Growth inhibition of Kirkman-Robbins hepatoma by 1-(1,3-dihydroxy-2-propoxymethyl)-5,6-tetramethyleneuracil and possible mechanism of its biological activity.

1-(1,3-Dihydroxy-2-propoxymethyl)-5,6-tetramethylene-uracil (DHPTU) is a newly synthesized acyclonucleoside which shows cytostatic properties. It was tested in Syrian hamster 6 days after heterotransplantation of Kirkman-Robbins hepatoma. A reduction of tumour weight by 61% was found 48 h after its intraperitoneal (i.p.) administration in doses of 20 mg per kg of body weight. Inhibition of tumour growth is accompanied by a reduction of dThd, dGuo and dTMP kinase activities in tumour cytosol (by 91% and 74% and 55%, respectively) and decrease in contents of dTTP, dGTP and dATP (by 92%, 77% and 67%, respectively) in dNTP pool. DHPTU is not phosphorylated by any tumour dN kinases, but undergoes cleavage with TU release in reaction catalyzed by the tumour cell enzyme, competitively inhibited by FA. After [14C]DHPTU or [14C]TU had been given i.p. to the animals with the tumour, 90% of the subcellular fraction labelling fell into the nuclear fraction. However, if [14C]DHPTU was administered with FA and DCF, 27% of radioisotope was found in the nuclear fractions and 68% in cytosol. Since DCF which prevented FA deamination to FB (which is not an inhibitor of the mentioned enzyme) reduces DHPTU-induced changes in activity of dN kinases and dTMP kinase in hepatoma cells, the cytostatic activity of DHPTU seems to be connected to an enzyme which releases TU from DHPTU.