Relative mutagenic potencies of several nucleoside analogs, alone or in drug pairs, at the HPRT and TK loci of human TK6 lymphoblastoid cells

Experiments were performed to investigate the impact of didanosine (ddl), lamivudine (KC), and stavudine (d4T) on cell survival and mutagenicity in two reporter genes, hypoxonthine-quanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK), using a cell cloning assay for assessing the effects of individual nucleoside analogs (NRTIs)/drug combinations in human TK6 B-lymphoblastoid cells. Three-day treatments with 0, 33, 100, or 300 mu M ddl, 3TC, or dcl-3TC produced positive trends for increased HPRT and TK mutant frequencies. While dose-related trends were too small to reach significance after treatments with d4T or d4T-3TC, pairwise comparisons with control cells indicated that exposure to 100 mu M d4T or d4T-3TC caused significant elevations in HPRT mutants. Measurements of mutagenicity in cells exposed to d4T (or d4T-3TC) were complicated by the cytotoxicity of this NRTl. Enhanced increases in mutagenic responses to combined NRTI treatments, compared with single drug treatments, occurred as additive to synergistic effects in the HPRT gene of cells exposed to 100 mu M ddl3TC or 100 mu M d4T-3TC, and in the TK gene of cells exposed to 100 or 300 mu M ddl-3TC. Comparisons of these data to mutagenicity studies of other NRTls in the same system (Meng Q et al. [2000c]: Proc Nall Acad Sci USA 97:12667-126671; Torres SM et al. [2007]: Environ Mal Mutagen 48:224-238) indicate that the relative mutagenic potencies for all drugs tested to date are: AZT-ddl > ddl-3TC > AZT3TC congruent to AZT-3TC-ABC (abacavir)> AZT >= ddl > d4T3TC > 3TC > d4T > ABC. These collective data suggest that all NRTls with antiviral activity against HIV-1 may cause host cell DNA damage and mutations, and impose a cancer risk. Environ. Mol. Mutagen. 48:239-247, 2007. (c) 2007 Wiley-Liss, Inc.