Synergistic cytotoxicity of cisplatin and topotecan or SN-38 in a panel of eight solid-tumor cell lines in vitro.
The cytotoxicity of cisplatin alone and in combination with topotecan (TPT) or SN-38, two novel topoisomerase I (topo I) inhibitors, was determined in a panel of eight well-characterized human solid-tumor cell lines. Interactions between cisplatin and these topo I inhibitors were investigated using three different administration schedules: (1) simultaneous incubation (C + T and C + S), (2) cisplatin followed by TPT or SN-38 (C --> T and C --> S), and (3) TPT or SN-38 followed by cisplatin (T --> C and S --> C). Median-effect analysis revealed synergistic cytotoxicity in seven of the eight cell lines used. In addition, a significant schedule-dependent synergistic cytotoxicity was found in three of the cell lines used, with C --> T (or C --> S) being the most active schedule. The formation and repair of total cisplatin-DNA adducts in the IGROV-1 ovarian cancer cell line and its cisplatin-resistant subline IGROV(CDDP) was not significantly affected by TPT on simultaneous incubation. In contrast, the number of cisplatin-DNA interstrand cross-links detected in the IGROV-1 and IGROV(CDDP) lines at certain time points was significantly lower after coincubation of the cells with TPT. Assessment of the cell-cycle distribution revealed an accumulation of cells in the G2/M phase after exposure to cisplatin. After exposure to TPT a different pattern was observed that was cell-type-specific and dependent upon the TPT concentration. Although up to 4-fold differences in topo I activity were observed in this panel of cell lines, these differences did not appear to be related to the synergy observed between cisplatin and TPT or SN-38. The observed synergy may at least partly be explained by the increased retention of cisplatin-DNA interstrand cross-links in the presence of topo I inhibitors.
Ma
J
J
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek)/University Hospital, The Netherlands.
Maliepaard
M
M
Nooter
K
K
Boersma
A W
AW
Verweij
J
J
Stoter
G
G
Schellens
J H
JH
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000494:pharmacology; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D018736:DNA Adducts / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D000077146:Irinotecan; D019772:Topotecan / Q000009:adverse effects* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018736:DNA Adducts; D000077146:Irinotecan; D019772:Topotecan; D002945:Cisplatin; D002166:Camptothecin