Abstract
Extract: Some arabinosyl nucleosides and halogenated deoxyribosides are currently being used as antiviral chemotherapeutic agents. The halogenated deoxyriboside, 5-fluoro-2′-deoxyuri-dine (FUDR), the arabinosyl nucleoside, 3-β-D-arabino-furanosylcytosine (Ara-C), and other antimetabolites are known to interfere specifically with growth and cellular organization of the cerebellum postnatally. It has been shown that there is a difference in toxicity in in vitro tissue culture, adult animals and humans, between Ara-C and adenine arabinoside (Ara-A). Therefore, we compared these nucleosides and the deaminated metabolite of Ara-A, 9-β-D-arabino-furanosylhypoxanthine (hypoxanthine arabinoside, Ara-Hx), by administering varying doses of each nucleoside to two litters each (19–25 animals) of 2-day-old white rats. The Ara-C was given in doses of 3, 5, 10, and 15 mg/kg; the Ara-A 3, 5, 10, 20, 30, and 50 mg/kg; and the Ara-Hx 10 and 20 mg/kg. Injections were given on days 2, 3, 4, and 5. Additional litters were given injections of saline solution and used as controls. All animals were observed for survival, weight gain, vigor, and developmental motor behavior. The cerebellum was examined grossly and histologically at various intervals. The Ara-A and Ara-Hx-treated animals differed in no way in any of the variables studied from saline-injected controls. There was a definite increase in morbidity and mortality among the Ara-C-treated animals. Those receiving the lowest dose of Ara-C (3 mg/kg) were retarded in growth and there was disorganization of the cytoarchitecture of the cerebellum early in development; however, repair occurred and no behavioral or developmental abnormalities resulted in mature animals. With the higher doses of Ara-C (≥ 5 mg/kg), profound disruption of cerebellar cytoarchitecture occurred; both gross neurologic abnormalities and marked growth retardation developed in adult animals which survived.
Speculation: There are problems with assuming direct or unifying structure-action relations among chemotherapeutic agents. Efforts should be exerted to determine accurately the kinetic parameters and therapeutic index for each new drug as it comes into use. The data presented here show that, in doses effective against DNA viral infection, the purine nucleosides Ara-A and Ara-Hx did not substantially impair DNA replication and inhibit cellular function in the rat cerebellum in comparison to the pyrimidine nucleoside, Ara-C. It is interesting to speculate that Ara-A may be incorporated preferentially into viral nucleic acid by viral enzymes, as in the case of 5-bromodeoxycytidine by herpes virus-infected cells. Assuming that Ara-A is proven further to be an effective antiviral compound, the lack of toxicity upon rapidly replicating cells of various systems gives it an obvious advantage in comparison with other compounds which inhibit DNA viral replication.
Similar content being viewed by others
Article PDF
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Fishaut, J., Connor, J. & Lampert, P. Comparative Effects of Arabinosyl Nucleosides upon the Postnatal Growth and Development of the Rat. Pediatr Res 8, 825–829 (1974). https://doi.org/10.1203/00006450-197410000-00002
Issue Date:
DOI: https://doi.org/10.1203/00006450-197410000-00002