Targeting hypoxia and angiogenesis through HIF-1α inhibition

Cancer Biology and Therapy

Volumn 4, Issue 10, 2005, Pages 1055-1062

  Diaz Gonzalez, Juan A ^a   Russell, James ^a   Rouzaut, Ana ^b   Gil Bazo, Ignacio ^a   Montuenga, Luis ^b  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b UNIVERSITY OF NAVARRA   (Spain)

Author keywords

Angiogenesis; HIF 1 ; Hypoxia; Molecular imaging; Molecular inhibitors; Molecular therapy; Targeted therapy

Indexed keywords

1 BENZYL 3 (5 HYDROXYMETHYL 2 FURYL)INDAZOLE; 17 ALLYLAMINO 17 DEMETHOXYGELDANAMYCIN; 17 DIMETHYLAMINOETHYLAMINO 17 DEMETHOXYGELDANAMYCIN; 2 METHOXYESTRADIOL; 2 MORPHOLINO 8 PHENYLCHROMONE; 7 ETHYL 10 HYDROXYCAMPTOTHECIN; 9 BETA DEXTRO ARABINOFURASONYL 2 FLUOROADENINE; ABT 578; ANTINEOPLASTIC AGENT; AP 23481; AP 23573; CHETOMIN; DNA TOPOISOMERASE INHIBITOR; ETOPOSIDE; EVEROLIMUS; HYPOXIA INDUCIBLE FACTOR 1; IRINOTECAN; LONAFARNIB; PEPTIDE; PROTEIN FARNESYLTRANSFERASE INHIBITOR; PX 478; RAPAMYCIN; SEMAXANIB; TEMSIROLIMUS; TIPIFARNIB; TOPOTECAN; UNCLASSIFIED DRUG;

ANGIOGENESIS; CANCER CHEMOTHERAPY; CANCER INVASION; CANCER RADIOTHERAPY; CANCER THERAPY; CLINICAL TRIAL; DOWN REGULATION; GLYCOLYSIS; HUMAN; HYPOXIA; METABOLISM; MICROENVIRONMENT; MICROTUBULE ASSEMBLY; MOLECULAR IMAGING; NONHUMAN; POSITRON EMISSION TOMOGRAPHY; PROTEIN FUNCTION; PROTEIN SYNTHESIS; REVIEW; SIGNAL TRANSDUCTION; TRANSCRIPTION INITIATION; TUMOR GROWTH;

EID: 27744536543     PISSN: 15384047     EISSN: 15558576     Source Type: Journal    
DOI: 10.4161/cbt.4.10.2195     Document Type: Review

References (105)

1. Hockel M, Vaupel P. Tumor hypoxia: Definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 2001; 93:266-76.
2. Semenza GL. HIF-1 and human disease: One highly involved factor. Genes Dev 2000; 14:1983-91.
3. Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, Yoo MA, Song EJ, Lee KJ, Kim KW. Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell 2002; 111:709-20.
4. Kaelin Jr WG. How oxygen makes its presence felt. Genes Dev 2002; 16:1441-5.
5. Semenza GL. Hypoxia-inducible factor 1: Oxygen homeostasis and disease pathophysiology. Trends in Molecular Medicine 2001; 7:345-50.
6. Harris AL. Hypoxia - a key regulatory factor in tumour growth. Nat Rev Cancer 2002; 2:38-47.
7. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: Role of the HIF system. Nat Med 2003; 9:677-84.
8. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW. Overexpression of Hypoxia-inducible Factor 1{{alpha}} in Common Human Cancers and Their Metastases. Cancer Res 1999; 59:5830-5.
9. Birner P, Gatterbauer B, Oberhuber G, Schindl M, Rossler K, Prodinger A, Budka H, Hainfellner JA. Expression of hypoxia-inducible factor-1 alpha in oligodendrogliomas: Its impact on prognosis and on neoangiogenesis. Cancer 2001; 92:165-71.
10. Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G. Overexpression of Hypoxia-inducible factor 1{{alpha}} is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 2000; 60:4693-6.
11. Bos R, van der GP, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der WE. Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 2003; 97:1573-81.
12. Lidgren A, Hedberg Y, Grankvist K, Rasmuson T, Vasko J, Ljungberg B. The expression of hypoxia-inducible factor 1{alpha} is a favorable independent prognostic factor in renal Cell Carcinoma. Clin Cancer Res 2005; 11:1129-35.
13. Schindl M, Schoppmann SF, Samonigg H, Hausmaninger H, Kwasny W, Gnant M, Jakesz R, Kubista E, Birner P, Oberhuber G. Overexpression of hypoxia-inducible factor 1{alpha} is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin Cancer Res 2002; 8:1831-7.
14. Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH, Semenza GL. Expression of hypoxia-inducible factor-1alpha: A novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 2001; 61:2911-6.
15. Bachtiary B, Schindl M, Potter R, Dreier B, Knocke TH, Hainfellner JA, Horvat R, Birner P. Overexpression of hypoxia-inducible factor 1{alpha} indicates diminished response to radiotherapy and unfavorable prognosis in patients receiving radical radiotherapy for cervical cancer. Clin Cancer Res 2003; 9:2234-40.
16. Beasley NJP, Leek R, Alam M, Turley H, Cox GJ, Gatter K, Millard P, Fuggle S, Harris AL. Hypoxia-inducible factors HIF-1{alpha} and HIF-2{alpha} in head and neck cancer: Relationship to tumor biology and treatment outcome in surgically resected patients. Cancer Res 2002; 62:2493-7.
17. Hui EP, Chan ATC, Pezzella F, Turley H, To KF, Poon TCW, Zee B, Mo F, Teo PML, Huang DP, Gatter KC, Johnson PJ, Harris AL. Coexpression of hypoxia-inducible factors 1{alpha} and 2{alpha}, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. Clin Cancer Res 2002; 8:2595-604.
18. Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Turley H, Talks K, Gatter KC, Harris AL. Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002; 53:1192-202.
19. Kuwai T, Kitadai Y, Tanaka S, Onogawa S, Matsutani N, Kaio E, Ito M, Chayama K. Expression of hypoxia-inducible factor-1alpha is associated with tumor vascularization in human colorectal carcinoma. Int J Cancer 2003; 105:176-81.
20. Swinson DE, Jones JL, Cox G, Richardson D, Harris AL, O'Byrne KJ. Hypoxia-inducible factor-1 alpha in non small cell lung cancer: Relation to growth factor, protease and apoptosis pathways. Int J Cancer 2004; 111:43-50.
21. Unruh A, Ressel A, Mohamed HG, Johnson RS, Nadrowitz R, Richter E, Katschinski DM, Wenger RH. The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 2003; 22:3213-20.
22. Moeller BJ, Cao Y, Li CY, Dewhirst MW. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: Role of reoxygenation, free radicals, and stress granules. Cancer Cell 2004; 5:429-41.
23. Toi M, Matsumoto T, Bando H. Vascular endothelial growth factor: Its prognostic, predictive, and therapeutic implications. Lancet Oncol 2001; 2:667-73.
24. Potter C, Harris AL. Hypoxia inducible carbonic anhydrase IX, marker of tumour hypoxia, survival pathway and therapy target. Cell Cycle 2004; 3:164-7.
25. Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 2002; 62:3387-94.
26. Erler JT, Cawthorne CJ, Williams KJ, Koritzinsky M, Wouters BG, Wilson C, Miller C, Demonacos C, Stratford IJ, Dive C. Hypoxia-mediated downregulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance. Mol Cell Biol 2004; 24:2875-89.
27. Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A, Fuks Z, Kolesnick R. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 2003; 300:1155-9.
28. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296:1655-7.
29. Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 2004; 22:2954-63.
30. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2:489-501.
31. Fresno Vara JA, Casado E, de CJ, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 2004; 30:193-204.
32. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: Novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 2001; 21:3995-4004.
33. Mabjeesh NJ, Willard MT, Frederickson CE, Zhong H, Simons JW. Androgens stimulate hypoxia-inducible factor 1 activation via autocrine loop of tyrosine kinase receptor/phosphatidylinositol 3′-kinase/protein kinase B in prostate cancer cells. Clin Cancer Res 2003; 9:2416-25.
34. Fukuda R, Hirota K, Fan F, Jung YD, Ellis LM, Semenza GL. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem 2002; 277:38205-11.
35. Stiehl DP, Jelkmann W, Wenger RH, Hellwig-Burgel T. Normoxic induction of the hypoxia-inducible factor 1alpha by insulin and interleukin-1beta involves the phosphatidylinositol 3-kinase pathway. FEBS Lett 2002; 512:157-62.
36. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, Semenza GL. Modulation of hypoxia-inducible factor 1alpha 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; 60:1541-5.
37. Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB, Stokoe D, Giaccia AJ. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 2000; 14:391-6.
38. Alvarez-Tejado M, Alfranca A, Aragones J, Vara A, Landazuri MO, del PL. Lack of evidence for the involvement of the phosphoinositide 3-kinase/Akt pathway in the activation of hypoxia-inducible factors by low oxygen tension. J Biol Chem 2002; 277:13508-17.
39. Arsham AM, Plas DR, Thompson CB, Simon MC. Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-1 alpha nor sufficient for HIF-1-dependent target gene transcription. J Biol Chem 2002; 277:15162-70.
40. Sandau KB, Faus HG, Brune B. Induction of hypoxia-inducible-factor 1 by nitric oxide is mediated via the PI 3K pathway. Biochem Biophys Res Commun 2000; 278:263-7.
41. Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van OE. Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J Biol Chem 2002; 277:27975-81.
42. Fang J, Cao Z, Chen YC, Reed E, Jiang BH. 9-beta-D-arabinofuranosyl-2- fluoroadenine inhibits expression of vascular endothelial growth factor through hypoxia-inducible factor-1 in human ovarian cancer cells. Mol Pharmacol 2004; 66:178-86.
43. Geng L, Donnelly E, McMahon G, Lin PC, Sierra-Rivera E, Oshinka H, Hallahan DE. Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res 2001; 61:2413-9.
44. Schuuring J, Bussink J, Bernsen HJ, Peeters W, van Der Kogel AJ. Irradiation combined with SU5416: Microvascular changes and growth delay in a human xenograft glioblastoma tumor line. Int J Radiat Oncol Biol Phys 2005; 61:529-34.
45. Zhong XS, Zheng JZ, Reed E, Jiang BH. SU5416 inhibited VEGF and HIF-1alpha expression through the PI3K/AKT/p70S6K1 signaling pathway. Biochem Biophys Res Commun 2004; 324:471-80.
46. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002; 22:7004-14.
47. Abraham RT. mTOR as a positive regulator of tumor cell responses to hypoxia. Curr Top Microbiol Immunol 2004; 279:299-319.
48. Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 2004; 10:594-601.
49. Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin Jr WG. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 2003; 4:147-158.
50. Sang N, Stiehl DP, Bohensky J, Leshchinsky I, Srinivas V, Caro J. MAPK signaling upregulates the activity of hypoxia-inducible factors by its effects on p300. J Biol Chem 2003; 278:14013-9.
51. Cohen-Jonathan E, Muschel RJ, Gillies MW, Evans SM, Cerniglia G, Mick R, Kusewitt D, Sebti SM, Hamilton AD, Oliff A, Kohl N, Gibbs JB, Bernhard EJ. Farnesyltransferase inhibitors potentiate the antitumor effect of radiation on a human tumor xenograft expressing activated HRAS. Radiat Res 2000; 154:125-32.
52. Cohen-Jonathan E, Evans SM, Koch CJ, Muschel RJ, McKenna WG, Wu J, Bernhard EJ. The farnesyltransferase inhibitor L744,832 reduces hypoxia in tumors expressing activated H-ras. Cancer Res 2001; 61:2289-93.
53. Delmas C, End D, Rochaix P, Favre G, Toulas C, Cohen-Jonathan E. The farnesyltransferase inhibitor R115777 reduces hypoxia and matrix metalloproteinase 2 expression in human glioma xenograft. Clinical Cancer Research 2003; 9:6062-8.
54. Hohfeld J, Cyr DM, Patterson C. From the cradle to the grave: Molecular chaperones that may choose between folding and degradation. EMBO Rep 2001; 2:885-90.
55. Isaacs JS, Xu W, Neckers L. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 2003; 3:213-17.
56. Maloney A, Workman P. HSP90 as a new therapeutic target for cancer therapy: The story unfolds. Expert Opin Biol Ther 2002; 2:3-24.
57. Workman P. Altered states: Selectively drugging the Hsp90 cancer chaperone. Trends Mol Med 2004; 10:47-51.
58. Kamal A, Boehm MF, Burrows FJ. Therapeutic and diagnostic implications of Hsp90 activation. Trends Mol Med 2004; 10:283-90.
59. Isaacs JS, Jung YJ, Neckers L. Aryl hydrocarbon nuclear translocator (ARNT) promotes oxygen-independent stabilization of hypoxia-inducible factor-1alpha by modulating an Hsp90-dependent regulatory pathway. J Biol Chem 2004; 279:16128-35.
60. Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J Biol Chem 2002; 277:29936-44.
61. Mabjeesh NJ, Post DE, Willard MT, Kaur B, Van Meir EG, Simons JW, Zhong H. Geldanamycin induces degradation of hypoxia-inducible factor 1alpha protein via the proteosome pathway in prostate cancer cells. Cancer Res 2002; 62:2478-82.
62. Grenert JP, Sullivan WP, Fadden P, Haystead TA, Clark J, Mimnaugh E, Krutzsch H, Ochel HJ, Schulte TW, Sausville E, Neckers LM, Toft DO. The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation. J Biol Chem 1997; 272:23843-50.
63. Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP. Crystal structure of an Hsp90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent. Cell 1997; 89:239-50.
64. Neckers L, Schulte TW, Mimnaugh E. Geldanamycin as a potential anti-cancer agent: Its molecular target and biochemical activity. Invest New Drugs 1999; 17:361-73.
65. Zagzag D, Nomura M, Friedlander DR, Blanco CY, Gagner JP, Nomura N, Newcomb EW. Geldanamycin inhibits migration of glioma cells in vitro: A potential role for hypoxia-inducible factor (HIF-1alpha) in glioma cell invasion. J Cell Physiol 2003; 196:394-402.
66. Kelland LR, Sharp SY, Rogers PM, Myers TG, Workman P. DT-Diaphorase expression and tumor cell sensitivity to 17-allylamino, 17- demethoxygeldanamycin, an inhibitor of heat shock protein 90. J Natl Cancer Inst 1999; 91:1940-9.
67. Basso AD, Solit DB, Munster PN, Rosen N. Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2. Oncogene 2002; 21:1159-66.
68. Solit DB, Zheng FF, Drobnjak M, Munster PN, Higgins B, Verbel D, Heller G, Tong W, Cordon-Cardo C, Agus DB, Scher HI, Rosen N. 17-Allylamino-17- demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res 2002; 8:986-93.
69. Goetz MP, Toft D, Reid J, Ames M, Stensgard B, Safgren S, Adjei AA, Sloan J, Atherton P, Vasile V, Salazaar S, Adjei A, Croghan G, Erlichman C. Phase I Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients With Advanced Cancer. J Clin Oncol 2005; 23:1078-87.
70. Sausville EA, Tomaszewski JE, Ivy P. Clinical development of 17-allylamino, 17-demethoxygeldanamycin. Curr Cancer Drug Targets 2003; 3:377-83.
71. Russell JS, Burgan W, Oswald KA, Camphausen K, Tofilon PJ. Enhanced cell killing induced by the combination of radiation and the heat shock protein 90 inhibitor 17-allylamino-17- demethoxygeldanamycin: A multitarget approach to radiosensitization. Clin Cancer Res 2003; 9:3749-55.
72. Bisht KS, Bradbury CM, Mattson D, Kaushal A, Sowers A, Markovina S, Ortiz KL, Sieck LK, Isaacs JS, Brechbiel MW, Mitchell JB, Neckers LM, Gius D. Geldanamycin and 17-allylamino-17-demethoxygeldanamycin potentiate the in vitro and in vivo radiation response of cervical tumor cells via the heat shock protein 90-mediated intracellular signaling and cytotoxicity. Cancer Res 2003; 63:8984-95.
73. Chen X, Bies RR, Ramanathan RK, Zukowski EG, Trump DL, Egorin MJ. Population pharmacokinetic analysis of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) in adult patients with advanced malignancies. Cancer Chemother Pharmacol 2005; 55:237-43.
74. Egorin MJ, Rosen DM, Wolff JH, Callery PS, Musser SM, Eiseman JL. Metabolism of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) by murine and human hepatic preparations. Cancer Res 1998; 58:2385-96.
75. Hollingshead M, Alley M, Burger AM, Borgel S, Pacula-Cox C, Fiebig HH, Sausville EA. In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino- 17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative. Cancer Chemother Pharmacol 2005; 56:115-25.
76. 2 and S phase arrest by the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin. Clin Cancer Res 2004; 10:8077-84.
77. Shoemaker RH, Scudiero DA, Melillo G, Currens MJ, Monks AP, Rabow AA, Covell DG, Sausville EA. Application of high-throughput, molecular-targeted screening to anticancer drug discovery. Curr Top Med Chem 2002; 2:229-46.
78. Rapisarda A, Uranchimeg B, Scudiero DA, Selby M, Sausville EA, Shoemaker RH, Melillo G. Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Res 2002; 62:4316-24.
79. Rapisarda A, Uranchimeg B, Sordet O, Pommier Y, Shoemaker RH, Melillo G. Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: Mechanism and therapeutic implications. Cancer Res 2004; 64:1475-82.
80. Rapisarda A, Zalek J, Hollingshead M, Braunschweig T, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP, Hewitt SM, Shoemaker RH, Melillo G. Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res 2004; 64:6845-8.
81. Kamiyama H, Takano S, Tsuboi K, Matsumura A. Anti-angiogenic effects of SN38 (active metabolite of irinotecan): Inhibition of hypoxia-inducible factor 1 alpha (HIF-1alpha)/vascular endothelial growth factor (VEGF) expression of glioma and growth of endothelial cells. J Cancer Res Clin Oncol 2005; 131:205-13.
82. Edsall AB, Mohanakrishnan AK, Yang D, Fanwick PE, Hamel E, Hanson AD, Agoston GE, Cushman M. Effects of altering the electronics of 2-methoxyestradiol on cell proliferation, on cytotoxicity in human cancer cell cultures, and on tubulin polymerization. J Med Chem 2004; 47:5126-39.
83. Zhou NN, Zhu XF, Zhou JM, Li MZ, Zhang XS, Huang P, Jiang WQ. 2-methoxyestradiol induces cell cycle arrest and apoptosis of nasopharyngeal carcinoma cells. Acta Pharmacol Sin 2004; 25:1515-20.
84. Lis A, Ciesielski MJ, Barone TA, Scott BE, Fenstermaker RA, Plunkett RJ. 2-methoxyestradiol inhibits proliferation of normal and neoplastic glial cells, and induces cell death, in vitro. Cancer Lett 2004; 213:57-65.
85. Ricker JL, Chen Z, Yang XP, Pribluda VS, Swartz GM, Van WC. 2-methoxyestradiol inhibits hypoxia-inducible factor 1alpha, tumor growth, and angiogenesis and augments paclitaxel efficacy in head and neck squamous cell carcinoma. Clin Cancer Res 2004; 10:8665-73.
86. Amorino GP, Freeman ML, Choy H. Enhancement of radiation effects in vitro by the estrogen metabolite 2-methoxyestradiol. Radiat Res 2000; 153:384-91.
87. Han GZ, Liu ZJ, Shimoi K, Zhu BT. Synergism between the anticancer actions of 2-methoxyestradiol and microtubule-disrupting agents in human breast cancer. Cancer Res 2005; 65:387-93.
88. Fotsis T, Zhang Y, Pepper MS, Adlercreutz H, Montesano R, Nawroth PP, Schweigerer L. The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature 1994; 368:237-9.
89. Mabjeesh NJ, Escuin D, LaVallee TM, Pribluda VS, Swartz GM, Johnson MS, Willard MT, Zhong H, Simons JW, Giannakakou P. 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell 2003; 3:363-75.
90. Powis G, Montfort WR. Properties and biological activities of thioredoxins. Annu Rev Pharmacol Toxicol 2001; 41:261-95.
91. Welsh SJ, Bellamy WT, Briehl MM, Powis G. The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. Cancer Res 2002; 62:5089-95.
92. Welsh SJ, Williams RR, Birmingham A, Newman DJ, Kirkpatrick DL, Powis G. The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation. Mol Cancer Ther 2003; 2:235-43.
93. Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA, Bunn HF, Livingston DM. An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci USA 1996; 93:12969-73.
94. Kung AL, Wang S, Klco JM, Kaelin WG, Livingston DM. Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nat Med 2000; 6:1335-40.
95. Dames SA, Martinez-Yamout M, De Guzman RN, Dyson HJ, Wright PE. Structural basis for Hif-1 alpha/CBP recognition in the cellular hypoxic response. Proc Natl Acad Sci USA 2002; 99:5271-6.
96. Kung AL, Zabludoff SD, France DS, Freedman SJ, Tanner EA, Vieira A, Cornell-Kennon S, Lee J, Wang B, Wang J, Memmert K, Naegeli HU, Petersen F, Eck MJ, Bair KW, Wood AW, Livingston DM. Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell 2004; 6:33-43.
97. Yeo EJ, Chun YS, Cho YS, Kim J, Lee JC, Kim MS, Park JW. YC-1: A potential anticancer drug targeting hypoxia-inducible factor 1. J Natl Cancer Inst 2003; 95:516-25.
98. Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G, Powis G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther 2004; 3:233-44.
99. Weissleder R, Mahmood U. Molecular imaging. Radiology 2001; 219:316-33.
100. Waldherr C, Mellinghoff IK, Tran C, Halpern BS, Rozengurt N, Safaei A, Weber WA, Stout D, Satyamurthy N, Barrio J, Phelps ME, Silverman DH, Sawyers CL, Czernin J. Monitoring antiproliferative responses to kinase inhibitor therapy in mice with 3′-deoxy-3′-18F-fluorothymidine PET. J Nucl Med 2005; 46:114-20.
101. Liu G, Rugo HS, Wilding G, McShane TM, Evelhoch JL, Ng C, Jackson E, Kelcz F, Yeh BM, Lee Jr FT. Charnsangavej C, Park JW, Ashton EA, Steinfeldt HM, Pithavala YK, Reich SD, Herbst RS. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: Results from a phase I study. J Clin Oncol 2005; 23:5464-73.
102. Smith-Jones PM, Solit DB, Akhurst T, Afroze F, Rosen N, Larson SM. Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Nat Biotechnol 2004; 22:701-6.
103. Koch CJ, Evans SM. Noninvasive PET and SPECT imaging of tissue hypoxia using isotopically labeled 2-nitroimidazoles. Adv Exp Med Biol 2003; 510:285-92.
104. Serganova I, Doubrovin M, Vider J, Ponomarev V, Soghomonyan S, Beresten T, Ageyeva L, Serganov A, Cai S, Balatoni J, Blasberg R, Gelovani J. Molecular imaging of temporal dynamics and spatial heterogeneity of hypoxia-inducible factor-1 signal transduction activity in tumors in living mice. Cancer Res 2004; 64:6101-8.
105. Wen B, Burgman P, Zanzonico P, O'donoghue J, Cai S, Finn R, Serganova I, Blasberg R, Gelovani J, Li GC, Ling CC. A preclinical model for noninvasive imaging of hypoxia-induced gene expression; comparison with an exogenous marker of tumor hypoxia. Eur J Nucl Med Mol Imaging 2004; 31:1530-8.