Cytogenetic Effects of CPT-11 and Its Active Metabolite, SN-38 on Human Lymphocytes

CPT-11, a new camptothecin analogue, has been demonstrated tobe a promising antineoplastic agent. Late side effects of carcinogenicityand teratogenicity have been unclear from clinical phase I andII trials. In order to elucidate the carcinogenicity and teratogenicityof CPT-11, we have examined the cytogenetic changes in humanperipheral blood lymphocytes induced by CPT-11 and its activemetabolite, SM-38. We have also analyzed the correlation betweenchromosomal damage and acute clinical side effects. When peripheralblood lymphocytes obtained from a healthy donor were exposedto CPT-11, SN-38, cisplatin and mitomycin C, a significant dose-dependentincrease of sister chromatid exchange (SCE) was obtained. TheSCE frequency per cell cultured with 0.244 nM SN-38 was similarto that cultured with 100 nM CPT-11, 300-500 times the concentrationof SN-38. A transient increase in SCE frequency was also observedin the peripheral blood lymphocytes of 11 cancer patients receiving100mg/m² of CPT-11 intravenously, compared with pretreatmentvalues (P= 0.0001). In addition, a significant correlation wasobserved between the frequency of SCE on day 3 and the degreeof decrease in platelet count (P= 0.012). In conclusion, SN-38might possibly have a high risk of mutagenicity and carcinogenicity;and measurement of SCE values in peripheral blood lymphocytesappears to have a potential application in the clinical predictionof chemotherapy-induced side effects.