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Biochemical Strategy of Cancer Cells and the Targeting of Chemotherapy with Tiazofurin, Acivicin, and Dipyridamole

  • George Weber

Abstract

It is 25 years since I introduced the ideas of the molecular correlation concept as a theoretical and experimental method for discovering the pattern of biochemical imbalance and its link with neoplastic transformation and progression (1). This approach was tested through application of the concept of key enzymes in a particularly meaningful model system, the rat hepatomas of different growth rates. The testing of the molecular correlation concept proved that the biochemical strategy of the genome in neoplasia can be identified by elucidating the pattern of gene expression as revealed in the activity, amount, and isozymic program of the key enzymes. It was shown that the activities of the key enzymes and metabolic pathways and the concentrations of strategic nucleotides and amino acids are stringently linked with neoplastic transformation and progression. Parameters that are not stringently linked yield no pattern. The conclusion was drawn that what is important about cancer is ordered; what is not, is the random element and the diversity. This field was recently reviewed (2,3).

Keywords

Ribonucleotide Reductase Glutamine Metabolism Pyrimidine Metabolism Purine Biosynthesis Biochemical Strategy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    G. Weber, Behavior of Liver Enzymes During Hepatocarcinogenesis, Adv. Cancer Res. 6: 403 (1961).PubMedCrossRefGoogle Scholar
  2. 2.
    G. Weber, Enzymology of Cancer Cells, Parts 1 and 2, N. Eng. J. Med. 296: 486 (1977).CrossRefGoogle Scholar
  3. 3.
    G. Weber, Biochemical Strategy of Cancer Cells and the Design of Chemotherapy: G. H. A. Clowes Memorial Lecture, Cancer Res. 43: 3466 (1983).PubMedGoogle Scholar
  4. 4.
    K. Snell, Enzymes of Serine Metabolism in Normal, Developing and Neoplastic Rat Tissues, Adv. Enz. Reg. 22: 325 (1984).CrossRefGoogle Scholar
  5. 5.
    K. Snell and G. Weber, Enzymic Imbalance in Serine Metabolism in Rat Hepatomas, Biochem. J. 233: 617 (1986).PubMedGoogle Scholar
  6. 6.
    M.-H. T. Lai and G. Weber, Increased Concentration of Thymidine Kinase in Rat Hepatomas, Biochem. Biophys. Res. Comm. 111: 280 (1983).PubMedCrossRefGoogle Scholar
  7. 7.
    M. A. Reardon and G. Weber, Increased Carbamoyl-phosphate Synthetase II Concentration in Rat Hepatomas: Immunological Evidence, Cancer Res. 45: 4412 (1985).PubMedGoogle Scholar
  8. 8.
    T. Ikegami, Y. Natsumeda, and G. Weber, Decreased Concentration of Xanthine Dehydrogenase (EC 1.1.1.204), submitted for publication (1986).Google Scholar
  9. 9.
    N. Prajda, Biochemical Phenotype in Human and Animal Liver Tumors, Proc. 13th International Cancer Congress, Part D, Research and Treatment, A. R. Liss, Inc., New York (1983).Google Scholar
  10. 10.
    J. E. Denton, M. S. Lui, T. Aoki, J. Sebolt, E. Takeda, J. N. Eble, J. L. Glover, and G. Weber, Enzymology of Pyrimidine and Carbohydrate Metabolism in Human Colon Carcinomas, Cancer Res. 42: 1176 (1982).PubMedGoogle Scholar
  11. 11.
    Y. Natsumeda, M. S. Lui, J. Emrani, M. A. Faderan, M. A. Reardon, J. N. Eble, J. L. Glover, and G. Weber, Purine Enzymology of Human Colon Carcinomas, Cancer Res. 45: 2556 (1985).PubMedGoogle Scholar
  12. 12.
    M. S. Lui, M. A. Faderan, J. J. Liepnieks, Y. Natsumeda, E. Olah, H. N. Jayaram, and G. Weber, Modulation of IMP Dehydrogenase Activity and Guanylate Metabolism by Tiazofurin (2–13-D-ribofuranosylthiazole-4carboxamide), J. Biol. Chem. 259: 5078 (1984).PubMedGoogle Scholar
  13. 13.
    G. Weber, Y. Natsumeda, M. S. Lui, M. A. Faderan, J. J. Liepnieks, and W. L. Elliott, Control of Enzymic Programs and Nucleotide Pattern in Cancer Cells by Acivicin and Tiazofurin, Adv. Enz. Reg. 22: 69 (1984).CrossRefGoogle Scholar
  14. 14.
    H. N. Jayaram, Biochemical Mechanisms of Resistance to Tiazofurin, Adv. Enz. Reg. 24: 67 (1985).CrossRefGoogle Scholar
  15. 15.
    G. Weber, Y. Natsumeda, and K. Pillwein, Targets and Markers of Selective Action of Tiazofurin, Adv. Enz. Reg. 24: 45 (1985).CrossRefGoogle Scholar
  16. 16.
    Y.-S. Zhen, M. S. Lui, and G. Weber, Effects of Acivicin and Dipyridamole on Hepatoma 3924A Cells, Cancer Res. 43: 1616 (1983).PubMedGoogle Scholar
  17. 17.
    R. C. Jackson, G. Weber, and H. P. Morris, IMP Dehydrogenase, an Enzyme Linked with Proliferation and Malignancy, Nature 256: 331 (1975).PubMedCrossRefGoogle Scholar
  18. 18.
    G. Weber, Enzymes of Purine Metabolism in Cancer, Clin. Biochem. 16: 57 (1983).PubMedCrossRefGoogle Scholar
  19. 19.
    T. J. Boritzki, R. C. Jackson, H. P. Morris, and G. Weber, Guanosine5’-phosphate Synthase and Guanosine-5’-phosphate Kinase in Rat Hepatomas and Kidney Tumors, Biochim. Biophys. Acta 658: 102 (1981).PubMedCrossRefGoogle Scholar
  20. 20.
    R. C. Jackon, M. S. Lui, T. J. Boritzki, H. P. Morris, and G. Weber, Purine and Pyrimidine Nucleotide Patterns of Normal, Differentiating and Regenerating Liver and Hepatomas in Rats, Cancer Res. 40: 1286 (1980).Google Scholar
  21. 21.
    Y. Natsumeda, N. Prajda, J. P. Donohue, J. L. Glover, and G. Weber, Enzymic Capacities of Purine De Novo and Salvage Pathways for Nucleotide Synthesis in Normal and Neoplastic Tissues, Cancer Res. 44: 2475 (1984).PubMedGoogle Scholar
  22. 22.
    E. Takeda and G. Weber, Role of Ribonucleotide Reductase in Expression of the Neoplastic Program, Life Sci. 28: 1007 (1981).PubMedCrossRefGoogle Scholar
  23. 23.
    G. Weber, N. Prajda, and R. C. Jackson, Key Enzymes of IMP Metabolism: Transformation-and Proliferation-linked Alterations in Gene Expression, Adv. Enz. Reg. 14: 3 (1976).CrossRefGoogle Scholar
  24. 24.
    R. K. Robins, G. R. Revankar, P. A. McKernan, B. K. Murray, J. J. Kirsi, and J. A. North, The Importance of IMP Dehydrogenase Inhibition in the Broad Spectrum Antiviral Activity of Ribavirin and Selenazofurin, Adv. Enz. Reg. 24: 29 (1985).CrossRefGoogle Scholar
  25. 25.
    G. Gebeyehu, V. E. Marquez, A. C. Van Cott, D. A. Cooney, J. A. Kelley, H. N. Jayaram, G. S. Ahluwalia, R. L. Dion, Y. A. Wilson, and D. G. Johns, Ribavirin, Tiazofurin, and Selenazofurin; Mononucleotides and Nicotinamide Adenine Dinucleotide Analogs, Synthesis, Structure and Interactions with IMP Dehydrogenase, J. Med. Chem. 28: 99 (1985).PubMedCrossRefGoogle Scholar
  26. 26.
    D. A. Cooney, H. N. Jayaram, R. I. Glazer, J. A. Kelley, V. E. Marquez, G. Gebeyehu, A. C. Van Cott, L. A. Zwelling, and D. G. Johns, Studies on the Mechanism of Action of Tiazofurin Metabolism to an Analog of NAD with Potent IMP Dehydrogenase-inhibitory Activity, Adv. Enz. Reg. 21: 271 (1983).CrossRefGoogle Scholar
  27. 27.
    J. J. Liepnieks, M. A. Faderan, M. S. Lui, and G. Weber, Tiazofurin-induced Selective Depression of NAD Content in Hepatoma 3924A, Biochem. Biophys. Res. Comm. 122: 345 (1984).PubMedCrossRefGoogle Scholar
  28. 28.
    G. Weber, M. S. Lui, J. Sebolt, and M. A. Faderan, Molecular Targets of Anti-glutamine Therapy with Acivicin in Cancer Cells, in: “Glutamine Metabolism in Mammalian Tissues, ” D. Häussinger and H. Sies, eds., Springer Verlag, Heidelberg (1984).Google Scholar
  29. 29.
    J. S. Sebolt and G. Weber, Negative Correlation of L-glutamine Concentration with Proliferation Rate in Rat Hepatomass, Life Sci. 34: 301 (1984).PubMedCrossRefGoogle Scholar
  30. 30.
    N. Prajda, Enzyme Targets of Antiglutamine Agents in Cancer Chemotherapy, Adv. Enz. Reg. 24: 207 (1985).CrossRefGoogle Scholar
  31. 31.
    R. H. Earhart and G. L. Neil, Acivicin in 1985, Adv. Enzyme Reg. 24: 179 (1985).CrossRefGoogle Scholar
  32. 32.
    T. Aoki, J. Sebolt, and G. Weber, In Vivo Inactivation by Acivicin of Carbamoyl-phosphate Synthetase II in Rat Hepatoma, Biochem. Pharm. 31:927 (1982).PubMedCrossRefGoogle Scholar
  33. 33.
    T. Aoki, H. P. Morris, and G. Weber, Regulatory Properties and Behavior of Activity of Carbamoyl Phosphate Synthetase II (glutamine-hydrolyzing) in Normal and Proliferating Tissues, J. Biol. Chem. 257: 432 (1982).PubMedGoogle Scholar
  34. 34.
    M. S. Lui, H. Kizaki, and G. Weber, Biochemical Pharmacology of Acivicin in Rat Hepatoma Cells, Biochem. Pharm. 31: 3469 (1982).PubMedCrossRefGoogle Scholar
  35. 35.
    J. S. Sebolt, T. Aoki, J. N. Eble, J. L. Glover, and G. Weber, Inactivation by Acivicin of Carbamoyl-phosphate Synthetase II of Human Colon Carcinoma, Biochem. Pharm. 34: 97 (1985).PubMedCrossRefGoogle Scholar
  36. 36.
    W. I. Elliott and G. Weber, In Vivo Inactivation of Formylglycinamidine Ribonucleotide Synthetase in Rat Hepatoma, Biochem. Pharm. 34:243 (1985).PubMedCrossRefGoogle Scholar
  37. 37.
    G. Weber, J. E. Denton, M. S. Lui, T. Aoki, J. Sebolt, N. Prajda, Y.-S. Zhen, M. E. Burt, M. A. Faderan, and M. A. Reardon, Multi-enzymetargeted Chemotherapy by Acivicin and Actinomycin, Adv. Enz. Reg. 20: 75 (1982).CrossRefGoogle Scholar
  38. 38.
    J. E. Denton, M. S. Lui, T. Aoki, J. Sebolt, and G. Weber, Rapid In Vivo Inactivation by Acivicin of CTP Synthetase, Carbamoyl-phosphate Synthetase II, and Amidophosphoribosyltransferase in Hepatoma, Life Sci. 30: 1073 (1982).PubMedCrossRefGoogle Scholar
  39. 39.
    G. Weber, M. S. Lui, Y. Natsumeda, and M. A. Faderan, Salvage Capacity of Hepatoma 3924A and Action of Dipyridamole, Adv. Enz. Reg.. 21: 53 (1982).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1987

Authors and Affiliations

  • George Weber
    • 1
  1. 1.Laboratory for Experimental OncologyIndiana University School of MedicineIndianapolisUSA

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