DNA damaging and cell cycle effects of the topoisomerase I poison camptothecin in irradiated human cells.
This study addressed the potential radiosensitizing and DNA-damaging actions of the DNA topoisomerase I poison camptothecin (CPT) on SV40 transformed normal (MRC5CVI) and ataxia-telangiectasia (AT5BIVA) fibroblast cell lines. In both cell lines CPT induced a dose-dependent delay of cells in S phase, followed by a dose-dependent trapping in G2/M phase. Acute X-irradiation produced patterns of G2/M arrest and S-phase delay similar to those observed for CPT in the MRC5CVI cell line, but no S phase delay was observed in the AT5BIVA cell line consistent with the ataxiatelangiectasia phenotype of this cell line. X-irradiation of CPT-treated cells resulted in additive prolongation of S phase delay in MRC5CVI cultures and additive effects for cell killing in both cell lines. The potential for topoisomerase I-DNA cross-linking by CPT was not altered by 24h pretreatment with CPT, or by acute X-irradiation. Hypersensitivity of AT5BIVA to CPT was not attributable to elevated levels of complex trapping. These findings suggest that in a rapidly proliferating human tumour there is unlikely to be synergistic therapeutic gain when the two agents are used concurrently, and that previously reported radiosensitization by CPT is restricted to G0 phase cells.
Falk
S J
SJ
MRC Clinical Oncology and Radiotherapeutics Unit, MRC Centre, Cambridge, UK.
Smith
P J
PJ
D002166:Camptothecin / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects* / Q000528:radiation effects*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006801:Humans; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors
D011838:Radiation-Sensitizing Agents; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin