N-trifluoroacetyladriamycin-14-valerate and adriamycin induced DNA damage in the RPMI-6410 human lymphoblastoid cell line.
The adriamycin- and N-trifluoroacetyladriamycin-14-valerate (AD-32) induced DNA cross-linking and breakage in human RPMI-6410 cells was compared using the alkaline elution technique of Kohn and co-workers. At comparable growth-inhibitory concentrations both adriamycin and AD-32 caused DNA cross-linking. Treatment with proteinase-K showed this cross-linking to be mainly DNA-protein in character. Proteinase-K treatment also revealed that both drugs caused either single-strand DNA breaks or increased alkaline sensitivity. With adriamycin the degree of cross-linking and breakage was dose related over the range studied (0.05 - 0.4 micron/mL), whereas with AD-32 there appeared to be a saturation of both effects at concentrations in excess of 3 micron/mL. With both drugs the extent of cross-linking and breakage was maximal at the end of the drug exposure. This work suggests that AD-32 or some metabolite of its binds to DNA and this binding leads to DNA damage that is similar to that caused by adriamycin. These AD-32 results are somewhat surprising in light of earlier model studies showing that AD-32 does not bind to isolated DNA.
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019286:Endopeptidase K; D010450:Endopeptidases; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes / Q000187:drug effects*
D003432:Cross-Linking Reagents; C016163:valrubicin; D004317:Doxorubicin; D004247:DNA; D010450:Endopeptidases; D019286:Endopeptidase K