Hepatotoxicity of camptothecin derivatives in a primary culture system of rat hepatocytes

The topoisomerase I inhibitors are a new class of antineoplastic agents cur rently under clinical development. Among these compounds there are some cam ptothecin (CPT) derivatives with improved toxicity profiles and antitumor a ctivity: irinotecan (CPT-11) and topotecan (TPT), particularly active again st colon, lung and ovarian cancer. The aim of this study was to evaluate the cytotoxicity of CPT, CPT-11, its metabolite SN38 and TBT in a primary culture system of rat hepatocytes. Cyt otoxicity was evaluated by measuring the leakage of lactate dehydrogenase ( LDH) into the medium and by assessing cell viability in terms of tetrazoliu m salts (MTT) reduction by mitochondrial dehydrogenase activity. Our result s showed that cytotoxicity was limited in the case of short drug exposure. There was a significant and time-dependent increase in LDH leakage and a si gnificant time- and dose-dependent decrease in MTT reduction after 3h of in cubation (p<0.01). In the treatments with doses related to peak plasma leve ls, CPT-11 was less responsible for the observed in vitro hepatotoxicity th an its metabolite SN38; TPT had lower LDH leakage compared to SN38 and CPT- 11 but showed significant and early (3h) decrease in MTT reduction: this ma y mean a different mechanism of cellular damage. These results demonstrate that CPT derivatives are directly toxic to liver cells in a distinct time- and dose-related response.