AZT, A GENOTOXIC TRANSPLACENTAL CARCINOGEN IN RODENTS, IS INCORPORATED INTO HUMAN FETAL AND MATERNAL DNA.

ABSTRACT 8

Background: Treatment of HIV-1 positive pregnant women with AZT for the last two trimesters reduces vertical transmission of the HIV-1 virus from ∼25% to ∼7%, with unknown consequences to the fetus. This may be of concern since AZT is a moderate transplacental carcinogen in the mouse. Offspring of pregnant CD-1 mice given daily doses of 25.0 mg AZT for the last 7 days (37%) of gestation had lung and liver tumor incidences 3- to 8-fold higher than in the controls and a 17% incidence of female reproductive organ tumors with none in the controls. (Olivero et al., JNCI, 1997). In newborn mice given the same AZT exposure, AZT-DNA incorporation, up to 76 molecules of AZT/10⁶ nucleotides, was detectable in lung, liver, kidney and skin DNA.

Methods: Incorporation of AZT into DNA of peripheral blood mononuclear cells (PBMC) from ten AZT treated mothers and cord blood from their infants was determined by AZT-DNA radioimmunoassay.

Results: AZT-DNA incorporation was detected in peripheral blood of 5 out of the 10 mothers and in cord blood from 7 of the 10 infants. Levels of AZT were 50.4 ± 15.8 molecules of AZT/10⁶ nucleotides in the mothers and 97.4 ± 41.0 molecules of AZT/10⁶ nucleotides in the infants. These levels of incorporation were comparable to the values detected in the newborn mouse tissues.

Conclusions: Similar levels of AZT-DNA incorporation were detected in peripheral blood from HIV-1-positive mothers and cord blood from their infants and tissues from newborn mice exposed to tumorigenic doses of AZT in utero. Therefore, the biologically effective dose (i.e. the amount of AZT that incorporated into DNA) was similar in both species even though the mouse daily dose of AZT was much higher than that received by humans. The data suggest that surveillance of AZT-exposed children should be carried out well into adulthood.