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Biotech / Medical : Kosan BioSciences -- KOSN -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (699)	1/16/2008 1:56:47 PM
From: tuck	Respond to of 933

[17-AAG & Carboplatin versus ovarian cancer] >>Cancer Chemother Pharmacol. 2008 Jan 10 [Epub ahead of print] An in vitro and in vivo study of the combination of the heat shock protein inhibitor 17-allylamino-17-demethoxygeldanamycin and carboplatin in human ovarian cancer models. Banerji U, Sain N, Sharp SY, Valenti M, Asad Y, Ruddle R, Raynaud F, Walton M, Eccles SA, Judson I, Jackman AL, Workman P. Cancer Research UK Centre for Cancer Therapeutics, Haddow Laboratories, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK, Paul.Workman@icr.ac.uk. PURPOSE: To study the interactions of the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) and carboplatin in vitro and in vivo. EXPERIMENTAL DESIGN: The combination of 17-AAG and carboplatin on the growth inhibition of A2780, SKOV-3, IGROV-1 and HX62 human ovarian cancer cells was studied in vitro by MTT assays. The effect of the sequence of administration of both drugs was further investigated in A2780 cells by sulforhodamine B assays. The ability of 17-AAG to deplete HSP90 client proteins either alone or in combination with carboplatin was evaluated by western blotting. Tumor concentrations of 17-AAG and carboplatin alone or in combination in vivo were determined by validated liquid chromatography with ultraviolet detection and atomic absorption spectroscopy methods. The growth inhibitory effects of 17-AAG, carboplatin and the combination were studied in the A2780 xenograft model. RESULTS: The combination index (CI) at fu(0.5) for 17-AAG plus carboplatin was 0.97 (+/-0.12 SD) when A2780 cells were exposed to carboplatin followed by 17-AAG indicating additivity. The addition of carboplatin did not alter the ability of 17-AAG to cause C-RAF, CDK4 and p-AKT depletion or HSP70 induction. Tumor 17-AAG and carboplatin concentrations were not significantly different in the single agent and combination arms. Tumor weights relative to controls on day 6 (T/C) were 67% for the carboplatin, 64% for the 17-AAG and 22% for the combination. CONCLUSION: In the specified sequences of drug exposure, 17-AAG and carboplatin have additive growth inhibitory effects in vitro and beneficial effects were seen with the combination in vivo. These findings form the basis for the possible evaluation of 17-AAG and carboplatin in a clinical trial.<< Cheers, Tuck

To: tuck who wrote (699)	1/21/2008 1:24:43 PM
From: tuck	Respond to of 933

[Inhibition of Hsp90 down-regulates mutant EGFR expression and sensitizes EGFR mutant tumors to paclitaxel] >>Cancer Res. 2008 Jan 15;68(2):589-96. Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel. Sawai A, Chandarlapaty S, Greulich H, Gonen M, Ye Q, Arteaga CL, Sellers W, Rosen N, Solit DB. Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are found in a subset of patients with lung cancer and correlate with response to EGFR tyrosine kinase inhibitors (TKI). Resistance to these agents invariably develops, and current treatment strategies have limited efficacy in this setting. Hsp90 inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), induce the degradation of EGFR and other Hsp90 interacting proteins and may thus have utility in tumors dependent upon sensitive Hsp90 clients. We find that the EGFR mutations found most commonly in patients with lung adenocarcinoma who respond to EGFR TKIs are potently degraded by 17-AAG. Although the expression of wild-type EGFR was also down-regulated by 17-AAG, its degradation required higher concentrations of drug and a longer duration of drug exposure. In animal models, a single dose of 17-AAG was sufficient to induce degradation of mutant EGFR and inhibit downstream signaling. 17-AAG treatment, at its maximal tolerated dose, caused a significant delay in H3255 (L858R EGFR) xenograft growth but was less effective than the EGFR TKI gefitinib. 17-AAG alone delayed, but did not completely inhibit, the growth of H1650 and H1975 xenografts, two EGFR mutant models which show intermediate and high levels of gefitinib resistance. 17-AAG could be safely coadministered with paclitaxel, and the combination was significantly more effective than either drug alone. These data suggest that Hsp90 inhibition in combination with chemotherapy may represent an effective treatment strategy for patients whose tumors express EGFR kinase domain mutations, including those with de novo and acquired resistance to EGFR TKIs.<< Cheers, Tuck