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

The systemic toxicity and efficacy of cisplatin (CDDP) were examined i n vitro and in vivo. Procedures were performed before and after the an tineoplastic agent was encapsulated into multilamellar liposomes (L-CD DP). In vitro cytotoxicity evaluation in L1210 murine leukaemia and NI H 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 intr avenously 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 observe d with CDDP. The values of platinum in liver, spleen, kidneys, lungs a nd 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 CD2 F1 mice). CDDP and L-CDDP showed similar cytotoxicity in tissue cultur e. At the highest dose given, 12 mg/kg intraperitoneally (i.p.), L-CDD P 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 n itrogen and creatinine evaluation) of L-CDDP administered i.p. was sig nificantly less than with CDDP. In addition, the ability of kidney sli ces to transport organic anions [paraaminohippurate (PAH)] and consume O2 was substantially decreased in rats treated with free CDDP compare d to L-CDDP. Accordingly, the liposomal encapsulation of CDDP attenuat es its nephrotoxicity, but allows maintenance of antitumour efficacy a nd may be a potentially effective modality in clinical settings.