Differential cytotoxicity and DNA-damaging effects produced in human cells of the Mer+ and Mer- phenotypes by a series of alkyltriazenylimidazoles.

Abstract

A series of alkyltriazenylimidazoles have been investigated for their differential cytotoxicity towards the HT-29 (Mer+) and BE (Mer-) cell lines and for their ability to cause DNA strand breaks and cross-links. A monomethyltriazene, and some hydroxymethyltriazene derivatives capable of generating the monomethyltriazene in situ, were preferentially cytotoxic towards the BE cell line compared with the HT-29 cell line, with very close similarity in the differential toxicity 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 BE and HT-29 cell lines. With another pair of human cell lines, the IMR-90 (Mer+) and VA-13 (Mer-) cells, the monomethyl- and monochloroethyltriazenes were again more cytotoxic to the Mer- cells. Neither the formation of DNA single-strand breaks or DNA-protein cross-links could account for the differential cytotoxicity observed in the Mer+ and Mer- cells. More importantly, the inability of the monofunctional monomethyltriazene to cross-link DNA tends to question the role of DNA inter-strand cross-linking as a mechanism for cell killing by chloroethylating agents.