Inhibition of potentially lethal and sublethal damage repair by camptothecin and etoposide in human melanoma cell lines.
We investigated the ability of camptothecin (CPT), an inhibitor of topoisomerase (topo) I, and etoposide (VP-16), an inhibitor of topo II, to potentiate X-radiation response and to inhibit the repair of potentially lethal damage (PLDR) and sublethal damage (SLDR) in confluent cultures of a radioresistant (Sk-Mel-3) and a radiosensitive (HT-144) human melanoma cell line. CPT or VP-16 were present both during irradiation and during the subsequent delayed plating period allowed for repair of X-radiation damage. When the direct toxicities of CPT or VP-16 were corrected for, we found that a dose of either drug that killed approximately 15% of the clonogenic cells potentiated the effects of radiation differentially on the cell lines. CPT and VP-16 inhibited the increase in survival brought about by delayed plating of HT-144 but not Sk-Mel-3 cells. In both cell lines, CPT inhibited SLDR but not PLDR. VP-16 also inhibited SLDR in both cell lines, however, in contrast with CPT, it also inhibited PLDR in HT-144 cells. Our results therefore suggest that either topo I and II are both implicated in the repair of X-radiation damage, or that the lesions formed by CPT and VP-16 with DNA are able to impair the processing of X-radiation repair. In addition, we found that in the absence of the topo inhibitors, the two cell lines repaired similar amounts of PLD from an isosurvival level. Sk-Mel-3, however, repaired significantly increased SLD from an isosurvival level (about three-fold, p < 0.05) compared with HT-144.
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Ottawa Regional Cancer Centre, Ontario, Canada.
Bussey
A M
AM
Raaphorst
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GP
D002166:Camptothecin / Q000494:pharmacology*; D016923:Cell Death; D004247:DNA / Q000187:drug effects* / Q000528:radiation effects*; D004260:DNA Repair; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D008545:Melanoma; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D011838:Radiation-Sensitizing Agents; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin