Topoisomerase I Inhibition by the Camptothecin Analog G1147211C

The development of camptothecin-like compounds as inhibitors of DNA topoisomerase I for the treatment of solid tumors has generated clinical excitement in this new class of drugs. We have discovered, developed, and entered into clinical trial a novel, potent, and water-soluble camptothecin analog with significant antitumor activity. This compound, Gl147211C [7-(4-methylpiperaziinomethylene)-10, 11-ethylenedioxy-20(S)-camptothecin hydrochloride] is a specific inhibitor of DNA topoisomerase I. Compared to topotecan, Gl147211C is approximately three times as potent in the cleavable complex assay and approximately twice as soluble in aqueous medium. Human tumor cell line cytotoxicity assays indicated that Gl147211C was approximately 3- to 5-fold more potent than topotecan, while both compounds were relatively insensitive to the multidrug resistance P-glycoprotein. The in vivo preclinical antitumor activity of Gl147211C was compared to topotecan in an array of human tumor xenograft models in nude mice. In general, Gl147211C was able to induce regression of established tumors whereas topotecan was not. Microscopic evaluation of necropsied tissues indicated that drug-induced toxicity was mild, primarily limited to the gastrointestinal tract, and was comparable for both Gl147211C and topotecan. Based on these observations, Gl147211C moved through preclinical development and subsequently into Phase I clinical trial. A summary of Phase I trial results to date is provided.