Frequency of Tk and Hprt lymphocyte mutants and bone marrow micronuclei in B6C3F(1)/Tk+/- mice treated neonatally with zidovudine and lamivudine

• Published in: Carcinogenesis (New York) 2002-09, Vol.23 (9), p.1427
• Main Authors: Von Tungeln, Linda S, Hamilton, L Patrice, Dobrovolsky, Vasily N, Bishop, Michelle E, Shaddock, Joseph G, Heflich, Robert H, Beland, Frederick A
• Format: Article
• Language: English
• Subjects: Animals; Anti-HIV Agents - pharmacology; Bone Marrow - drug effects; Bromodeoxyuridine - pharmacology; Drug Interactions; Drug Resistance, Neoplasm - genetics; Erythrocytes - cytology; Female; Gene Frequency; Hypoxanthine Phosphoribosyltransferase - genetics; Lamivudine - pharmacology; Loss of Heterozygosity; Lymphocytes - drug effects; Lymphocytes - enzymology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Micronuclei, Chromosome-Defective - drug effects; Mutation; Thymidine Kinase - genetics; Zidovudine - pharmacology
• ISSN: 0143-3334
• DOI: 10.1093/carcin/23.9.1427

Mother-to-child transmission of the human immunodeficiency virus is substantially reduced by prenatal and postnatal treatment with anti-retroviral nucleoside analogues; however, the long-term consequences of these drug interventions are not known. The nucleoside analogue zidovudine (3'-azido-2',3'-dideoxythymidine; AZT) is carcinogenic in mice when administered transplacentally or neonatally, and this may be due to a genotoxic mechanism. Since single-drug treatment with AZT is being superseded by multidrug combinations, we have investigated the induction of mutations and micronuclei in mice treated neonatally with AZT, lamivudine (3'-thia-2',3'-dideoxycytidine; 3TC), or a combination of the two drugs. B6C3F(1)/Tk+/- mice were treated daily from days 1-8 of age with 200 mg AZT/kg/day, 200 mg 3TC/kg/day, or a mixture of 200 mg AZT + 200 mg 3TC/kg/day (AZT/3TC). One and 2 days after the last dose, bone marrow was collected to assess the induction of micronuclei in polychromatic erythrocytes; 3 weeks following treatment, the induction of mutants was determined in the hypoxanthine-guanine phosphoribosyltransferase (Hprt) and thymidine kinase (Tk) genes of spleen lymphocytes. AZT and AZT/3TC, but not 3TC, caused a significant increase in micronuclei, with the response being greatest one day after the last dose. None of the drugs induced mutations in the Hprt gene, while AZT and AZT/3TC, but not 3TC, caused a significant increase in the Tk mutant frequency. The increase in Tk mutants by AZT and AZT/3TC was associated with loss of the wild-type (Tk+) allele (loss of heterozygosity). These data suggest that AZT, but not 3TC, is genotoxic in neonatal mice, and that 3TC does not alter significantly the responses observed with AZT alone.