Potent topoisomerase I inhibition by novel silatecans eliminates glioma proliferation in vitro and in vivo

Although topoisomerase inhibitors, such as camptothecin and topotecan, have been widely used in the treatment of nonglial tumors, their application fo r gliomas has been limited by poor efficacy relative to toxicity that may i n part reflect Limited bioavailability and blood stability of these agents. However, the potential promise of this class of agents has fostered effort s to develop new, more potent, ami less toxic inhibitors that may be clinic ally relevant. Using a cascade radical annulation route to the camptothecin family, we developed a series of novel camptothecin analogues, 7-silylcamp tothecins (''silatecans", that exhibited potent inhibition of topoisomerase I, dramatically improved blood stability, and sufficient lipophilicity to favor blood-brain barrier transit, We explored the efficacy of a series of these agents against a panel of five high-grade glioma cell lines to identi fy a promising compound for further preclinical testing. One of the most ac tive agents in our systems (DB67) inhibited tumor growth in vifro with an E D50 ranging between 2 and 40 ng/ml, at least 10-fold more potent than the e ffects observed with topotecan, and at least comparable with those of SN-38 , the active metabolite of CPT-11. Because DB67 also exhibited the highest human blood stability of any of the agents examined, this agent was then se lected for in vivo studies. A dose-escalation study of this agent in a nude mouse U87 glioma model system demonstrated a concentration-dependent effec t, with tumor growth inhibition at day 28 postimplantation (the day control animals began to require sacrifice because of large tumor size) of 61 +/- 7% and 73 +/- 38 after administration of DB67 doses of 3 and 10 mg/ng/day, respectively, for 5 days beginning on postimplantation day 7. Animals that continued treatment with 10 mg/kg/day in three additional 21-day cycles all remained progression free after >90 days of follow-up but later developed enlarging tumors after treatment was stopped However, a slightly higher dos e (30 mg/kg/day) induced complete tumor regression after only two cycles in all study animals and was effective even if treatment was delayed until la rge bulky tumors had developed. Application of the 30 mg/kg/day dose to tre at established intracranial glioma xenografts led to long-term (>90 day) su rvival in six of six animals, whereas all controls died of progressive dise ase (P < 0.00001). No apparent toxicity was encountered in any of the treat ed animals. In summary, the present studies indicate that silatecans may ho ld significant promise for the treatment of high-grade gliomas and provide a rationale for proceeding with further preclinical evaluation of their eff icacy and safety versus commercially available camptothecin derivatives.