Potentiation of cisplatin cytotoxicity by 9-aminocamptothecin.
Camptothecin (CPT) derivatives are presently in ongoing Phase I/II clinical trials. The interactions between 9-aminocamptothecin (9AC) and cisplatin (CDDP) have been studied in the IGROV-1 human ovarian cancer cell line used in the National Cancer Institute Drug Discovery Anticancer Screen. One-h simultaneous treatment with 9AC and CDDP produced synergistic cytotoxicity. Under these conditions, 9AC delayed the reversal of CDDP-induced DNA interstrand cross-links (ISCs) without modifying the maximum ISC frequency at 6 h after drug treatment. CDDP did not affect the amount and the kinetics of reversion of 9AC-induced DNA single-strand breaks. Simultaneous treatment with CDDP and 9AC prolonged the DNA synthesis inhibition produced by each drug alone. Consistently, flow cytometry analyses showed enhanced S-phase arrest in cells treated with the CDDP-9AC combination. The DNA polymerase inhibitor aphidicolin also increased the residual CDDP-induced ISCs. These results suggest that prolonged inhibition of DNA synthesis by CPTs potentiate the cytotoxicity of CDDP by inhibiting the reversal of CDDP-induced DNA damage. Therefore, the combination of CPTs and CDDP appears to be worthwhile in cancer chemotherapy.
Goldwasser
F
F
Laboratory of Molecular Pharmacology, Division of Basic Science, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA.
Valenti
M
M
Torres
R
R
Kohn
K W
KW
Pommier
Y
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016590:Aphidicolin / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D016196:S Phase / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004277:DNA, Single-Stranded; D016590:Aphidicolin; C080125:9-aminocamptothecin; D004247:DNA; D002945:Cisplatin; D002166:Camptothecin