title: Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD-1 mice to single agents or drug combinations.
abstract: Experiments were performed to investigate the impact of zidovudine (AZT), lamivudine (3TC), and abacavir (ABC) on cell survival and mutagenicity in two reporter genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK), using cell cloning assays for assessing the effects of individual drugs/drug combinations in (1) TK6 human lymphoblastoid cells exposed in vitro and (2) splenic lymphocytes from male CD-1 mice exposed transplacentally on days 12-18 of gestation. In TK6 cells, dose-related increases in HPRT and TK mutant frequencies were found following 3 days of exposure to AZT or 3TC alone (33, 100, or 300 microM), or to equimolar amounts of AZT-3TC. Compared with single drug exposures, AZT-3TC coexposures generally yielded enhanced elevations in HPRT and TK mutant frequencies. Mutagenicity experiments with ABC alone, or in combination with AZT-3TC, were complicated by the extreme cytotoxicity of ABC. Exposure of cells either to relatively high levels of AZT-3TC short-term (100 microM, 3 days), or to peak plasma-equivalent levels of AZT-3TC for an extended period (10 microM, 30 days), resulted in similar drug-induced mutagenic responses. Among sets of mice necropsied on days 13, 15, or 21 postpartum, Hprt mutant frequencies in T-cells were significantly elevated in the AZT-only (200 mg/kg bw/day) and AZT-3TC (200 mg AZT + 100 mg 3TC/kg bw/day) groups at 13 days of age. These results suggest that the mutagenicity by these nucleoside analogs is driven by cumulative dose, and raises the question of whether AZT-3TC has greater mutagenic effects than AZT alone in perinatally exposed children.
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors.forename: Salina M
authors.initials: SM
authors.lastname: Torres
authors.forename: Dale M
authors.initials: DM
authors.lastname: Walker
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Carter
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Cook
authors.forename: Consuelo L
authors.initials: CL
authors.lastname: McCash
authors.forename: Edmund M
authors.initials: EM
authors.lastname: Cordova
authors.forename: Ofelia A
authors.initials: OA
authors.lastname: Olivero
authors.forename: Miriam C
authors.initials: MC
authors.lastname: Poirier
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Walker
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D015224:Dideoxynucleosides / Q000633:toxicity*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D019259:Lamivudine / Q000633:toxicity*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D008815:Mice, Inbred Strains; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D011247:Pregnancy; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity*; D013937:Thymidine Kinase / Q000235:genetics; D015215:Zidovudine / Q000633:toxicity*; D000099227:Abacavir
chemical_list: D019380:Anti-HIV Agents; D004247:DNA; D015224:Dideoxynucleosides; D007041:Hypoxanthine Phosphoribosyltransferase; D019259:Lamivudine; D009153:Mutagens; D018894:Reverse Transcriptase Inhibitors; D013937:Thymidine Kinase; D015215:Zidovudine; D000099227:Abacavir