The
topoisomerase I inhibitor GL147211C [7-[(4-methylpiperazino)methyl]-10,11-(ethylenedioxy)-(20S)-campto thecin
trifluoroacetate], a
camptothecin analogue, has significant activity in
tumor cell cytotoxicity assays in vitro and antitumor activity in both animal
tumor models and human patients. Its toxicity is significant, however, effectively limiting the amount of
drug that can be administered and its clinical utility. To determine whether the therapeutic index of
GL147211C could be improved, the
drug was encapsulated in long-circulating, pegylated (STEALTH)
liposomes (SPI-355). The pharmacokinetics and antitumor activity of SPI-355 were compared to those of nonliposomal
GL147211C. The plasma pharmacokinetics of SPI-355 in rats were typical of those of other pegylated liposomal formulations, with significantly increased blood circulation time; the dose-corrected area under the curve and Cmax of SPI-355 (10 mg/kg) were 1250- and 35-fold higher, respectively, than those of nonliposomal GL14711C (8.72 mg/kg). The comparative antitumor activity of SPI-355 and nonliposomal GL1472211C was evaluated in nude mice implanted with HT29 colon
carcinoma xenografts. SPI-355 was 20-fold more effective than
GL147211C in inhibiting
tumor growth (1 mg/kg SPI-355 and 20 mg/kg
GL147211C) and produced durable complete remissions of
tumors at well-tolerated dose levels that were >5-fold lower than the maximally tolerated dose of
GL147211C, which induced no durable complete responses. Signs of toxicity were similar between the two drugs, but
liposome encapsulation increased the toxicity of
drug approximately 4-fold, with increased
weight loss and several deaths with SPI-355 (5 mg/kg SPI-355 versus 20 mg/kg
GL147211C). Despite the increased toxicity seen with SPI-355, the therapeutic index of the liposomal formulation was increased approximately 5-fold over that of nonliposomal
GL147211C, suggesting that such a pegylated liposomal formulation could demonstrate increased therapeutic index in human patients.