The farnesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in vivo

摘要: Purpose: SCH66336 is an orally active, farnesyl protein transferase inhibitor. inhibits ras farnesylation in tumor cells and suppresses growth human xenograft transgenic mouse cancer models vivo. The taxanes, paclitaxel (Taxol) docetaxel (Taxotere) block cell mitosis by enhancing polymerization of tubulin monomers into stabilized microtubule bundles, resulting apoptosis. We hypothesized that anticancer combination therapy with taxanes would be more efficacious than single drug therapy. Methods: tested the efficacy when used against proliferation vitro, NCI-H460 lung xenografts nude mice, mammary tumors wap-ras mice. Results: synergized 10 out 11 lines originating from breast, colon, lung, ovary, prostate, pancreas. also four five tested. In model, oral (20 mg/kg twice daily for 14 days) intraperitoneal (5 once 4 caused a inhibition 56% day 7 65% compared to alone. Male mice wap-ras/F substrain [FVB/N-TgN(WapHRAS)69LlnYSJL] spontaneously develop at 6–9 weeks age which have been previously shown resistant paclitaxel. Paclitaxel resistance was confirmed present study, while inhibited these tumors. Most importantly, able sensitize chemotherapy. Conclusion: Clinical investigation using patients warranted. Further, may useful sensitizing paclitaxel-resistant taxane treatment.