ABSTRACT
A derivative of pyrazinocarbazole the antidepressant pyrazidol, whose inhibition of serotonin deaminase activity of the brain mitochondrial monoamine oxidase is attended by induction of the property of catalysing histamine oxidation, inhibits the growth of glial tumors in experiments. Another derivative of pyrazinocarbazole, which inhibits serotonin deamination but does not induce the appearance of histamine deaminase activity, produces no effect on the growth of glial tumors of the brain.
Subject(s)
Astrocytoma/drug therapy , Brain Neoplasms/drug therapy , Brain/drug effects , Glioma/drug therapy , Mitochondria/drug effects , Monoamine Oxidase/drug effects , Animals , Antineoplastic Agents/therapeutic use , Astrocytoma/enzymology , Brain/enzymology , Brain Neoplasms/enzymology , Carbazoles/therapeutic use , Catalysis/drug effects , Drug Screening Assays, Antitumor , Glioma/enzymology , Mitochondria/enzymology , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/therapeutic use , Neoplasm Transplantation , Rats , Rats, Inbred StrainsABSTRACT
The disodium salt of 2,6-dimethyl-1,4-dihydropyridine-3,5-bis-carbonyl hydroxyacetic acid (I) used in the mg/kg dose decreases the cyclophosphane toxicity in mice and potentiates the cytostatic activity of cyclophosphane, 5-fluorouracil and arabinosyl cytosine against leukemia P388, murine sarcoma 37 and Walker's carcinosarcoma. Administered alone I exhibits no antitumour activity. The potentiation of the antitumour effect of drugs appears independent of the administration schedule. Biochemical evidence indicates that I does not block DNA synthesis in leukemic cells in vitro, but significantly enhances the DNA-blocking effect of cyclophosphane in the same cells in vivo.
Subject(s)
Antineoplastic Agents/pharmacology , Dihydropyridines , Neoplasms, Experimental/drug therapy , Pyridines/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/toxicity , Cells, Cultured , DNA, Neoplasm/biosynthesis , Drug Synergism , Lethal Dose 50 , Leukemia P388/drug therapy , Leukemia P388/metabolism , Male , Mice , Neoplasms, Experimental/metabolism , Pyridines/administration & dosage , Pyridines/toxicity , Sarcoma 37/drug therapy , Sarcoma 37/metabolismABSTRACT
Biotransformation of ftorafir (FT) was studied using 2-14C-ftorafur and 2;5'-14C-ftorafur. Both pyrimidine and tetrahydrofurane moieties of the FT underwent degradation to CO2 in rats. The cleavage of the pseudoglycosidic bonds C-N and formation of 5-fluorouracil was one of the steps of the FT metabolism that limited the velocity of the whole biotransformation process. Liver tissue NADPH-linked monooxygenating system was shown to participate in the process. The data obtained suggest that the role of enzymes involved in metabolism of nucleic acids was not significant in the FT metabolism under the conditions studied in vivo.
Subject(s)
Fluorouracil/analogs & derivatives , Tegafur/metabolism , Animals , Biotransformation , Carbon Radioisotopes , Kinetics , Liver/enzymology , Male , Mixed Function Oxygenases/metabolism , NADP , RatsABSTRACT
The pharmacokinetics of phthorafur-2-14C (Ph) was investigated after its intravenous injection to rats with Walker carcinosarcoma. The blood plasma level of Ph-2-14C and its metabolites proved to decrease in to a three-phase process. The content of the agent in the tissues decreased in the following sequence: the kidney, small intestine, tumour, stomach, muscle, heart, liver, lungs, spleen, brain and fat. The tumour was observed to contain Ph-2-14C and endogenous metabolite 5-phthoruracil-2-14C. Excretion of the agent continued for 48 hrs, 52.2% of the administered dose being eliminated via the urinary tract, 30% as 14CO2, and 0.8% in feces.
