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 top oisomerase (topo) I, and etoposide (VP-16), an inhibitor of topo II, t o potentiate X-radiation response and to inhibit the repair of potenti ally lethal damage (PLDR) and sublethal damage (SLDR) in confluent cul tures of a radioresistant (Sk-Mel-3) and a radiosensitive (HT-144) hum an melanoma cell line. CPT or VP-16 were present both during irradiati on and during the subsequent delayed plating period allowed for repair of X-radiation damage. When the direct toxicities of CPT or VP-16 wer e corrected for, we found that a dose of either drug that killed simil ar to 15% of the clonogenic cells potentiated the effects of radiation differentially on the cell lines. CPT and VP-16 inhibited the increas e in survival brought about by delayed plating of HT-144 but not Sk-Me l-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-radi ation 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 r epaired similar amounts of PLD from an isosurvival level. Sk-Mel-3, ho wever, repaired significantly increased SLD from an isosurvival level (about three-fold, p < 0.05) compared with HT-144.