TOXICITY OF AIDS DRUGS ON HUMAN PLACENTA

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HIV infection of infants generally occurs ante-or intra-partum. The logical approach to the prevention or the reduction in the severity of infection is to treat the infected mother. AZT and other nucleosides are currently under consideration for such use. However, the administration of AZT is often associated with bone marrow depression raising the possibility of a general adverse effect on rapidly proliferating tissue. The fetal tissue that is exposed to the highest concentration of maternally administered medication in the placenta. Interference with placental function could have serious secondary effects in the fetus. Our recent observation that AZT is extensively metabolized by the placenta raises the possibility of local toxicity. The antiviral effect of AZT, as well as its toxic effects, is attributed to metabolites of AZT, particularly the triphosphate. A safe technique for investigating these questions before clinical trials with AZT and other anti-AIDS drugs is highly desirable. It is proposed to employ human trophoblast in tissue culture to study the metabolism of AZT and its effect on growth, differentiation and function of the trophoblast. This approach will complement our previously funded study of the placental transfer and metabolism of drugs for AIDS using placental perfusion. That proposal focuses on the potential exposure of the developing fetus to AZT and other nucleosides and their metabolites in contrasts to the present proposal which will concentrate on the effects of AZT, and possibly other drugs related to the treatment of AIDS on the trophoblast itself. An additional approach which would add a new dimension to this line or inquiry is the development of a polarized syncytiotrophoblast barrier in vitro by using bicameral filter chamber devices. Such a model have a wide application in examining the effects of AZT and other drugs, on trophoblast function, the transmission of HIV virus and the transfer of other molecules across the placenta.