Cytogenetic effects of CPT-11 and its active metabolite, SN-38 on human lymphocytes.
CPT-11, a new camptothecin analogue, has been demonstrated to be a promising antineoplastic agent. Late side effects of carcinogenicity and teratogenicity have been unclear from clinical phase I and II trials. In order to elucidate the carcinogenicity and teratogenicity of CPT-11, we have examined the cytogenetic changes in human peripheral blood lymphocytes induced by CPT-11 and its active metabolite, SM-38. We have also analyzed the correlation between chromosomal damage and acute clinical side effects. When peripheral blood lymphocytes obtained from a healthy donor were exposed to CPT-11, SN-38, cisplatin and mitomycin C, a significant dose-dependent increase of sister chromatid exchange (SCE) was obtained. The SCE frequency per cell cultured with 0.244 nM SN-38 was similar to that cultured with 100 nM CPT-11, 300-500 times the concentration of SN-38. A transient increase in SCE frequency was also observed in the peripheral blood lymphocytes of 11 cancer patients receiving 100 mg/m2 of CPT-11 intravenously, compared with pretreatment values (P = 0.0001). In addition, a significant correlation was observed between the frequency of SCE on day 3 and the degree of decrease in platelet count (P = 0.012). In conclusion, SN-38 might possibly have a high risk of mutagenicity and carcinogenicity; and measurement of SCE values in peripheral blood lymphocytes appears to have a potential application in the clinical prediction of chemotherapy-induced side effects.
Department of Medical Oncology, National Cancer Center Hospital, Tokyo.
A
A
Kojima
T
T
Shinkai
N
N
Saijo
D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D002869:Chromosome Aberrations; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000077146:Irinotecan; D008214:Lymphocytes / Q000187:drug effects*; D009153:Mutagens / Q000009:adverse effects; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D009153:Mutagens; D000077146:Irinotecan; D002166:Camptothecin