Protein-linked DNA strand breaks produced by etoposide and teniposide in mouse L1210 and human VA-13 and HT-29 cell lines: relationship to cytotoxicity.
The two demethylepipodophyllotoxin glycosides, teniposide (VM-26) and etoposide (VP-16), have previously been reported to interact with DNA topoisomerase II by stabilizing a topoisomerase II-DNA covalent intermediate. This study examined the protein-associated aspect of the topoisomerase II-DNA-epipodophyllotoxin lesion. We found that in mouse (L1210) and human (VA-13 and HT-29) log-phase cell cultures, all DNA strand breaks produced by VP-16 or VM-26 were protein-associated. We found also that these protein-associated breaks occurred with a frequency which correlated with cytotoxicity in all three cell lines. For all three cell lines and for both compounds the regression lines were similar. Therefore, for a given class of topoisomerase II inhibitors, it may be possible to generate a characteristic line from which DNA-protein crosslink frequency predicts cytotoxicity.
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007700:Kinetics; D007939:Leukemia L1210 / Q000378:metabolism*; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D013713:Teniposide / Q000494:pharmacology* / Q000633:toxicity
D004273:DNA, Neoplasm; D005047:Etoposide; D013713:Teniposide; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin