The influence of alkoxymethyl purine and pyrimidine acyclonucleosides on growth inhibition of Kirkman-Robbins hepatoma and possible mechanism of their cytostatic activity.
Newly synthesized allyloxymethyl purine and pyrimidine acyclonucleosides [Fig. 1, comp. 1-6] were tested in Syrian hamster, six days after heterotransplantations of Kirkman-Robbins hepatoma and compared with Th5, Th5P and PMT [Fig. 1, comp. 7-9]. 48 hours after intraperitoneal (i.p.) administration of AMT and Th5 in a dose of 80 mg per kg body weight, these compounds reduced tumor weight by 42%, while AMU (in the same dose) by 30%. The inhibition of tumor weight is accompanied by a decrease in dThd and dGuo kinase activities in tumor cytosol by AMU (36% and 33%, respectively) by AMT (59% and 53%, respectively) and by Th5 (58% and 55%, respectively). AMU, AMT and Th5 are phosphorylated in vivo by kinases present in cytosol of growing hepatoma to mono, di and triphosphates, but allyloxymethyl residue of AMU and AMT is first hydrated to hydroxypropoxymethyl residue, having CH2OH group. The lack of phosphorylation of PMT in vivo (having saturated propoxymethyl residue) and phosphorylation of Th5P (when used as a substrate for dNMP kinase) only to Th5 diphosphate suggested that AMU, AMT and Th5 triphosphates are responsible for the inhibition of dTMP and dGMP synthesis.
Modrzejewska
H
H
Department of Biochemistry, Medical University of Lódź, Poland.
Greger
J
J
Dramiñski
M
M
Rutkowski
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D005260:Female; D007700:Kinetics; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008647:Mesocricetus; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011684:Purine Nucleosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000378:metabolism*; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D011684:Purine Nucleosides; D011741:Pyrimidine Nucleosides; D017853:Phosphotransferases (Alcohol Group Acceptor); C019165:deoxyguanosine kinase; D013937:Thymidine Kinase