Multiorgan transplacental and neonatal carcinogenicity of 3 '-azido-3 '-deoxythymidine in mice

The anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) is used successfully for reduction of perinatal viral transmission. However toxic side effects incl uding carcinogenesis are possible. To test this, pregnant CD-1 Swiss mice w ere given 25.0 or 12.5 mg AZT on gestation days 12-18. Previously we report ed an increase in lung, liver, and female reproductive system tumors in off spring euthanized at 1 year (Olivero et al., J. Natl. Cancer Inst. 89, 1602 -1608, 1997). Findings for all remaining offspring up to 2 years old are re ported here. AZT effects were most prominent in female offspring, with a si gnificant threefold increase in lung tumors, a reduction in lymphoblastic a nd follicle center cell lymphomas, and a significant increase in histiocyti c sarcomas (0 in controls, 3% after low-dose AZT, and 8% after high-dose AZ T, p = 0.022). Dose-dependent incidences of mammary gland, ovarian, and sem inal vesicle tumors were low but significant: 0/106 controls, 3/105 low-dos e, and 8/105 high-dose mice presented one of these neoplasms (p = 0.0025). Incidences of females showing any clearly AZT-related neoplasm, in lung, li ver, ovary, or mammary gland or histiocytic sarcoma, in the second year, we re 12/32 after the low dose and 14/27 after the high dose vs 3/23 controls (p = 0.0045). Also, the sensitivity of neonatal mice was assessed by admini stration of 25, 50, 100, or 200 mg/kg AZT on postnatal days 1 through 8. Th e effects at 2 years were similar to those seen after transplacental exposu re, with significant increases in lung, liver, and mammary tumors in female s. The results confirm that AZT is a moderately effective perinatal carcino gen in mice, targeting several tissue types.