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.
Greger
J
J
Department of General Chemistry, Institute of Physiology and Biochemistry, School of Medicine, Lódz, Poland.
Dramiński
M
M
D000818:Animals; D001711:Biotransformation; D006224:Cricetinae; D005260:Female; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D008647:Mesocricetus; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D013937:Thymidine Kinase / Q000378:metabolism; D014498:Uracil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use
C063619:1-(1,3-dihydroxy-2-propoxymethyl)-5,6-tetramethyleneuracil; D014498:Uracil; D010770:Phosphotransferases; D013937:Thymidine Kinase; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase