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

Purpose: SCH66336 is an orally active, farnesyl protein transferase inhibit or. SCH66336 inhibits ras farnesylation in tumor cells and suppresses tumor growth in human xenograft and transgenic mouse cancer models in vivo. The taxanes, paclitaxel (Taxol) and docetaxel (Taxotere) block cell mitosis by enhancing polymerization of tubulin monomers into stabilized microtubule bu ndles, resulting in apoptosis. We hypothesized that anticancer combination therapy with SCH66336 and taxanes would be more efficacious than single dru g therapy. Methods: We tested the efficacy of SCH66336 and taxanes when use d in combination against tumor cell proliferation in vitro, against NCI-H46 0 human lung tumor xenografts in nude mice, and against mammary tumors in w ap-ras transgenic mice. Results: SCH66336 synergized with paclitaxel in 10 out of 11 tumor cells lines originating from breast, colon, lung, ovary, pr ostate, and pancreas. SCH66336 also synergized with docetaxel in four out o f five cell lines tested. In the NCI-H460 lung cancer xenograft model, oral SCH66336 (20 mg/kg twice daily for 14 days) and intraperitoneal paclitaxel (5 mg/kg once daily for 4 days) caused a tumor growth inhibition of 56% by day 7 and 65% by day 14 compared to paclitaxel alone. Male transgenic mice of the wap-ras/F substrain [FVB/N-TgN(WapHRAS)69LlnYSJL] spontaneously dev elop mammary tumors at 6-9 weeks of age which have been previously shown to be resistant to paclitaxel. Paclitaxel resistance was confirmed in the pre sent study, while SCH66336 inhibited growth of these tumors. Most important ly, SCH66336 was able to sensitize wap-ras/F mammary tumors to paclitaxel c hemotherapy. Conclusion: Clinical investigation of combination therapy usin g SCH66336 and taxanes in cancer patients is warranted. Further, SCH66336 m ay be useful for sensitizing paclitaxel-resistant tumors to taxane treatmen t.