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 including carcinogenesis are possible. To test this, pregnant CD-1 Swiss mice were given 25.0 or 12.5 mg AZT on gestation days 12-18. Previously we reported an increase in lung, liver, and female reproductive system tumors in offspring 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 reported here. AZT effects were most prominent in female offspring, with a significant threefold increase in lung tumors, a reduction in lymphoblastic and follicle center cell lymphomas, and a significant increase in histiocytic sarcomas (0 in controls, 3% after low-dose AZT, and 8% after high-dose AZT, p = 0.022). Dose-dependent incidences of mammary gland, ovarian, and seminal vesicle tumors were low but significant: 0/106 controls, 3/105 low-dose, 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, liver, ovary, or mammary gland or histiocytic sarcoma, in the second year, were 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 administration of 25, 50, 100, or 200 mg/kg AZT on postnatal days 1 through 8. The effects at 2 years were similar to those seen after transplacental exposure, with significant increases in lung, liver, and mammary tumors in females. The results confirm that AZT is a moderately effective perinatal carcinogen in mice, targeting several tissue types.
Diwan
B A
BA
Division of Basic Sciences, SAIC-Frederick, Inc., Frederick, Maryland, 21702-1201, USA.
Riggs
C W
CW
Logsdon
D
D
Haines
D C
DC
Olivero
O A
OA
Rice
J M
JM
Yuspa
S H
SH
Poirier
M C
MC
Anderson
L M
LM
D000818:Animals; D000831:Animals, Newborn; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity; D001462:Barbital / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D019337:Hematologic Neoplasms / Q000139:chemically induced; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000556:secondary; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D011247:Pregnancy; D015996:Survival Rate; D013997:Time Factors; D014565:Urogenital Neoplasms / Q000139:chemically induced; D015215:Zidovudine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*
D019380:Anti-HIV Agents; D002273:Carcinogens; D015215:Zidovudine; D001462:Barbital