VAGINAL EPITHELIAL DNA-DAMAGE AND EXPRESSION OF PRENEOPLASTIC MARKERSIN MICE DURING CHRONIC DOSING WITH TUMORIGENIC LEVELS OF 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE

3'-Azido-2',3'-dideoxythymidine (AZT, Retrovir, zidovudine), a nucleos ide analogue currently used in the therapy of acquired immunodeficienc y syndrome, induces papillomas and carcinomas in vaginal epithelium of mice as a result of lifetime drug administration. In this study, fema le CD-1 mice were administered AZT at doses of 180, 360, and 720 mu g/ ml of drinking water for 28 days to determine whether AZT became incor porated into vaginal DNA and whether this was associated with preneopl astic changes within the target tissue. In addition, bone marrow, a ta rget for AZT-induced cytotoxicity in mice and humans, was examined for chromosomal aberrations. A positive correlation was observed between dose level of AZT, proliferation of cells in the basal layer of vagina l epithelium, and incorporation of AZT into vaginal DNA. Incorporation of AZT into vaginal DNA was originally detected by radioimmunoassay a nd confirmed by immunohistochemistry. An aberrant pattern for alpha 6 integrin distribution, similar to the pattern described in skin papill omas with high risk for malignant conversion, also increased with dose in mice given AZT. Chromosomal aberrations in bone marrow increased m ore than 4-fold in AZT-exposed animals. The genotoxicity demonstrated by incorporation of AZT into vaginal DNA and proliferation of vaginal epithelium may play an essential part in the ability of AZT to induce abnormal differentiation in vaginal epithelium and vaginal tumorigenes is in mice.