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Possible effects of antimetabolites on virus replication McMillan, Jeanette Margot

Abstract

Because of the varied opinions and findings concerning the effect of cellular antimetabolites on the replication of both RNA and DNA-containing animal viruses, this project was undertaken to observe the effects of antimetabolites on Newcastle disease and vaccinia viruses: an RNA and a DNA virus respectively. The compounds chosen were the pyrimidine analogues 5-fltrorouracil and 5-iodo-deoxyuridine, and thioguanine, a purine antimetabolite. These compounds were chosen because they have already been shown to have growth inhibiting properties in other systems. Inhibition of virus replication was attempted rather than protection of cells, although some effort was made at the outset to determine the tolerance of the 10 - 12 day old chick embryo for the antimetabolites used in this study. The tolerance of the 10 - 12 day old chick was determined by inoculating the yolk sac of the developing embryo with the analogues and noting the survival time. The maximal concentration of the analogue which allowed 3 out of 4 embryos to survive for 48 hours at 37°c was the dose employed in the tests. Inoculation of the embryos with the virus was via the allantoic cavity or the chorio-allantoic membrane. Administration of the antimetabolite was made via the yolk sac either immediately after virus inoculation or if- hours later. After incubation for 36 - 48 hours at 37°C, the allantoic fluid and homogenized chorio-allantoic membranes were assayed to determine whether, there was any decrease in the production of virus-specific material in the presence of the antimetabolites. Tissue cultures of chick fibroblast cells infected with vaccinia virus were treated with antimetabolite and observed for noticeable changes. Nucleic acid analogues appear to vary in their inhibitory effects on different viruses. The enzymatic mechanism of the inhibitions seems to differ in different organisms. Antimetabolites may inhibit replication of DNA viruses and not of RNA viruses, or they may vary in degree and manner of inhibition among the DNA or RNA containing viruses themselves. 5-Fluorouracil was found to inhibit partially the replication of vaccinia virus in the chick embryo. The antimetabolite appeared to have no significant effect on the replication of Newcastle Disease virus. There were no observable differences in the titers of either virus harvested from thioguanine treated embryos as compared with-untreated embryos.

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