Differential cytotoxicity and DNA-damaging effects produced in human cells of the Mer+ and Mer- phenotypes by a series of 1-aryl-3-alkyltriazenes.
A series of arylalkyltriazenes has been investigated for its differential cytotoxicity towards the HT-29 (Mer+) and BE (Mer-) cell lines and for its ability to cause DNA strand breaks and cross-links. A monomethyltriazene (MMPT) and some hydroxymethyltriazene derivatives capable of generating the monomethyltriazene in situ were preferentially cytotoxic to the BE cell line when compared with the HT-29 cell line. The differential toxicity of MMPT is very similar to the analogous monochloroethyltriazene. In contrast, the dimethyl- and monoethyltriazenes in the series display reduced toxicity towards the BE cell line with little or no differential toxicity between the BE and HT-29 cell lines. MMPT and monochloroethyltriazene caused single strand DNA breaks in the two cell lines, whereas little or no DNA strand breaks were observed in either cell line after exposure to the monoethyl- or dimethyltriazene. However, these lesions could not account for the differential cytotoxicity observed. In measurements of DNA interstrand cross-linking none of the agents tested, including monochloroethyltriazene and MMPT, was found to cause such linkages. In contrast to previous results obtained with bifunctional monochloroethylating agents, which produced a similar differential cytotoxicity between these two cell lines, our results tend to suggest that lesions other than DNA interstrand cross-links may be responsible for the mechanisms of cell killing by chloroethylating agents.
D000478:Alkylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008780:Methyltransferases / Q000032:analysis*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010641:Phenotype; D014226:Triazenes / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D014226:Triazenes; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase