Frequency of Tk and Hprt lymphocyte mutants and bone marrow micronuclei in B6C3F(1)/Tk+/- mice treated neonatally with zidovudine and lamivudine.
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 Since single-drug treatment with AZT is being superseded by multidrug combinations, we have investigated the induction of mutations and micronuclei in mice treated neonatally with AZT, lamivudine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.
Von Tungeln
Linda S
LS
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
Hamilton
L Patrice
LP
Dobrovolsky
Vasily N
VN
Bishop
Michelle E
ME
Shaddock
Joseph G
JG
Heflich
Robert H
RH
Beland
Frederick A
FA
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000494:pharmacology; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004912:Erythrocytes / Q000166:cytology; D005260:Female; D005787:Gene Frequency; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D019259:Lamivudine / Q000494:pharmacology*; D019656:Loss of Heterozygosity; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects*; D009154:Mutation; D013937:Thymidine Kinase / Q000235:genetics*; D015215:Zidovudine / Q000494:pharmacology*
D019380:Anti-HIV Agents; D019259:Lamivudine; D015215:Zidovudine; D007041:Hypoxanthine Phosphoribosyltransferase; D013937:Thymidine Kinase; D001973:Bromodeoxyuridine