PTEN hamartomatous tumor syndromes (PHTS): Rare syndromes with great relevance to common cancers and targeted drug development

Critical Reviews in Oncology/Hematology

Volumn 63, Issue 3, 2007, Pages 203-214

  LoPiccolo, Jaclyn ^a   Ballas, Marc S ^a   Dennis, Phillip A ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

Author keywords

Cowden syndrome; mTOR; PHTS; PTEN

Indexed keywords

3 INDOLEMETHANOL; 7 HYDROXYSTAUROSPORINE; CELECOXIB; CURCUMIN; DEGUELIN; DIALLYL TRISULFIDE; EVEROLIMUS; GENISTEIN; INOSITOL; LUPEOL; LUTEOLIN; LYCOPENE; MAMMALIAN TARGET OF RAPAMYCIN; NOBILETIN; PERIFOSINE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; QUERCETIN; RAPAMYCIN; SAPONIN DERIVATIVE; TEMSIROLIMUS;

AUTOSOMAL DOMINANT DISORDER; BANNAYAN RILEY RUVALCABA SYNDROME; BREAST CANCER; CARCINOGENESIS; CELL SURVIVAL; CELL TRANSFORMATION; CLINICAL FEATURE; CLINICAL TRIAL; COWDEN SYNDROME; DEGRADATION; DRUG EFFECT; DRUG EFFICACY; DRUG STRUCTURE; EARLY DIAGNOSIS; GENOTYPE PHENOTYPE CORRELATION; GERM LINE; HIGH RISK POPULATION; HUMAN; LHERMITTE DUCLOS DISEASE; METHYLATION; MULTIPLE CANCER; PRIMARY PREVENTION; PROTEIN DEPLETION; PROTEIN FUNCTION; PTEN HAMARTOMATOUS TUMOR SYNDROME; REVIEW; SIGNAL TRANSDUCTION; SOMATIC MUTATION; SYNDROME;

DRUG DELIVERY SYSTEMS; HAMARTOMA SYNDROME, MULTIPLE; HUMANS; NEOPLASMS; PTEN PHOSPHOHYDROLASE; SIGNAL TRANSDUCTION;

EID: 34547148932     PISSN: 10408428     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.critrevonc.2007.06.002     Document Type: Review

References (122)

1. Li J., Yen C., Liaw D., et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275 5308 (1997) 1943-1947
2. Zhou X.P., Loukola A., Salovaara R., et al. PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers. Am J Pathol 161 2 (2002) 439-447
3. Zhou X., Hampel H., Thiele H., et al. Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. Lancet 358 9277 (2001) 210-211
4. Marsh D.J., Coulon V., Lunetta K.L., et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet 7 3 (1998) 507-515
5. Cantley L.C., and Neel B.G. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 96 8 (1999) 4240-4245
6. Zhou X.P., Waite K.A., Pilarski R., et al. Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am J Hum Genet 73 2 (2003) 404-411
7. Eng C. PTEN: one gene, many syndromes. Hum Mutat 22 3 (2003) 183-198
8. Vantomme N., Van Calenbergh F., Goffin J., Sciot R., Demaerel P., and Plets C. Lhermitte-Duclos disease is a clinical manifestation of Cowden's syndrome. Surg Neurol 56 3 (2001) 201-204 [discussion 4-5]
9. Capone Mori A., Hoeltzenbein M., Poetsch M., Schneider J.F., Brandner S., and Boltshauser E. Lhermitte-Duclos disease in 3 children: a clinical long-term observation. Neuropediatrics 34 1 (2003) 30-35
10. Marsh D.J., Kum J.B., Lunetta K.L., et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 8 8 (1999) 1461-1472
11. Marsh D.J., Dahia P.L., Zheng Z., et al. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nat Genet 16 4 (1997) 333-334
12. Cohen Jr. M.M. Proteus syndrome: an update. Am J Med Genet C Semin Med Genet 137 1 (2005) 38-52
13. Starink T.M., van der Veen J.P., Arwert F., et al. The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet 29 3 (1986) 222-233
14. Schrager C.A., Schneider D., Gruener A.C., Tsou H.C., and Peacocke M. Clinical and pathological features of breast disease in Cowden's syndrome: an underrecognized syndrome with an increased risk of breast cancer. Hum Pathol 29 1 (1998) 47-53
15. Simpson L., Li J., Liaw D., et al. Pten expression causes feedback upregulation of insulin receptor substrate 2. Mol Cell Biol 21 12 (2001) 3947-3958
16. Weng L.P., Smith W.M., Brown J.L., and Eng C. PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model. Hum Mol Genet 10 6 (2001) 605-616
17. Shen W.H., Balajee A.S., Wang J., et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128 1 (2007) 157-170
18. Vivanco I., and Sawyers C.L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2 7 (2002) 489-501
19. Kim D.K., Myung S.J., Yang S.K., et al. Analysis of PTEN gene mutations in Korean patients with Cowden syndrome and polyposis syndrome. Dis Colon Rectum 48 9 (2005) 1714-1722
20. Torres J., and Pulido R. The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation. J Biol Chem 276 2 (2001) 993-998
21. Torres J., Rodriguez J., Myers M.P., et al. Phosphorylation-regulated cleavage of the tumor suppressor PTEN by caspase-3: implications for the control of protein stability and PTEN-protein interactions. J Biol Chem 278 33 (2003) 30652-30660
22. Vazquez F., Ramaswamy S., Nakamura N., and Sellers W.R. Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol 20 14 (2000) 5010-5018
23. Trotman L.C., Wang X., Alimonti A., et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128 1 (2007) 141-156
24. Wang X., Trotman L.C., Koppie T., et al. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128 1 (2007) 129-139
25. Di Cristofano A., Pesce B., Cordon-Cardo C., and Pandolfi P.P. Pten is essential for embryonic development and tumour suppression. Nat Genet 19 4 (1998) 348-355
26. Suzuki A., de la Pompa J.L., Stambolic V., et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol 8 21 (1998) 1169-1178
27. Podsypanina K., Ellenson L.H., Nemes A., et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci USA 96 4 (1999) 1563-1568
28. Luo J., Sobkiw C.L., Logsdon N.M., et al. Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/- mice by the p85 regulatory subunits of phosphoinositide 3-kinase. Proc Natl Acad Sci USA 102 29 (2005) 10238-10243
29. Furnari F.B., Lin H., Huang H.S., and Cavenee W.K. Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. Proc Natl Acad Sci USA 94 23 (1997) 12479-12484
30. Davies M.A., Lu Y., Sano T., et al. Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis. Cancer Res 58 23 (1998) 5285-5290 [published erratum appears in Cancer Res 1999 March 1;59(5):1167]
31. Davies M.A., Kim S.J., Parikh N.U., Dong Z., Bucana C.D., and Gallick G.E. Adenoviral-mediated expression of MMAC/PTEN inhibits proliferation and metastasis of human prostate cancer cells. Clin Cancer Res 8 6 (2002) 1904-1914
32. Stambolic V., Suzuki A., de la Pompa J.L., et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95 1 (1998) 29-39
33. Faisal Ahmed S., Marsh D.J., Weremowicz S., Morton C.C., Williams D.M., and Eng C. Balanced translocation of 10q and13q, including the PTEN gene, in a boy with a human chorionic gonadotropin-secreting tumor and the Bannayan-Riley-Ruvalcaba syndrome. J Clin Endocrinol Metab 84 12 (1999) 4665-4670
34. Trotman L.C., Niki M., Dotan Z.A., et al. Pten dose dictates cancer progression in the prostate. PLoS Biol 1 3 (2003) E59
35. Yeager N., Klein-Szanto A., Kimura S., and Di Cristofano A. Pten loss in the mouse thyroid causes goiter and follicular adenomas: insights into thyroid function and Cowden disease pathogenesis. Cancer Res 67 3 (2007) 959-966
36. Dinulescu D.M., Ince T.A., Quade B.J., Shafer S.A., Crowley D., and Jacks T. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med 11 1 (2005) 63-70
37. You M.J., Castrillon D.H., Bastian B.C., et al. Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice. Proc Natl Acad Sci USA 99 3 (2002) 1455-1460
38. Xiao A., Wu H., Pandolfi P.P., Louis D.N., and Van Dyke T. Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation. Cancer Cell 1 2 (2002) 157-168
39. Li Y., Podsypanina K., Liu X., et al. Deficiency of Pten accelerates mammary oncogenesis in MMTV-Wnt-1 transgenic mice. BMC Mol Biol 2 1 (2001) 2
40. Lloyd II K.M., and Dennis M. Cowden's disease. A possible new symptom complex with multiple system involvement. Ann Intern Med 58 (1963) 136-142
41. Liaw D., Marsh D.J., Li J., et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16 1 (1997) 64-67
42. Woodhouse J., and Ferguson M.M. Multiple hyperechoic testicular lesions are a common finding on ultrasound in Cowden disease and represent lipomatosis of the testis. Br J Radiol 79 946 (2006) 801-803
43. Longy M., and Lacombe D. Cowden disease. Report of a family and review. Ann Genet 39 1 (1996) 35-42
44. Nelen M.R., Padberg G.W., Peeters E.A., et al. Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet 13 1 (1996) 114-116
45. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 37 11 (2000) 828-830
46. Abel T.W., Baker S.J., Fraser M.M., et al. Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway. J Neuropathol Exp Neurol 64 4 (2005) 341-349
47. Ruvalcaba R.H., Myhre S., and Smith D.W. Sotos syndrome with intestinal polyposis and pigmentary changes of the genitalia. Clin Genet 18 6 (1980) 413-416
48. Bannayan G.A. Lipomatosis, angiomatosis, and macrencephalia. A previously undescribed congenital syndrome. Arch Pathol 92 1 (1971) 1-5
49. Zonana J., Rimoin D.L., and Davis D.C. Macrocephaly with multiple lipomas and hemangiomas. J Pediatr 89 4 (1976) 600-603
50. Gorlin R.J., Cohen Jr. M.M., Condon L.M., and Burke B.A. Bannayan-Riley-Ruvalcaba syndrome. Am J Med Genet 44 3 (1992) 307-314
51. Marsh D.J., Dahia P.L., Zheng Z., et al. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nat Genet 16 4 (1997) 333-334 [letter]
52. Marsh D.J., Dahia P.L., Caron S., et al. Germline PTEN mutations in Cowden syndrome-like families. J Med Genet 35 11 (1998) 881-885
53. Cohen M. Urinary tract infection re circumcision. J Pediatr 94 5 (1979) 851-852
54. Wiedemann H.R., Burgio G.R., Aldenhoff P., Kunze J., Kaufmann H.J., and Schirg E. The proteus syndrome. Partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies and possible accelerated growth and visceral affections. Eur J Pediatr 140 1 (1983) 5-12
55. Smith J.M., Kirk E.P., Theodosopoulos G., et al. Germline mutation of the tumour suppressor PTEN in Proteus syndrome. J Med Genet 39 12 (2002) 937-940
56. Cohen Jr. M.M., Turner J.T., and Biesecker L.G. Proteus syndrome: misdiagnosis with PTEN mutations. Am J Med Genet A 122 4 (2003) 323-324
57. Turner J.T., Cohen Jr. M.M., and Biesecker L.G. Reassessment of the Proteus syndrome literature: application of diagnostic criteria to published cases. Am J Med Genet A 130 2 (2004) 111-122
58. Zhou X.P., Marsh D.J., Hampel H., Mulliken J.B., Gimm O., and Eng C. Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis. Hum Mol Genet 9 5 (2000) 765-768
59. Brownstein M.H., Wolf M., and Bikowski J.B. Cowden's disease: a cutaneous marker of breast cancer. Cancer 41 6 (1978) 2393-2398
60. Meijers-Heijboer H., van Geel B., van Putten W.L., et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 345 3 (2001) 159-164
61. Hartmann L.C., Sellers T.A., Schaid D.J., et al. Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst 93 21 (2001) 1633-1637
62. Guillem J.G., Wood W.C., Moley J.F., et al. ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol 24 28 (2006) 4642-4660
63. Kim H.W., Park I.K., Cho C.S., et al. Aerosol delivery of glucosylated polyethylenimine/phosphatase and tensin homologue deleted on chromosome 10 complex suppresses Akt downstream pathways in the lung of K-ras null mice. Cancer Res 64 21 (2004 Nov 1) 7971-7976
64. Cavazzana-Calvo M., Hacein-Bey S., de Saint Basile G., et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288 5466 (2000) 669-672
65. Hacein-Bey-Abina S., Von Kalle C., Schmidt M., et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302 5644 (2003) 415-419
66. Harvey B.G., Leopold P.L., Hackett N.R., et al. Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus. J Clin Invest 104 9 (1999) 1245-1255
67. Zabner J., Ramsey B.W., Meeker D.P., et al. Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis. J Clin Invest 97 6 (1996) 1504-1511
68. Chinni S.R., and Sarkar F.H. Akt inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells. Clin Cancer Res 8 4 (2002) 1228-1236
69. Palozza P., Sheriff A., Serini S., et al. Lycopene induces apoptosis in immortalized fibroblasts exposed to tobacco smoke condensate through arresting cell cycle and down-regulating cyclin D1, pAKT and pBad. Apoptosis 10 6 (2005) 1445-1456
70. Saleem M., Kaur S., Kweon M.H., Adhami V.M., Afaq F., and Mukhtar H. Lupeol, a fruit and vegetable based triterpene, induces apoptotic death of human pancreatic adenocarcinoma cells via inhibition of Ras signaling pathway. Carcinogenesis 26 11 (2005) 1956-1964
71. Ellington A.A., Berhow M., and Singletary K.W. Induction of macroautophagy in human colon cancer cells by soybean B-group triterpenoid saponins. Carcinogenesis 26 1 (2005) 159-167
72. Ellington A.A., Berhow M.A., and Singletary K.W. Inhibition of Akt signaling and enhanced ERK1/2 activity are involved in induction of macroautophagy by triterpenoid B-group soyasaponins in colon cancer cells. Carcinogenesis 27 2 (2006) 298-306
73. Li Y., and Sarkar F.H. Inhibition of nuclear factor kappaB activation in PC3 cells by genistein is mediated via Akt signaling pathway. Clin Cancer Res 8 7 (2002) 2369-2377
74. Dave B., Eason R.R., Till S.R., et al. The soy isoflavone genistein promotes apoptosis in mammary epithelial cells by inducing the tumor suppressor PTEN. Carcinogenesis 26 10 (2005) 1793-1803
75. Chinni S.R., Alhasan S.A., Multani A.S., Pathak S., and Sarkar F.H. Pleotropic effects of genistein on MCF-7 breast cancer cells. Int J Mol Med 12 1 (2003) 29-34
76. Hu H., Jiang C., Li G., and Lu J. PKB/AKT and ERK regulation of caspase-mediated apoptosis by methylseleninic acid in LNCaP prostate cancer cells. Carcinogenesis 26 8 (2005) 1374-1381
77. Xiao D., Herman-Antosiewicz A., Antosiewicz J., et al. Diallyl trisulfide-induced G(2)-M phase cell cycle arrest in human prostate cancer cells is caused by reactive oxygen species-dependent destruction and hyperphosphorylation of Cdc 25 C. Oncogene 24 41 (2005) 6256-6268
78. Xiao D., and Singh S.V. Diallyl trisulfide, a constituent of processed garlic, inactivates Akt to trigger mitochondrial translocation of BAD and caspase-mediated apoptosis in human prostate cancer cells. Carcinogenesis 27 3 (2006) 533-540
79. Pianetti S., Guo S., Kavanagh K.T., and Sonenshein G.E. Green tea polyphenol epigallocatechin-3 gallate inhibits Her-2/neu signaling, proliferation, and transformed phenotype of breast cancer cells. Cancer Res 62 3 (2002) 652-655
80. Klein R.D., and Fischer S.M. Black tea polyphenols inhibit IGF-I-induced signaling through Akt in normal prostate epithelial cells and Du145 prostate carcinoma cells. Carcinogenesis 23 1 (2002) 217-221
81. Sato T., Koike L., Miyata Y., et al. Inhibition of activator protein-1 binding activity and phosphatidylinositol 3-kinase pathway by nobiletin, a polymethoxy flavonoid, results in augmentation of tissue inhibitor of metalloproteinases-1 production and suppression of production of matrix metalloproteinases-1 and -9 in human fibrosarcoma HT-1080 cells. Cancer Res 62 4 (2002) 1025-1029
82. Xagorari A., Papapetropoulos A., Mauromatis A., Economou M., Fotsis T., and Roussos C. Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and proinflammatory cytokine production in macrophages. J Pharmacol Exp Ther 296 1 (2001) 181-187
83. Yoshizumi M., Tsuchiya K., Kirima K., Kyaw M., Suzaki Y., and Tamaki T. Quercetin inhibits Shc- and phosphatidylinositol 3-kinase-mediated c-Jun N-terminal kinase activation by angiotensin II in cultured rat aortic smooth muscle cells. Mol Pharmacol 60 4 (2001) 656-665
84. Kumar A.P., Garcia G.E., Ghosh R., Rajnarayanan R.V., Alworth W.L., and Slaga T.J. 4-Hydroxy-3-methoxybenzoic acid methyl ester: a curcumin derivative targets Akt/NF kappa B cell survival signaling pathway: potential for prostate cancer management. Neoplasia 5 3 (2003) 255-266
85. Lee H.Y., Oh S.H., Woo J.K., et al. Chemopreventive effects of deguelin, a novel Akt inhibitor, on tobacco-induced lung tumorigenesis. J Natl Cancer Inst 97 22 (2005) 1695-1699
86. Chun K.H., Kosmeder II J.W., Sun S., et al. Effects of deguelin on the phosphatidylinositol 3-kinase/akt pathway and apoptosis in premalignant human bronchial epithelial cells. J Natl Cancer Inst 95 4 (2003) 291-302
87. Hsu A.L., Ching T.T., Wang D.S., Song X., Rangnekar V.M., and Chen C.S. The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2. J Biol Chem 275 15 (2000) 11397-11403
88. Arico S., Pattingre S., Bauvy C., et al. Celecoxib induces apoptosis by inhibiting 3-phosphoinositide-dependent protein kinase-1 activity in the human colon cancer HT-29 cell line. J Biol Chem 277 31 (2002) 27613-27621
89. Wattenberg L.W., and Estensen R.D. Chemopreventive effects of myo-inositol and dexamethasone on benzo[a]pyrene and 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone-induced pulmonary carcinogenesis in female A/J mice. Cancer Res 56 22 (1996) 5132-5135
90. Wattenberg L.W., Wiedmann T.S., Estensen R.D., et al. Chemoprevention of pulmonary carcinogenesis by brief exposures to aerosolized budesonide or beclomethasone dipropionate and by the combination of aerosolized budesonide and dietary myo-inositol. Carcinogenesis 21 2 (2000) 179-182
91. Hecht S.S., Kenney P.M., Wang M., and Upadhyaya P. Dose-response study of myo-inositol as an inhibitor of lung tumorigenesis induced in A/J mice by benzo. Cancer Lett 167 1 (2001) 1-6
92. Maffucci T., Piccolo E., Cumashi A., et al. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects. Cancer Res 65 18 (2005) 8339-8349
93. Piccolo E., Vignati S., Maffucci T., et al. Inositol pentakisphosphate promotes apoptosis through the PI 3-K/Akt pathway. Oncogene 23 9 (2004) 1754-1765
94. Meuillet E.J., Mahadevan D., Vankayalapati H., et al. Specific inhibition of the Akt1 pleckstrin homology domain by d-3-deoxy-phosphatidyl-myo-inositol analogues. Mol Cancer Ther 2 4 (2003) 389-399
95. Levine J., Barak Y., Gonzalves M., et al. Double-blind, controlled trial of inositol treatment of depression. Am J Psychiatry 152 5 (1995) 792-794
96. Gelber D., Levine J., and Belmaker R.H. Effect of inositol on bulimia nervosa and binge eating. Int J Eat Disord 29 3 (2001) 345-348
97. Palatnik A., Frolov K., Fux M., and Benjamin J. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol 21 3 (2001) 335-339
98. Gregersen G., Bertelsen B., Harbo H., et al. Oral supplementation of myoinositol: effects on peripheral nerve function in human diabetics and on the concentration in plasma, erythrocytes, urine and muscle tissue in human diabetics and normals. Acta Neurol Scand 67 3 (1983) 164-172
99. Lam S., McWilliams A., LeRiche J., MacAulay C., Wattenberg L., and Szabo E. A phase I study of myo-inositol for lung cancer chemoprevention. Cancer Epidemiol Biomarkers Prev 15 8 (2006) 1526-1531
100. Stambolic V., Tsao M.S., Macpherson D., Suzuki A., Chapman W.B., and Mak T.W. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice. Cancer Res 60 13 (2000) 3605-3611
101. Shi Y., Gera J., Hu L., et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 62 17 (2002) 5027-5034
102. Neshat M.S., Mellinghoff I.K., Tran C., et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 98 18 (2001) 10314-10319
103. Yu K., Toral-Barza L., Discafani C., et al. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 8 3 (2001) 249-258
104. Cao C., Subhawong T., Albert J.M., et al. Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res 66 20 (2006) 10040-10047
105. Douros J., and Suffness M. New antitumor substances of natural origin. Cancer Treat Rev 8 1 (1981) 63-87
106. Eng C.P., Sehgal S.N., and Vezina C. Activity of rapamycin (AY-22, 989) against transplanted tumors. J Antibiot (Tokyo) 37 10 (1984) 1231-1237
107. Houchens D.P., Ovejera A.A., Riblet S.M., and Slagel D.E. Human brain tumor xenografts in nude mice as a chemotherapy model. Eur J Cancer Clin Oncol 19 6 (1983) 799-805
108. Raymond E., Alexandre J., Depenbrock I.L., et al. CCI-779, a rapamycin analog with antitumor activity: a phase I study utilizing a weekly schedule. Proc Am Soc Clin Oncol (2000)
109. Forouzesh B., Buckner J., Adjei A., et al. Phase I, bioavailability, and pharmacokinetic study of oral dosage of CCI-779 administered to patients with advanced solid malignancies. Eur J Cancer 38 (2002)
110. Buckner J., Prados M., Rowinsky E., et al. A phase I study of the safety tolerability, and pharmakokinetics of intravenous CCI-779 given once daily for 5 days every 2 weeks to patients with CNS tumors. Neuro-Oncology 4 (2000)
111. Chan S., Johnston S., and Scheulen M. First report: a phase II study of the safety and activity of CCI-779 for patients with locally advanced or metastatic breast cancer failing prior chemotherapy. Proc Am Soc Clin Oncol (2002)
112. Witzig T., Greyer S., Salim M., et al. A phase II trial of the rapamycin analog CCI-779 in previously treated mantle cell non-hodgkins lymphoma; interim analysis of 18 patients. Blood 102 (2003)
113. Galanis E., Buckner J., Maurer M., et al. NCCTG phase II trial of CCI-779 in recurrent glioblastoma models as singel agent and in combination chemotherapy. Proc Am Soc Clin Oncol 23 (2004)
114. Margolin K., Longmate J., Baratta T., et al. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Proc Am Soc Clin Oncol 23 (2004)
115. O'Donnel A., Faivre S., Judson I., et al. A phase I study of the oral mTOR inhibitor RAD001 as monotherapy to identify the optimal biologiacally effective dose usnign toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints in patients with solid tumors. Proc Am Soc Clin Oncol (2003)
116. Atkins M.B., Hidalgo M., Stadler W.M., et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22 5 (2004) 909-918
117. Punt C.J., Boni J., Bruntsch U., Peters M., and Thielert C. Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors. Ann Oncol 14 6 (2003) 931-937
118. Van Oosterom A., Dumez H., Desai J., et al. Combination signal transduction inhibition: a phase I/II trial of the oral mTOR-inhibitor everolimus (E, RAD-001) and imatinib mesylate (IM) in patients with gastrointestinal stromal tumor (GIST) refractory to IM. Proc Am Soc Clin Oncol 23 (2004)
119. Hidalgo M., Buckner J.C., Erlichman C., et al. A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 12 19 (2006) 5755-5763
120. Sarbassov D.D., Guertin D.A., Ali S.M., and Sabatini D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307 5712 (2005) 1098-1101
121. Takano A., Usui I., Haruta T., et al. Mammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulin. Mol Cell Biol 21 15 (2001) 5050-5062
122. Hudes G., Carducci M., Tomczak P., et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356 22 (2007) 2271-2281