Biochemical programs and enzyme-pattern-targeted chemotherapy in cancer cells

George Weber, E. Oláh, May S. Lui, Diana Tzeng

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The gene logic of cancer cells was examined by elucidation of the behavior of key enzymes and metabolic pathways in chemically induced, transplantable carcinomas in rodents and in primary tumors in human. In this analysis emphasis was put on the identification of the shared program of enzymic imbalance that was expressed in the various tumors. These studies also pointed out the operation of tumor-type-specific aspects of the neoplastic program. The implications of these enzymic programs for the design of enzyme-pattern-targeted chemotherapy were outlined. The expression of enzymic programs of transformation in pyrimidine metabolism was analyzed. The activities of enzymes of biosynthesis, CTP synthetase, thymidine kinase, uridine kinase, uridine phosphorylase, uridine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine 5′-phosphate decarboxylase, and UDP kinase, were increased i all the tumors, whereas the activity of the catabolic enzyme, dihydrothymidne dehydrogenase, was decreased. The behavior of the activities of uridine phosphorylase, which appears to play a synthetic role in liver, and thymidine phosphorylase, a catabolic enzyme, was compared in hepatomas of different growth rates. The growth rate of these solid tumors varied between 52 and 2 weeks. The specific activity of uridine phoshorylase was significantly increase in the 13 liver tumors examined. The activity was particularly high in rapidly growing hepatoma 3683F, being 6-fold higher than that of normal liver. by contrast, the specific activity of thymidine phosphorylase was decreased in all the hepatomas examined. In applying the approaches of enzyme-pattern-targeted chemotherapy, we investigated the action of pyrazofurin and galactosamine in tissue culture and in tumor-bearing animals. Pyrazofurin, a C-nucleoside, inhibited hepatoma 3924A cells in tissue culture, yielding an I50 = 0.4 μM. Further studies indicated that pyrazofurin was inhibitory to the tumor cells only in the logarithmic phase and not in the plateau phase. In examining the sensitivity of pyrazofurin in different phases of the hepatoma cell cycle, it was demonstrated that this drug exerted a clearcut, phase-specific toxicity. Pyrazofurin was particularly toxic to early G1 and early S phase cells, but had little or no effect on tumor cells in other phases of the cell cycle. Since our studies showed that in hepatomas the activities of the salvage enzyme, uridine-cytidine kinase, uridine phosphorylase and uracil phosphoribosyltransferase, were markedly increased, it was of interest to determine the ability of various nucleosides to provide protection against pyrazofurin in tissue culture. Uridine or cytidine in concentrations 10- to 100- fold higher than pyrazofurin were able to protect tumor cells from the killing action of pyrazofurin. Uracil had very little protective action and neither did hypoxanthine, a purine metabolite. Pharmacological studies in tissue culture showed that pyrazofurin and galactosamine behaved synergistically in depressing CTP concentration in tissue culture. A similar depression of CTP concentration was also observed in hepatomas 8999 and 3924A carried in rats. The selectivity of this synergistic drug attack was evidenced by the fact that the CTP content was not depressed in the liver of these tumor-bearing animals. Tissue culture studies showed that pyrazofurin did not affect the pools of ATP, dATP, GTP or dGTP, whereas it decreased UTP, CTP, dTTP and dCTP concentrations to 22, 9, 10 and 51%, respectively, of untreated controls. This selective depression of uridylate, cytidylate, dTTP ad dCTP pools provides further insight into the primary action of pyrazofurin in pyrmidine metabolism.

Original languageEnglish
Pages (from-to)1-21
Number of pages21
JournalAdvances in Enzyme Regulation
Volume17
Issue numberC
DOIs
Publication statusPublished - 1979

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pyrazofurin
Chemotherapy
Tumors
Cells
Tissue culture
Drug Therapy
Hepatocellular Carcinoma
Enzymes
Cytidine Triphosphate
Uridine Phosphorylase
Neoplasms
Liver
Uridine
Uridine Kinase
Bearings (structural)
Thymidine Phosphorylase
Galactosamine
uracil phosphoribosyltransferase
CTP synthetase
Nucleosides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Biochemical programs and enzyme-pattern-targeted chemotherapy in cancer cells. / Weber, George; Oláh, E.; Lui, May S.; Tzeng, Diana.

In: Advances in Enzyme Regulation, Vol. 17, No. C, 1979, p. 1-21.

Research output: Contribution to journalArticle

Weber, George ; Oláh, E. ; Lui, May S. ; Tzeng, Diana. / Biochemical programs and enzyme-pattern-targeted chemotherapy in cancer cells. In: Advances in Enzyme Regulation. 1979 ; Vol. 17, No. C. pp. 1-21.
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N2 - The gene logic of cancer cells was examined by elucidation of the behavior of key enzymes and metabolic pathways in chemically induced, transplantable carcinomas in rodents and in primary tumors in human. In this analysis emphasis was put on the identification of the shared program of enzymic imbalance that was expressed in the various tumors. These studies also pointed out the operation of tumor-type-specific aspects of the neoplastic program. The implications of these enzymic programs for the design of enzyme-pattern-targeted chemotherapy were outlined. The expression of enzymic programs of transformation in pyrimidine metabolism was analyzed. The activities of enzymes of biosynthesis, CTP synthetase, thymidine kinase, uridine kinase, uridine phosphorylase, uridine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine 5′-phosphate decarboxylase, and UDP kinase, were increased i all the tumors, whereas the activity of the catabolic enzyme, dihydrothymidne dehydrogenase, was decreased. The behavior of the activities of uridine phosphorylase, which appears to play a synthetic role in liver, and thymidine phosphorylase, a catabolic enzyme, was compared in hepatomas of different growth rates. The growth rate of these solid tumors varied between 52 and 2 weeks. The specific activity of uridine phoshorylase was significantly increase in the 13 liver tumors examined. The activity was particularly high in rapidly growing hepatoma 3683F, being 6-fold higher than that of normal liver. by contrast, the specific activity of thymidine phosphorylase was decreased in all the hepatomas examined. In applying the approaches of enzyme-pattern-targeted chemotherapy, we investigated the action of pyrazofurin and galactosamine in tissue culture and in tumor-bearing animals. Pyrazofurin, a C-nucleoside, inhibited hepatoma 3924A cells in tissue culture, yielding an I50 = 0.4 μM. Further studies indicated that pyrazofurin was inhibitory to the tumor cells only in the logarithmic phase and not in the plateau phase. In examining the sensitivity of pyrazofurin in different phases of the hepatoma cell cycle, it was demonstrated that this drug exerted a clearcut, phase-specific toxicity. Pyrazofurin was particularly toxic to early G1 and early S phase cells, but had little or no effect on tumor cells in other phases of the cell cycle. Since our studies showed that in hepatomas the activities of the salvage enzyme, uridine-cytidine kinase, uridine phosphorylase and uracil phosphoribosyltransferase, were markedly increased, it was of interest to determine the ability of various nucleosides to provide protection against pyrazofurin in tissue culture. Uridine or cytidine in concentrations 10- to 100- fold higher than pyrazofurin were able to protect tumor cells from the killing action of pyrazofurin. Uracil had very little protective action and neither did hypoxanthine, a purine metabolite. Pharmacological studies in tissue culture showed that pyrazofurin and galactosamine behaved synergistically in depressing CTP concentration in tissue culture. A similar depression of CTP concentration was also observed in hepatomas 8999 and 3924A carried in rats. The selectivity of this synergistic drug attack was evidenced by the fact that the CTP content was not depressed in the liver of these tumor-bearing animals. Tissue culture studies showed that pyrazofurin did not affect the pools of ATP, dATP, GTP or dGTP, whereas it decreased UTP, CTP, dTTP and dCTP concentrations to 22, 9, 10 and 51%, respectively, of untreated controls. This selective depression of uridylate, cytidylate, dTTP ad dCTP pools provides further insight into the primary action of pyrazofurin in pyrmidine metabolism.

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