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

被引:60
作者
Diwan, BA [1 ]
Riggs, CW
Logsdon, D
Haines, DC
Olivero, OA
Rice, JM
Yuspa, SH
Poirier, MC
Anderson, LM
机构
[1] Data Management Serv Inc, Intramural Res Support Program, Frederick, MD 21702 USA
[2] SAIC Frederick Inc, Lab Anim Sci Program, Frederick, MD 21702 USA
[3] SAIC Frederick Inc, Pathol Histotechnol Lab, Frederick, MD 21702 USA
[4] NCI, Comparat Carcinogenesis Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA
[5] NCI, Cellular Carcinogenesis & Tumor Promot Lab, Div Basic Sci, Bethesda, MD 20892 USA
[6] Int Agcy Res Canc, F-69372 Lyon, France
关键词
carcinogenesis; transplacental; perinatal; AZT; fetus; mice;
D O I
10.1006/taap.1999.8782
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
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页码:82 / 99
页数:18
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