2158

We have previously examined the activity of Bortezomib (B) alone and in combination in human tumor primary cultures (Nagourney RA Proc AACR, 2003). The favorable results recently reported (Aghajanian C. J.Clin.Oncol 23:2005) for B & carboplatin in recurrent ovarian cancer (OVCA) suggest a role for B combinations in this disease. To examine B activity in OVCA we conducted ex vivo analyses on 71 tumor specimens. Cytotoxic activity was assessed by morphologic (delayed-loss-of-membrane-integrity) and metabolic (MTT, ATP) endpoints. Synergy was analyzed by median effect. Drug combination activities, as LC50 values, were compared to the solid tumor database by Z-score, while favorable interactions were provided as % of specimens revealing synergy. By rank order of LC50 Z-Score, the activity for B combinations reveal Topotecan > CDDP > Gemcitabine > Vinorelbine > Doxorubicin >> Taxol. Synergy by % of specimens reveals Topotecan (50%) > Vinorelbine (46%) > Doxorubicin (40%) > Gemcitabine (34%) > CDDP (28%) >>>Taxol (6%). The B&Taxol low activity, lack of synergy and high degree of antagonism (85%) is of interest and consistent with our prior observations. Whether this is a property inherent to B’s interaction with taxanes or reflects sequence dependence is being examined. We conclude that that B interacts favorably with several cytotoxic agents in OVCA. Novel drug combinations may hold clinical potential in this disease. Drug sequence remains a focus of investigation with additional analyses to be reported. Supported in part by the Vanguard Cancer Foundation and The Tina Robinson Research Fund.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]