res. 2003, 9, 4340-4346.
213. Kim, R.; Toge, T. Changes in therapy for solid tumors: potential for overcoming drug resistance in vivo with molecular targeting agents. Surg. Today 2004, 34, 293-303.
214. Rogers, P. M.; Beale, P. J.; Al-Moundhri, M.; Boxall, F.; Patterson, L.; Valenti, M.; Raynaud, F.; Hobbs, S.; Johnston, S.; Kelland, L. R. Overexpression of BclXL in a human ovarian carcinoma cell line: paradoxic effects on chemosensitivity in vitro versus in vivo. Int. J. Cancer 2002, 97, 858-863.
215. Siddik, Z. H. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003, 22, 7265-7279.
216. He, Q.; Liang, C. H.; Lippard, S. J. Steroid hormones induce HMG1 overexpression and sensitize breast cancer cells to cisplatin and carboplatin. Proc. Natl. Acad. Sci. USA 2000, 97, 5768-5772.
217. Gowen, L. C.; Avrutskaya, A. V.; Latour, A. M.; Koller, B. H.; Leadon, S. A. BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 1998, 281, 1009-1012.
218. Husain, A.; He, G.; Venkatraman, E. S.; Spriggs, D. R. BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II). Cancer Res. 1998, 58, 1120-1123.
219. Slamon, D. J.; Clark, G. M.; Wong, S. G.; Levin, W. J.; Ullrich, A.; McGuire, W. L. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987, 235, 177-182.
220. Harris, A. L.; Nicholson, S.; Sainsbury, J. R. C.; Farndon, J.; Wright, C. Epidermal growth factor receptors in breast cancer: association with early relapse and death, poor response to hormones and interactions with neu. J. Steroid Biochem. 1998, 34, 123-131.
221. Hung, M. C.; Lau, Y. K. Basic science of HER-2/neu: a review. Semin. Oncol. 1999, 26, 51-59.
222. Zhou, B. P.; Liao, Y.; Xia, W.; Zou, Y.; Spohn, B.; Hung, M. C. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat. Cell Biol. 2001, 3, 973-982.
223. Slamon, D. J.; Godolphin, W.; Jones, L. A.; Holt, J. A.; Wong, S. G.; Keith, D. E.; Levin, W. J.; Stuart, S. G.; Udove, J.; Ullrich, A.; Press, M. F. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989, 244, 707-712.
224. Hengstler, J. G.; Lange, J.; Kett, A.; Dornhofer, N.; Meinert, R.; Arand, M.; Knapstein, P. G.; Becker, R.; Oesch, F.; Tanner, B. Contribution of c-erbB-2 and topoisomerase IIalpha to chemoresistance in ovarian cancer. Cancer Res. 1999, 59, 3206-3214.
225. Arteaga, C. L.; Winnier, A. R.; Poirier, M. C.; Lopez-Larraza, D. M.; Shawver, L. K.; Hurd, S. D.; Stewart, S. J. p185c-erbB-2 signal enhances cisplatin-induced cytotoxicity in human breast carcinoma cells: association between an oncogenic receptor tyrosine kinase and drug-induced DNA repair. Cancer Res. 1994, 54, 3758-3765.
226. Dickson, R. B.; Lippman, M. E. Estrogenic regulation of growth and polypeptide growth factor secretion in human breast carcinoma. Endocr. Rev. 1987, 8, 29-43.
227. Lippman, M. E.; Dickson, R. B. Mechanisms of growth control in normal and malignant breast epithelium. Recent Prog. Horm. Res. 1989, 45, 383-435.
228. Morris, R. G.; Hargreaves, A. D.; Duvall, E.; Wyllie, A. H. Hormone-induced cell death. 2. Surface changes in thymocytes undergoing apoptosis. Am. J. Pathol. 1984, 115, 426-436.
229. Huang, Y.; Ray, S.; Reed, J. C.; Ibrado, A. M.; Tang, C.; Nawabi, A.; Bhalla, K. Estrogen increases intracellular p26Bcl-2 to p21Bax ratios and inhibits taxol-induced apoptosis of human breast cancer MCF-7 cells. Breast Cancer Res. Treat. 1997, 42, 73-81.
230. Teixeira, C.; Reed, J. C.; Pratt, M. A. Estrogen promotes chemotherapeutic drug resistance by a mechanism involving Bcl-2 proto-oncogene expression in human breast cancer cells. Cancer Res. 1995, 55, 3902.
231. Krainer, M. Efficacy of combination therapy versus monotherapy. Breast Can. Res. Treat. 2003, 81, S11-S15.
232. Jiang, B. H.; Jiang, G.; Zheng, J. Z.; Lu, Z.; Hunter, T.; Vogt, P. K. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell. Growth Differ. 2001, 12, 363-369.
233. Fukuda, R.; Hirota, K.; Fan, F.; Jung, Y. D.; Ellis, L. M.; Semenza, G. L. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial cell growth factor expression, which is depedent on MAP kinase and PI-3-kinase signaling in colon cancer cells. J. Biol. Chem. 2002, 277, 38205-38211.
234. Tan, C.; Cruet-Hennequart, S.; Troussard, A.; Fazli, L.; Costello, P.; Sutton, K.; Wheeler, J.; Gleave, M.; Sanghera, J.; Dedhar, S. Regulation of tumor angiogenesis by integrin-linked kinase (ILK). Cancer Cell 2004, 5, 79-90.
235. Hannigan, G. E.; Leung-Hagesteijn, C.; Fitz-Gibbon, L.; Coppolino, M.; Radeva, G.; Filmus, J.; Bell, J. C.; Dedhar, S. Regulations of cell adhesion and anchorage-dependent growth by a new β1-integrin-linked protein kinase. Nature 1996, 379, 91-96.
236. Radeva, G.; Petrocelli, T.; Behrend, E.; Leung-Hagesteijn, C.; Filmus, J.; Slingerland, J.; Dedhar, S. Overexpression of the integrin-linked kinase promotes anchorage-independent cell cycle progression. J. Biol. Chem. 1997, 272, 13937-13944.
237. Attwell, S.; Roskelley, C.; Dedhar, S. The integrin-linked kinase (ILK) suppresses anoikis. Oncogene 2000, 19, 3811-3815.
238. Johnston, S. R. D.; Head, J.; Pancholi, S.; Detre, S.; Martin, L. -A.; Smith, I. E.; Dowsett, M. Integreation of Signal Transduction Inhibitors with Endocrine Therapy: An Approach to Overcoming Hormone Resistance in Breast Cancer. Clin. Cancer Res. 2003, 9, 524-532.
239. Clarke, C. L.; Sutherland, R. L. Progestin regulation of cellular proliferation. Endocr. Rev. 1990, 11, 266-301.
240. Kester, H. A.; van der Leede, B. M.; van der Saag, P. T.; van der Burg, B. Novel progesterone target genes identified by an improved differential display technique suggest that progestin-induced growth inhibition of breast cancer cells coincides with enhancement of differentiation. J. Biol. Chem. 1997, 272, 16637-16643.
241. Horwitz, K. B.; Mechanisms of hormone resistance in breast cancer. Breast Can. Res. Treat. 1993, 26, 119-130.
242. Knight, W. A. 3rd.; Osborne, C. K.; Yochmowitz, M. G.; McGuire, W. L. Steroid hormone receptors in the management of human breast cancer. Ann. Clin. Res. 1980, 12, 202-207.
243. Young, P. C.; Ehrlich, C. E.; Einhorn, L. H. Relationship between steroid receptors and response to endocrine therapy and cytotoxic chemotherapy in metastatic breast cancer. Cancer 1980, 46, 2961-2963.
244. Osborne, C. K.; Yochmowitz, M. G.; Knight, W. A. 3rd; McGuire, W. L. The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer 1980, 46, 2884-2888.
245. Sitruk-Ware, R.; Plu-Bureau, G.; Birrell, S. N.; Hall, R. E.; Tilley, W. D. Progestins and cancer. Gynecol. Endocrinol. 1999, 4, 3-9.
246. Groshong, S. D.; Owen, G. I.; Grimison, B.; Schauer, I. E.; Todd, M. C.; Langan, T. A.; Sclafani, R. A.; Lange, C. A.; Horwitz, K. B. Biphasic regulation of breast cancer cell growth by progesterone: role of the cyclin-dependent kinase inhibitors, p21 and p27(Kip1). Mol. Endocrinol. 1997, 11, 1593-1607.
247. Salcedo, R.; Martins-Green, M.; Gertz, B.; Oppenheim, J. J.; Murphy, W. J. Combined Administration of Antibodies to Human Interleukin 8 and Epidermal Growth Factor Receptor Results in Increased Antimetastatic Effects on Human Breast Carcinoma Xenografts. Clin. Cancer Res. 2002, 8, 2655-2665.
248. Kumar, R. Role of animal models in oncology drug discovery. Breast Cancer Res. 2003, 5, 15.
249. DeGeorge, J. J.; Ahn, C. H.; Andrews, P. A.; Brower, M. E.; Giorgio, D. W.; Goheer, M. A.; Lee-Ham, D. Y.; McGuinn, W. D.; Schmidt, W.; Sun, C. J.; Tripathi, S. C. Regulatory considerations for preclinical development of anticancer drugs. Cancer Chemother. Pharmacol. 1998, 41, 173-185.
250. Cardiff, R. D.; Wellings, S. R. The comparative pathology of human and mouse mammary glands. J. Mammary Gland Biol. Neoplasia 1999, 4, 105-122.
251. Wagner, K. -U. Models of breast cancer: quo vadis, animal modeling? Breast Cancer Res. 2003, 6, 31-38.
252. Wang, Y. Z.; Sudilovsky, D.; Zhang, B.; Haughney, P. C.; Rosen, M. A.; Wu, D. S.; Cunha, T. J.; Dahiya, R.; Cunha, G. R.; Hayward, S. W. A human prostatic epithelial model of hormonal carcinogenesis. Cancer Res. 2001, 61, 6064-6072.
253. Brinster, R.; Palmiter, R. Introduction of genes into the germ line of animals. Harvey Lect. 1984-1985, 80, 1-38.
254. Finkle, D.; Quan, Z. R.; Asghari, V.; Kloss, J.; Ghaboosi, N.; Mai, E.; Wong, W. L.; Hollingshead, P.; Schwall, R.; Koeppen, H.; Erickson, S. HER2-targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus huHER2-transgenic mice. Clin. Cancer Res. 2004, 10, 2499-2511.
255. Ko, J.; Shin, S. M.; Oh, Y. M.; Lee, Y. S.; Ryoo, Z. Y.; Lee, Y. H.; Na, D. S.; Kim, J. W. Transgenic mouse model for breast cancer: induction of breast cancer in novel oncogene HCCR-2 transgenic mice. Oncogene 2004, 23, 1950-1953.
256. Liu, M.; Howes, A.; Lesperance, J.; Stallcup, W. B.; Hauser, C. A.; Kadoya, K.; Oshima, R. G.; Abraham, R. T. Antitumor Activity of Rapamycin in a Transgenic Mouse Model of ErbB2-Dependent Human Breast Cancer. Cancer Res. 2005, 65, 5325-5336.
257. Gupta, V.; Carey, J. L.; Kawakubo, H.; Muzikansky, A.; Green, J. E.; Donahoe, P. K.; MacLaughlin, D. T.; Maheswaran, S. Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model. Proc. Natl. Acad. Sci. USA 2005, 102, 3219-3224.
258. Kim, J. B.; O'Hare, M. J.; Stein, R. Models of breast cancer: is merging human and animal models the future? Breast Cancer Res. 2004, 6, 22-30.
259. Zanzonico, P. Positron emission tomography: a review of basic principles, scanner design and performance, and current systems. Semin. Nucl. Med. 2004, 34, 87-111.
260. Symms, M.; Jager, H. R.; Schmierer, K.; Yousry, T. A. A review of structural magnetic resonance neuroimaging. J. Neurol. Neurosurg. Psychiatry 2004, 75, 1235-1244.
261. Maier, C. F.; Paran, Y.; Bendel, P.; Rutt, B. K.; Degani, H. Quantitative diffusion imaging in implanted human breast tumors. Magn. Reson. Med. 1997, 37, 576-581.
262. Desprechins, B.; Stadnik, T.; Koerts, G.; Shabana, W.; Breucq, C.; Osteaux, M. Use of diffusion-weighted MR imaging in differential diagnosis between intracerebral necrotic tumors and cerebral abscesses. Am. J. Neuroradiol. 1999, 20, 1252-1257.
263. Tofts, P. S.; Brix, G.; Buckley, D. L.; Evelhoch, J. L.; Henderson, E.; Knopp, M. V.; Larsson, H. B.; Lee, T. Y.; Mayr, N. A.; Parker, G. J.; Port, R. E.; Taylor, J.; Weisskoff, R. M. Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols. J. Magn. Reson. Imaging 1999, 10, 223-232.
264. Tropres, I.; Grimault, S.; Vaeth, A.; Grillon, E.; Julien, C.; Payen, J. F.; Lamalle, L.; Decorps, M. Vessel size imaging. Magn. Reson. Med. 2001, 45, 397-408.
265. Kost, G. J. pH standardization for phosphorus-31 magnetic resonance heart spectroscopy at different temperatures. Magn. Reson. Med. 1990, 14, 496-506.
266. Dolbier, W. R., Jr.; Li, A. R.; Koch, C. J.; Shiue, C. Y.; Kachur, A. V. [18F]-EF5, a marker for PET detection of hypoxia: synthesis of precursor and a new fluorination procedure. Appl. Radiat. Isot. 2001, 54, 73-80.
267. Koch, C. J.; Evans, S. M.; Lord, E. M. Oxygen dependence of cellular uptake of EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)a cet amide]: analysis of drug adducts by fluorescent antibodies vs bound radioactivity. Br. J. Cancer 1995, 72, 869-874.
268. Koch, C. J.; Hahn, S. M.; Rockwell, K., Jr.; Covey, J. M.; McKenna, W. G.; Evans, S. M. Pharmacokinetics of EF5 [2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2, 3,3,3-pentafluoropropyl) acetamide]in human patients: implications for hypoxia measurements in vivo by 2-nitroimidazoles. Cancer Chemother. Pharmacol. 2001, 48, 177-187.
269. Laughlin, K. M.; Evans, S. M.; Lord, E. M.; Koch, C. J. Biodistribution of the nitroimidazole EF5 (2-[2-nitro-1H-imidazol-1-yl]-N-(2,2,3,3,3- pentafluoropropyl)acetamide) in mice bearing subcutaneous EMT6 tumors. J. Pharm. Exp. Ther. 1996, 277, 1049-1057.
270. Lord, E. M.; Harwell, L.; Koch, C. J. Detection of hypoxic cells by monoclonal antibody recognizing 2-nitroimidazole adducts. Cancer Res. 1993, 53, 5721-5726.
271. Ziemer, L. S.; Evans, S. M.; Kachur, A. V.; Shuman, A. L.; Cardi, C. A.; Jenkins, W. T.; Karp, J. S.; Alavi, A.; Dolbier, W. R., Jr.; Koch, C. J. Noninvasive imaging of tumor hypoxia in rats using the 2-nitroimidazole 18F-EF5. Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 259-266.
272. Couturier, O.; Luxen, A.; Chatal, J. F.; Vuillez, J. P.; Rigo, P.; Hustinx, R. Fluorinated tracers for imaging cancer with positron emission tomography. Eur. J. Nucl. Med. Mol. Imaging 2004, 31, 1182-1206.
273. Galasko, C. S. The pathological basis for skeletal scintigraphy. J. Bone Joint Surg. Br. 1975, 57, 353-359.
274. Berger, F., Lee, Y. P., Loening, A. M., Chatziioannou, A., Freedland, S. J., Leahy, R., Lieberman, J. R., Belldegrun, A. S., Sawyers, C. L., Gambhir, S. S. Whole-body skeletal imaging in mice utilizing microPET: optimization of reproducibility and applications in animal models of bone disease. Eur. J. Nucl. Med. Mol. Imaging 2002, 29, 1225-1236.
275. Messa, C.; Goodman, W. G.; Hoh, C. K.; Choi, Y.; Nissenson, A. R.; Salusky, I. B.; Phelps, M. E.; Hawkins, R. A. Bone metabolic activity measured with positron emission tomography and [18F]fluoride ion in renal osteodystrophy: correlation with bone histomorphometry. J. Clin. Endocrinol. Metab. 1993, 77, 949-955.
276. Kozlowski, P.; Wong J.; Goldenberg S. L. Serial Tumour Blood Flow Measurements in the Androgen Dependent and Androgen Independent Shionogi Tumour Model. Br. J. Urol. 2005, 95, 644-649.
277. Goodwin, J. S.; Ceuppens, J. Regulation of the immune response by prostaglandins. J. Clin. Immun. 1983, 3, 295-315.
278. Sheng, H.; Shao, J.; Morrow, J. D.; Beauchamp, R. D.; DuBois, R. N. Modulation of apoptosis by Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res. 1998, 58, 362-366.
279. Tsujii, M.; Kawano, S.; DuBois, R. N. Cyclooxygenase-2 expresssion in human colon cancer cells increases the metastatic potential. Proc. Natl. Acad. Sci. USA 1997, 94, 3336-3340.
280. Tsujii, M.; Kawano, S.; Tsuji, S.; Sawaoka, H.; Hori, M.; DuBois, R. N. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998, 93, 705-716.
281. Subbaramaiah, K.; Dannenberg, A. J. Cyclooxygenase-2: a molecular target for cancer prevention and treatment. Trends Pharm. Sci. 2003, 24, 96-102.
282. Boland, G. P.; Butt, I. S.; Prasad, R.; Knox, F.; Bundred N. J. COX-2 and HER2 expression are related in ductal carcinoma in situ (DCIS) Breast Cancer Res. Treat. 2002, 76, 469a.
283. Soslow, R. A.; Dannenberg, A. J.; Rush, D.; Woerner, B. M.; Khan, K. N.; Masferrer, J.; Koki. A. T. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 2000, 89, 2637-2645.
284. Dang, C. T.; Dannenberg, A. J.; Subbaramaiah, K.; Dickler, M. N.; Moasser, M. M.; Seidman, A. D.; D'Andrea, G. M.; Theodoulou, M.; Panageas, K. S.; Norton, L.; Hudis, C. A. Phase II Study of Celecoxib and Trastuzumab in Metastatic Breast Cancer Patients Who Have Progressed after Prior Trastuzumab-Based Treatments Clin. Cancer Res. 2004, 10, 4062-4067.
285. Tan, A. R.; Yang, X.; Berman, A.; Zhai, S.; Sparreboom, A.; Parr, A. L.; Chow, C.; Brahim, J. S.; Steinberg, S. M.; Figg, W. D.; Swain, S. M. Phase I Trial of the Cyclin-Dependent Kinase Inhibitor Flavopiridol in Combination with Docetaxel in Patients with Metastatic Breast Cancer. Clin. Cancer Res. 2004, 10, 5038-5077.
286. Argiris, A.; Wang, C. -X.; Whalen, S. G.; DiGiovanna, M. P. Synergistic Interactions between Tamoxifen and Trastuzumab (Herceptin) Clin Cancer Res. 2004, 10, 1409-1420.
287. Tortora, G.; Caputo, R.; Damiano, V.; Melisi, D. Combination of a Selective Cyclooxygenase-2 Inhibitor with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 and Protein Kinase A Antisense Causes Cooperative Antitumor and Antiangiogenic Effect. Clin. Cancer Res. 2002, 9, 1566-1572.
288. Von Eschenbach, A. C. A vision for the National Cancer Program in the United States. Nat. Rev. Cancer 2004, 4, 820-828.
289. Mosby's Drug Consult. Elsevier. http://www.mosbysdrugconsult. com/DrugConsult/. 2005.
290. U.S. Food and Drug Administration. Definition of a combination product. http://www.fda.gov/oc/combination/definition.html (accessed June 2005).
291. Sorlie, T.; Perou, C. M.; Tibshirani, R.; Aas, T.; Geisler, S.; Johnsen, H.; Hastie, T.; Eisen, M. B.; van de Rijn, M.; Jeffrey, S. S.; Thorsen, T.; Quist, H.; Matese, J. C.; Brown, P. O.; Botstein, D.; Eystein Lonning, P.; Borresen-Dale, A. L. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl. Acad. Sci. USA 2001, 98, 10869-10874.
292. van 't Veer, L. J.; Dai, H.; van de Vijver, M. J.; He, Y. D.; Hart, A. A.; Mao, M.; Peterse, H. L.; van der Kooy, K.; Marton, M. J.; Witteveen, A. T.; Schreiber, G. J.; Kerkhoven, R. M.; Roberts, C.; Linsley, P. S.; Bernards, R.; Friend, S. H. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002, 415, 530-536.
293. Wang, J.; Buchholz, T. A.; Middleton, L. P.; Allred, D. C.; Tucker, S. L.; Kuerer, H. M.; Esteva, F. J.; Hortobagyi, G. N.; Sahin, A. A. Assessment of histologic features and expression of biomarkers in predicting pathologic response to anthracycline-based neoadjuvant chemotherapy in patients with breast carcinoma. Cancer 2002, 94, 3107-3114.
294. Allred, D. C.; Clark, G. M.; Tandon, A. K.; Molina, R.; Tormey, D. C.; Osborne, C. K.; Gilchrist, K. A. W.; Mansour, E. G.; Abeloff, M.; Eudey, L.; McGuire, W. L. HER2/neu in nodenegative breast cancer: prognostic significance of overexpression influenced by the presence of in situ carcinoma. J. Clin. Oncol. 1992, 10, 599-605.
295. Paik, S.; Hazan, R.; Fisher, E. R.; Sass, R. E.; Fisher, B.; Redmond, C.; Schlessinger, J.; Lippman, M. E.; King, C. R. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J. Clin. Oncol. 1990, 8, 103-112.
296. Pich, A.; Margaria, E.; Chiusa, L. Oncogenes and male breast carcinoma: c-erbB-2 and p53 coexpression predicts a poor survival. J. Clin. Oncol. 2000, 18, 2948-2956.