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Titre du document / Document title

Transplacental effects of 3'-azido-2',3 -dideoxythymidine (AZT) : Tumorigenicity in mice and genotoxicity in mice and monkeys

Auteur(s) / Author(s)

OLIVERO O. A. (1) ; ANDERSON M. L. (2) ; DIWAN B. A. (3) ; HAINES D. C. (4) ; HARBAUGH S. W. (5) ; MOSKAL T. J. (5) ; JONES A. B. (2) ; RICE J. M. (6) ; RIGGS C. W. (7) ; LOGSDON D. (8) ; YUSPA S. H. (1) ; POIRIER M. C. (1) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Laboratory of Cellular Carcinogenesis and Tumor Promotion, Division of Basic Sciences, National Cancer Institute, Bethesda, MD, ETATS-UNIS
(2) Laboratory of Comparative Carcinogenesis, Division of Basic Sciences, National Cancer Institute, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD, ETATS-UNIS
(3) Intramural Research Supported Program, Science Applications International Corp.-National Cancer Institute-Frederick Cancer Research and Development Center, ETATS-UNIS
(4) Pathology/ Histotechnology Laboratory, Science Applications International Corp.-National Cancer Institute-Frederick Cancer Research and Development Center, ETATS-UNIS
(5) BioQual, Inc., Rockville, MD, ETATS-UNIS
(6) International Agency for Research on Cancer, Lyon, FRANCE
(7) Data Management Services, Inc., National Cancer Institute-Frederick Cancer Research and Development Center, ETATS-UNIS
(8) Laboratory Animal Sciences Program, Science Applications International Corp.-National Cancer Institute-Frederick Cancer Research and Development Center, ETATS-UNIS

Résumé / Abstract

Background: When given during pregnancy, the drug 3'-azido-2',3'-dideoxy-thymidine (AZT) substantially reduces maternal-fetal transmission of human immunodeficiency virus type 1 (HIV-1). However, AZT has been shown to be carcinogenic in adult mice after lifetime oral administration. In this study, we assessed the transplacental tumorigenic and genotoxic effects of AZT in the offspring of CD-1 mice and Erythrocebus patas monkeys given AZT orally during pregnancy. Methods: Pregnant mice were given daily doses of either 12.5 or 25.0 mg AZT on days 12 through 18 of gestation (last 37% of gestation period). Pregnant monkeys were given a daily dose of 10.0 mg AZT 5 days a week for the last 9.5-10 weeks of gestation (final 41%-43% of gestation period). AZT incorporation into nuclear and mitochondrial DNA and the length of chromosomal end (telomere) DNA were examined in multiple tissues of newborn mice and fetal monkeys. Additional mice were followed from birth and received no further treatment until subjected to necropsy and complete pathologic examination at 1 year of age. An anti-AZT radioimmunoassay was used to monitor AZT incorporation into DNA. Results: At 1 year of age, the offspring of AZT-treated mice exhibited statistically sig nificant, dose-dependent increases in tumor incidence and tumor multiplicity in the lungs, liver, and female reproductive organs. AZT incorporation into nuclear and mitochondrial DNA was detected in multiple organs of transplacentally exposed mice and monkeys. Shorter chromosomal telomeres were detected in liver and brain tissues from most AZT-exposed newborn mice but not in tissues from fetal monkeys. Conclusions : AZT is genotoxic in fetal mice and monkeys and is a moderately strong transplacental carcinogen in mice examined at 1 year of age. Careful long-term follow-up of AZT-exposed children would seem to be appropriate.

Revue / Journal Title

Journal of the National Cancer Institute    ISSN  0027-8874 

Source / Source

1997, vol. 89, no21, pp. 1602-1608 (39 ref.)

Langue / Language

Anglais

Editeur / Publisher

Oxford University Press, Cary, NC, ETATS-UNIS  (1940) (Revue)

Mots-clés anglais / English Keywords

Zidovudine

;

Antiviral

;

Pregnancy

;

Carcinogen

;

Mutagenicity testing

;

Toxicity

;

DNA

;

Placental transfer

;

Tumorigenicity

;

Mouse

;

Monkey

;

Animal

;

Pyrimidine nucleoside

;

Dideoxynucleoside

;

Rodentia

;

Mammalia

;

Vertebrata

;

Primates

;

Mots-clés français / French Keywords

Zidovudine

;

Antiviral

;

Gestation

;

Carcinogène

;

Test mutagénicité

;

Toxicité

;

DNA

;

Passage transplacentaire

;

Tumorigénicité

;

Souris

;

Singe

;

Animal

;

Pyrimidine nucléoside

;

Didésoxynucléoside

;

Rodentia

;

Mammalia

;

Vertebrata

;

Primates

;

Mots-clés espagnols / Spanish Keywords

Zidovudina

;

Antiviral

;

Gestación

;

Carcinógeno

;

Prueba mutagenicidad

;

Toxicidad

;

DNA

;

Paso transplacentario

;

Tumorigenicidad

;

Ratón

;

Mono

;

Animal

;

Pirimidina nucleósido

;

Didesoxinucleósido

;

Rodentia

;

Mammalia

;

Vertebrata

;

Primates

;

Localisation / Location

INIST-CNRS, Cote INIST : 3364, 35400007782080.0060

Nº notice refdoc (ud4) : 2120708



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