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Alvespimycin

Alvespimycin hydrochloride is the hydrochloride salt of alvespimycin, an analogue of the antineoplastic benzoquinone antibiotic geldanamycin. Alvespimycin binds to HSP90, a chaperone protein that aids in the assembly, maturation and folding of proteins. Subsequently, the function of Hsp90 is inhibited, leading to the degradation and depletion of its client proteins such as kinases and transcription factors involved with cell cycle regulation and signal transduction. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    Kosan Biosciences Incorporated

Phase I study of Alvespimycin:  Twenty-five patients received 17-DMAG (range 2.5-106 mg/m(2)). At 106 mg/m(2) of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m(2). Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m(2) or less. In peripheral blood mononuclear cells significant (P < 0.05) HSP72 induction was detected (≥ 20 mg/m(2)) and sustained for 96 hours (≥ 40 mg/m(2)). Plasma HSP72 levels were greatest in the two patients who experienced DLT. At 80 mg/m(2) client protein (CDK4, LCK) depletion was detected and tumor samples from 3 of 5 patients confirmed HSP90 inhibition. Clinical activity included complete response (castration refractory prostate cancer, CRPC 124 weeks), partial response (melanoma, 159 weeks), and stable disease (chondrosarcoma, CRPC, and renal cancer for 28, 59, and 76 weeks, respectively). CONCLUSIONS:  The recommended phase II dose of 17-DMAG is 80 mg/m(2) weekly i.v. (source: Clin Cancer Res. 2011 Mar 15;17(6):1561-70.)

Phase I study of Alvespinmycin in patients with AML: Patients with advanced AML received escalating doses of intravenous alvespimycin (8-32 mg/m(2)), twice weekly, for 2 of 3 weeks. Dose-limiting toxicities (DLTs) were assessed during cycle 1. A total of 24 enrolled patients were evaluable for toxicity. Alvespimycin was well tolerated; the MTD was 24 mg/m(2) twice weekly. Common toxicities included neutropenic fever, fatigue, nausea and diarrhea. Cardiac DLTs occurred at 32 mg/m(2) (elevated troponin and myocardial infarction). Pharmacokinetics revealed linear increases in C(max) and area under the curve (AUC) from 8 to 32 mg/m(2) and minor accumulation upon repeated doses. Pharmacodynamic analyses on day 15 revealed increased apoptosis and Hsp70 levels when compared with baseline within marrow blasts. Antileukemia activity occurred in 3 of 17 evaluable patients (complete remission with incomplete blood count recovery). The twice-weekly administered alvespimycin was well tolerated in patients with advanced AML, showing linear pharmacokinetics, target inhibition and signs of clinical activity. We determined a recommended phase 2 dose of 24 mg/m(2). (source: Leukemia. 2010 Apr;24(4):699-705. ).

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2: Kiang JG, Agravante NG, Smith JT, Bowman PD. 17-DMAG diminishes hemorrhage-induced small intestine injury by elevating Bcl-2 protein and inhibiting iNOS pathway, TNF-α increase, and caspase-3 activation. Cell Biosci. 2011 Jun 3;1(1):21. PubMed PMID: 21711488; PubMed Central PMCID: PMC3135504.

3: Fukumoto R, Kiang JG. Geldanamycin analog 17-DMAG limits apoptosis in human peripheral blood cells by inhibition of p53 activation and its interaction with heat-shock protein 90 kDa after exposure to ionizing radiation. Radiat Res. 2011 Sep;176(3):333-45. Epub 2011 Jun 10. PubMed PMID: 21663398.

4: Pacey S, Wilson RH, Walton M, Eatock MM, Hardcastle A, Zetterlund A, Arkenau HT, Moreno-Farre J, Banerji U, Roels B, Peachey H, Aherne W, de Bono JS, Raynaud F, Workman P, Judson I. A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors. Clin Cancer Res. 2011 Mar 15;17(6):1561-70. Epub 2011 Jan 28. PubMed PMID: 21278242; PubMed Central PMCID: PMC3060938.

5: Hertlein E, Wagner AJ, Jones J, Lin TS, Maddocks KJ, Towns WH 3rd, Goettl VM, Zhang X, Jarjoura D, Raymond CA, West DA, Croce CM, Byrd JC, Johnson AJ. 17-DMAG targets the nuclear factor-kappaB family of proteins to induce apoptosis in chronic lymphocytic leukemia: clinical implications of HSP90 inhibition. Blood. 2010 Jul 8;116(1):45-53. Epub 2010 Mar 29. PubMed PMID: 20351313; PubMed Central PMCID: PMC2904580.

6: Lancet JE, Gojo I, Burton M, Quinn M, Tighe SM, Kersey K, Zhong Z, Albitar MX, Bhalla K, Hannah AL, Baer MR. Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia. Leukemia. 2010 Apr;24(4):699-705. Epub 2010 Jan 28. PubMed PMID: 20111068.

7: Ghoshal S, Rao I, Earp JC, Jusko WJ, Wetzler M. Down-regulation of heat shock protein 70 improves arsenic trioxide and 17-DMAG effects on constitutive signal transducer and activator of transcription 3 activity. Cancer Chemother Pharmacol. 2010 Sep;66(4):681-9. Epub 2009 Dec 25. PubMed PMID: 20035426; PubMed Central PMCID: PMC3152797.

8: Kummar S, Gutierrez ME, Gardner ER, Chen X, Figg WD, Zajac-Kaye M, Chen M, Steinberg SM, Muir CA, Yancey MA, Horneffer YR, Juwara L, Melillo G, Ivy SP, Merino M, Neckers L, Steeg PS, Conley BA, Giaccone G, Doroshow JH, Murgo AJ. Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies. Eur J Cancer. 2010 Jan;46(2):340-7. Epub 2009 Nov 27. PubMed PMID: 19945858; PubMed Central PMCID: PMC2818572.

9: Ayrault O, Godeny MD, Dillon C, Zindy F, Fitzgerald P, Roussel MF, Beere HM. Inhibition of Hsp90 via 17-DMAG induces apoptosis in a p53-dependent manner to prevent medulloblastoma. Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):17037-42. Epub 2009 Sep 23. PubMed PMID: 19805107; PubMed Central PMCID: PMC2761355.

10: Kiang JG, Smith JT, Agravante NG. Geldanamycin analog 17-DMAG inhibits iNOS and caspases in gamma-irradiated human T cells. Radiat Res. 2009 Sep;172(3):321-30. PubMed PMID: 19708781.

11: Schwock J, Dhani N, Cao MP, Zheng J, Clarkson R, Radulovich N, Navab R, Horn LC, Hedley DW. Targeting focal adhesion kinase with dominant-negative FRNK or Hsp90 inhibitor 17-DMAG suppresses tumor growth and metastasis of SiHa cervical xenografts. Cancer Res. 2009 Jun 1;69(11):4750-9. Epub 2009 May 19. PubMed PMID: 19458065.

12: Niu G, Li Z, Cao Q, Chen X. Monitoring therapeutic response of human ovarian cancer to 17-DMAG by noninvasive PET imaging with (64)Cu-DOTA-trastuzumab. Eur J Nucl Med Mol Imaging. 2009 Sep;36(9):1510-9. Epub 2009 May 14. PubMed PMID: 19440708.

13: Wu YC, Yen WY, Lee TC, Yih LH. Heat shock protein inhibitors, 17-DMAG and KNK437, enhance arsenic trioxide-induced mitotic apoptosis. Toxicol Appl Pharmacol. 2009 Apr 15;236(2):231-8. Epub 2009 Feb 12. PubMed PMID: 19371599.

14: Tokui K, Adachi H, Waza M, Katsuno M, Minamiyama M, Doi H, Tanaka K, Hamazaki J, Murata S, Tanaka F, Sobue G. 17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse. Hum Mol Genet. 2009 Mar 1;18(5):898-910. Epub 2008 Dec 9. PubMed PMID: 19066230.

15: Babchia N, Calipel A, Mouriaux F, Faussat AM, Mascarelli F. 17-AAG and 17-DMAG-induced inhibition of cell proliferation through B-Raf downregulation in WT B-Raf-expressing uveal melanoma cell lines. Invest Ophthalmol Vis Sci. 2008 Jun;49(6):2348-56. Epub 2008 Feb 15. PubMed PMID: 18281615.

16: Smith MA, Morton CL, Phelps DA, Kolb EA, Lock R, Carol H, Reynolds CP, Maris JM, Keir ST, Wu J, Houghton PJ. Stage 1 testing and pharmacodynamic evaluation of the HSP90 inhibitor alvespimycin (17-DMAG, KOS-1022) by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008 Jul;51(1):34-41. PubMed PMID: 18260120.

17: Moreno-Farre J, Asad Y, Pacey S, Workman P, Raynaud FI. Development and validation of a liquid chromatography/tandem mass spectrometry method for the determination of the novel anticancer agent 17-DMAG in human plasma. Rapid Commun Mass Spectrom. 2006;20(19):2845-50. PubMed PMID: 16941534.

18: Glaze ER, Lambert AL, Smith AC, Page JG, Johnson WD, McCormick DL, Brown AP, Levine BS, Covey JM, Egorin MJ, Eiseman JL, Holleran JL, Sausville EA, Tomaszewski JE. Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), in rats and dogs: potential clinical relevance. Cancer Chemother Pharmacol. 2005 Dec;56(6):637-47. Epub 2005 Jun 29. PubMed PMID: 15986212.

19: 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 Aug;56(2):115-25. Epub 2005 Mar 25. PubMed PMID: 15791458.

20: Ivy PS, Schoenfeldt M. Clinical trials referral resource. Current clinical trials of 17-AG and 17-DMAG. Oncology (Williston Park). 2004 May;18(5):610, 615, 619-20. PubMed PMID: 15209189.

21: Jez JM, Chen JC, Rastelli G, Stroud RM, Santi DV. Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90. Chem Biol. 2003 Apr;10(4):361-8. PubMed PMID: 12725864.