Frequency of Tk and Hprt lymphocyte mutants and bone marrow micronuclei in B6C3F1/Tk+/– mice treated neonatally with zidovudine and lamivudine

• Published in: Carcinogenesis (New York) 2002-09, Vol.23 (9), p.1427-1432
• 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: 3TC; 3′-azido-2; 3′-dideoxycytidine; 3′-dideoxyinosine; 3′-dideoxythymidine; 3′-thia-2; 5-bromodeoxyuridine-resistant; 6-TGR; 6-thioguanine-resistant; acquired immunodeficiency syndrome; adenine phosphoribosyltransferase (gene); AIDS; analysis of variance; ANOVA; APrC; AZT; Biological and medical sciences; BrdUR; ddI; didanosine; dimethylsulfoxide; DMSO; Drug toxicity and drugs side effects treatment; ENU; HIV; Hprt; human immunodeficiency virus type 1; hypoxanthine-guanine phosphoribosyltransferase (gene); lamivudine; LOH; loss of heterozygosity; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); N-ethyl-N-nitrosourea; PCE; PCR; Pharmacology. Drug treatments; PND; polychromatic erythrocytes; polymerase chain reaction; postnatal day; SEM; standard error of the mean; thymidine kinase (gene); zidovudine
• ISSN: 0143-3334; 1460-2180; 1460-2180
• 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 Since single-drug treatment with AZT is being superseded by multidrug combinations, we have investigated the induction of mutations and micronuclei in mice treated neonatally with AZT, lamivudine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. B6C3F1/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.