Pyrazofurin interactions with anti-metabolites

Williams, Christopher John Hacon (1979) Pyrazofurin interactions with anti-metabolites. University of Southampton, Doctoral Thesis.

Abstract

This study was designed to test the hypothesis that pyrazofurin could increase the anti-tumour effects of other anti-metabolites. A secondary aim was to assess whether synergistic drug interactions are likely to be clinically useful. The anti-tumour activity of pyrazofurin in combination with other pyrimidine antagonists was tested in TLX/5 lymphoma in tissue culture and CBA/Ca mice; toxicity was assessed in uninoculated CAA/Ca mice. The nature of drug interactions was assessed by the method of isobolograms. Amongst various interactions, pyrazofurin and 5-azacytidine was the most synergistic for anti-tumour activity. Concomitant synergism for toxicity occurred and uridine (a rescue agent) was non-specific in reversing the effects of the combination. High pressure liquid chromatography of the nucleotides from cells treated with pyrazofurinn alone and pyrazofurin and 5-azacytidine showed substantial reductions in UTP and CTP levels; lesser reductions in UTP and CTP occurred in 5-azacytidine treated cells. Although a peak for aza-CTP was not identified, reduction of LIP and CTP levels in this study and evidence from recent studies suggests that the reduction in levels of UTP and CTP releases a feed-back inhibition on uridine cytidine kinase, and that this causes increased incorporation of 5-azacytidine into RNA and inhibition of protein synthesis. Although the drug combinations used in this study showed interactions, including synergism for anti-tumour effects, these interactions were non-specific. Such interactions are unlikely to be of clinical importance and the general role of pre-clinical testing of drug interactions as an aid to the rational choice of drugs for combination chemotherapy is discussed.

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