Hepatotoxicity of camptothecin derivatives in a primary culture system of rat hepatocytes.
The topoisomerase I inhibitors are a new class of antineoplastic agents currently under clinical development. Among these compounds there are some camptothecin (CPT) derivatives with improved toxicity profiles and antitumor activity: irinotecan (CPT-11) and topotecan (TPT), particularly active against colon, lung and ovarian cancer. The aim of this study was to evaluate the cytotoxicity of CPT, CPT-11, its metabolite SN38 and TPT in a primary culture system of rat hepatocytes. Cytotoxicity was evaluated by measuring the leakage of lactate dehydrogenase (LDH) into the medium and by assessing cell viability in terms of tetrazolium salts (MTT) reduction by mitochondrial dehydrogenase activity. Our results 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 significant time- and dose-dependent decrease in MTT reduction after 3 h of incubation (p<0.01). In the treatments with doses related to peak plasma levels, CPT-11 was less responsible for the observed in vitro hepatotoxicity than its metabolite SN38; TPT had lower LDH leakage compared to SN38 and CPT-11 but showed significant and early (3 h) decrease in MTT reduction: this may 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.
Fulco
R A
RA
Sez. Dec. IST-Genova c/o Institute of Oncology, Faculty of Medicine, University of Messina, Italy.
Costa
C
C
Germanò
M P
MP
Torre
E A
EA
Viscomi
M G
MG
Salimbeni
V
V
Maisano
R
R
Giudice
A
A
Costa
G
G
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013778:Tetrazolium Salts / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D013778:Tetrazolium Salts; D007770:L-Lactate Dehydrogenase; D002166:Camptothecin