1. Synergistic cytotoxicity of cisplatin and topotecan or SN-38 in a panel of eight solid-tumor cell lines in vitro
- Author
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Antonius W. M. Boersma, Marc Maliepaard, Jaap Verweij, Kees Nooter, Jan H.M. Schellens, Gerrit Stoter, J. Ma, and Medical Oncology
- Subjects
Cancer Research ,Stereochemistry ,SN-38 ,In Vitro Techniques ,Irinotecan ,Toxicology ,Drug Administration Schedule ,DNA Adducts ,chemistry.chemical_compound ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Cells, Cultured ,medicine ,Humans ,Pharmacology (medical) ,Cytotoxicity ,Pharmacology ,Cisplatin ,biology ,Topoisomerase ,Drug Synergism ,Cell cycle ,Molecular biology ,Oncology ,chemistry ,Cell culture ,Enzyme inhibitor ,biology.protein ,Camptothecin ,Topotecan ,medicine.drug - Abstract
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.
- Published
- 1998
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