COMPARATIVE PHARMACOLOGICAL, TOXICOLOGICAL AND ANTITUMORAL EVALUATION OF FREE AND LIPOSOME-ENCAPSULATED CISPLATIN IN RODENTS

The systemic toxicity and efficacy of cisplatin (CDDP) were examined in vitro and in vivo. Procedures were performed before and after the antineoplastic agent was encapsulated into multilamellar liposomes (L-CDDP). In vitro cytotoxicity evaluation in L1210 murine leukaemia and NIH OVCAR human ovarian cancer cells showed IC50 values of 0.14 and 0.05 mug/ml with CDDP or L-CDDP, respectively. In vivo, mice injected intravenously with L-CDDP had plasma levels of platinum 4-fold higher than with CDDP. The t1/2alpha was 2 h and the t1/2beta exceeded 48 h with L-CDDP; whereas a t1/2alpha of 15 min and t1/2beta of 12 h was observed with CDDP. The values of platinum in liver, spleen, kidneys, lungs and heart were substantially higher in L-CDDP-treated compared to CDDP-treated mice. Cytotoxic evaluation of both agents was tested in vitro (murine L1210 leukaemia and NIH OVCAR cell line) and in vivo (male CD2F1 mice). CDDP and L-CDDP showed similar cytotoxicity in tissue culture. At the highest dose given, 12 mg/kg intraperitoneally (i.p.), L-CDDP showed higher antitumour efficacy demonstrated by an increased life span of the mice. The CDDP treatment at the highest dose was lethal to all the tumour bearing mice. The nephrotoxicity in rats (blood urea nitrogen and creatinine evaluation) of L-CDDP administered i.p. was significantly less than with CDDP. In addition, the ability of kidney slices to transport organic anions [paraaminohippurate (PAH)] and consume O2 was substantially decreased in rats treated with free CDDP compared to L-CDDP. Accordingly, the liposomal encapsulation of CDDP attenuates its nephrotoxicity, but allows maintenance of antitumour efficacy and may be a potentially effective modality in clinical settings.