J. E. Leakey1 , F. W. Lee1 , S. M. Lewis1 , G. Olson2 , J. K. Dunnick3 , W. T. Allaben1 , 1OSC, 2TPA, 3900 NCTR Rd, Jefferson, AR 72079, 3NIEHS, POB 12233, Research Triangle Park, NC 27709
AZT/3TC antiretroviral drug combinations are given during pregnancy to reduce maternal-fetal HIV transmission. AZT is genotoxic in fetal mice and monkeys and carcinogenic in mice. We assessed a new C3B6-trp53tm1Brd[N12]F1 p53 haplodeficient transgenic mouse model for use in cancer bioassays. These mice, produced by mating Taconic C57Bl6(N12)trp53(-/-) males and C3H females, possibly have similar tumor profiles to B6C3F1 mice. Haplodeficient C3B6-trp53tm1Brd[N12]F1 mice were dosed with 0, 40, 80, 160, 240 mg/kg AZT or 160 mg/kg AZT combined with100 mg/kg 3TC, by gavage in aqueous methylcellulose/polysorbate 80 (0.2/0.1%), transplacentally from GD12 to GD18 then postnatally from PND1 until6 or 9 months old. During the initial postnatal period (PND1- PND28), survival was >95% and >82% for the control and dosed groups respectively. The AZT and AZT/3TC treatment produced only small (<10%) reductions in body weight gain, but mice from the AZT/3TC dose groups showed increased hprt mutation frequency when evaluated at PND 28. Both AZT at all 4 concentrations and AZT/3TC increased blood reticulocyte micronuclei formation at PND1, 10 and 28. AZT treatment did not significantly reduce hepatic mitochondrial gene expression or increase serum lactate levels, but did increase tumor incidence at 6 months of age. In male mice, preliminary data showed overall tumor rate increased from 0/25 in controls to 6/26 (23%) in the 240 mg/kg AZT group. Tumor types included 3 malignant lymphomas and 2 brain tumors. Thus, the C3B6-trp53tm1Brd[N12]F1 mouse may be a good model for evaluating cancer risk of antiretroviral drugs.