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Biochemical Modulation of 5-Fluorouracil by Pala: Mechanism of Action

  • Daniel S. Martin
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 339)

Abstract

Selectivity is, of course, the key to all chemotherapy. However, selectivity is very difficult to achieve against cancer cells in vivo because the biochemical differences between cancer and normal cells are quantitative rather than qualitative. Consequently, anticancer agents have a narrow therapeutic index and, therefore, chemotherapy is frequently toxic to the patient as well as to the tumor.

Keywords

Maximal Tolerate Dose Biochemical Modulation Pyrimidine Synthesis Aspartate Transcarbamylase Biochemical Heterogeneity 
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.
    L.E. Schnipper, Clinical implications of tumor cell heterogeneity, New Engl J Med 314: 1423–1431 (1986).PubMedCrossRefGoogle Scholar
  2. 2.
    G.H. Heppner, and B.E. Miller, Therapeutic implications of tumor heterogeneity, Semin Oncol 16: 91–105 (1989).PubMedGoogle Scholar
  3. 3.
    D.S. Martin, Purine and pyrimidine biochemistry, and some relevant clinical and preclinical cancer chemotherapy research, in Powis G, Prough RA (eds): Metabolism and Action of Anti-Cancer Drugs, London, Taylor and Francis, (1987), pp. 91–140.Google Scholar
  4. 4.
    D.S. Martin, Biochemical modulation: Perspectives and objectives, in Harrap K, Connors T (eds): New Avenues in Developmental Chemotherapy, London, Academic Press, (1987), pp 113–162.Google Scholar
  5. 5.
    D.S. Martin, R.L. Stolfi, R.C. Saywer, et al, Therapeutic utility of utilizing low doses of N-(phosphonacetyl)-L-aspartic acid in combination with 5-fluorouracil: A murine study with clinical relevance, Cancer Res 43: 2317–2321 (1983).PubMedGoogle Scholar
  6. 6.
    E.S. Casper, K. Vale, L. J. Williams, et al, Phase I and clinical pharmacological evaluation of biochemical modulation of 5-fluorouracil with N-(phosphonacetyl)-L-aspartic acid, Cancer Res 43: 2324–2329, (1983).PubMedGoogle Scholar
  7. 7.
    D.S. Martin, R.L. Stolfi, R. C. Sawyer, et al, The application of biochemical modulation with a therapeutically inactive modulating agent in clinical trials of cancer chemotherapy, Cancer Treat Rep 69: 421–423 (1985).PubMedGoogle Scholar
  8. 8.
    B. Ardalan, G. Singh, and H. Silberman, A randomized phase I and II study of short-term infusion of high-dose fluorouracil with or without N-(phosphonacetyl)-L-asparatic acid in patients with advanced pancreatic and colorectal cancers, J. Clin Oncol 6: 1053–1058 (1988).PubMedGoogle Scholar
  9. 9.
    P. J. O’Dwyer, A. R. Paul, J. Walczak, et al, Phase II study of biochemical modulation of fluorouracil by low-dose PALA in patients with colorectal cancer, J. Clin. Oncol 8: 1497–1503 (1990).PubMedGoogle Scholar
  10. 10.
    S. Speigelman, R. Sawyer, R. Nayak, et al, Improving the anti-tumor activity of 5-fluorouracil by increasing its incorporation into RNA via metabolic modulation, Proc. Natl. Acad Sci USA 77: 4966 (1980).CrossRefGoogle Scholar
  11. 11.
    R.C. Sawyer, R.L. Stolfi, R. Nayak, et al, Mechanism of cytotoxicity in 5-fluorouracil chemotherapy of two murine solid tumors, in Tattersall MHN, Fox RM (eds): Nucleosides and Cancer Treatment, New York, NY, Academic Press, (1981), pp 308–338.Google Scholar
  12. 12.
    R. Heimer, and A.C. Sartorelli, RNA polymerase II transcripts as targets for 5-fluorouridine cytotoxicity: Antagonism of 5-fluorouridine actions by a-amanitin, Cancer Chemother Pharmacol 24: 80–86 (1989).PubMedCrossRefGoogle Scholar
  13. 13.
    D.A. Greenhalgh, and J. H. Parish, Effect of 5-fluorouracil combination therapy on RNA processing in human colonic carcinoma cells, Br J Cancer 61: 415–419 (1990).PubMedCrossRefGoogle Scholar
  14. 14.
    D. S. Wilkinson, and H. C. Pitot, Inhibition of ribosomal ribonucleic acid maturation in Novikoff hepatoma cells by 5-fluorouracil and 5-fluorouridine. J Biol Chem 248: 63–68 (1973).PubMedGoogle Scholar
  15. 15.
    B. J. Dolnick, and J. J. Pink, Effects of 5-fluorouracil on dihydrofolate reductase dihydrofolate reductase mRNA from methotrexate-resistant KB cells, J Biol Chem 260: 3006–3014 (1985).PubMedGoogle Scholar
  16. 16.
    S-L. Doong, and B.J. Dolnick, 5-Fluorouracil substition alters pre-mRNA splicing in vitro. J Biol Chem 263: 4467–4473 (1988).PubMedGoogle Scholar
  17. 17.
    L. D. Nord, and D. S. Martin, Loss of murine tumor thymidine kinase activity in vivo following 5-fluorouracil (FUra) treatment by incorporation of FUra into RNA, Biochem Pharmacol 42: 2369–2375 (1991).PubMedCrossRefGoogle Scholar
  18. 18.
    D. W. Kufe, and E. M. Egan, Enhancement of 5-fluorouracil incorporation into human lymphoblast ribonucleic acid, Biochem Pharmacol 30: 129–133 (1981).PubMedCrossRefGoogle Scholar
  19. 19.
    D. W. Kufe, and P. P. Major, 5-Fluorouracil incorporation into human breast carcinoma RNA correlates with cytoxicity, J Biol Chem 256: 9803–9805 (1981).Google Scholar
  20. 20.
    B. Ardalan, R. I. Glazer, T. W. Kensler, et al, Synergistic effect of 5-fluorouracil and N-(phosphonacetyl)-L-aspartate on cell growth and ribonucleic acid synthesis in a human mammary carcinoma, Biochem. Pharmacol 30: 2045–2049 (1981).Google Scholar
  21. 21.
    D. S. Martin, R. L. Stolfi, and S. Spiegelman, Striking augmentation of the in vivo anticancer activity of 5-fluorouracil (5-FU) by combination with pyrimidine nucleosides: An RNA effect, Proc. Am Assoc Cancer Res 19: 221 (1978).Google Scholar
  22. 22.
    G. Weckbecker, and D. S. Keppler, Substrate properties of 5-fluorouridine diphospho sugars detected in hepatoma cells, Biochem Pharmacol 33: 2291–2298 (1984).PubMedCrossRefGoogle Scholar
  23. 23.
    F. Valeriote, and G. Santelli, 5-Fluorouracil (FUra), Pharmac Ther 24: 107–132 (1984).CrossRefGoogle Scholar
  24. 24.
    R. J. Epstein, Drug-induced DNA damage and tumor chemothersensitivity, J Clin Oncol 8: 2062–2084 (1990).PubMedGoogle Scholar
  25. 25.
    W. B. Parker, and Y-C. Cheng, Metabolism and mechanism of action of 5-fluorouracil, Pharmac Ther 48: 381–395 (1990).CrossRefGoogle Scholar
  26. 26.
    R. M. Evans, J. D. Laskin, and M. T. Hakala, Assessment of growth-limiting events caused by 5-fluorouracil in mouse cells and in human cells, Cancer Res 40: 4113–4122 (1980).PubMedGoogle Scholar
  27. 27.
    K. D. Collins, and G. R. Stark, Aspartate transcarbamylase interaction with the transition state analogue N-(phosphonacetyl)-L-aspartate, J. Biol. Chem 246: 6599–6605 (1971).PubMedGoogle Scholar
  28. 28.
    D. S. Martin, R. Nayak, R. Sawyer, et al, Enhancement of 5-fluorouracil chemotherapy with emphasis on the use of excess thymidine, Cancer Bull 30: 219–222 (1978).Google Scholar
  29. 29.
    D. S. Martin, R.L. Stolfi, R. C. Sawyer, et al, An overview of thymidine, Cancer 45: 1117–1128 (1980).PubMedCrossRefGoogle Scholar
  30. 30.
    R. K. Johnson, J. J. Clement, and W. S. Howard, Treatment of murine tumors with 5-fluorouracil in combination with de novo pyrimidine synthesis inhibitors PALA or pyrazofurin, Proc Am Assoc Cancer Res 21: 292 (1980).Google Scholar
  31. 31.
    B. Ardalan, R. Glazer, T. Kensler, et al, Biochemical mechanism for the synergism of 5-fluorouracil (5-FU) and phosphonacetyl-L-aspartate (PALA) in human mammary carcinoma cells, Proc Am Assoc Cancer Res 21: 8 (1980).Google Scholar
  32. 32.
    D. S. Martin, R. L. Stolfi, R. C. Sawyer, et al, Biochemical modulation of 5-fluorouracil and cytosine arabinoside with emphasis on thymidine, PALA, and 6-methylmercaptopurine riboside, in Tattersall MHN, Fox RM (eds): Nucleosides and Cancer Treatment. Sydney, Academic Press, (1981), pp. 339–382.Google Scholar
  33. 33.
    G. J. Peters, E. Laurensse, A. Leyva, et al, The concentration of 5-phosphoribosyl 1-pyrophosphate in monolayer tumor cells and the effect of various pyrimidine antimetabolites, Int J Biochem 17: 95–99 (1985).PubMedCrossRefGoogle Scholar
  34. 34.
    P. P. Major, E. M. Egan, L. Sargent, et al, Modulation of 5-FU metabolism in human MCF-7 breast carcinoma cells, Cancer Chemother. Pharmacol 8: 87–91 (1982).Google Scholar
  35. 35.
    A. A. Miller, E. C. Moore, R. B. Hurlbert, et al, Pharmacological and biochemical interactions of N-(phosphonacetyl)-L-aspartate and 5-fluorouracil in beagles, Cancer Res 43: 2565–2570 (1983).PubMedGoogle Scholar
  36. 36.
    C. E. Moore, J. Friedman, M. Valdivieso, et al, Aspartate carbamoyltransferase activity, drug concentrations and pyrimidine nucleotides in tissue from patients treated with N-(phosphonacetyl)-L-aspartate, Biochem Pharmacol 31: 3317–3321 (1982).PubMedCrossRefGoogle Scholar
  37. 37.
    W. W. Ackerman, and V. R. Potter, Enzyme inhibition in relation to chemotherapy, Proc Soc Biol Med 72: 1–9 (1949).Google Scholar
  38. 38.
    C. M. Liang, R. C., Donehower, and B. A. Chabner, Biochemical interactions between N-(phosphonacetyl)-L-aspartate and 5-fluorouracil, Mol Pharmacol 21: 224–230 (1982).PubMedGoogle Scholar
  39. 39.
    J. L. Grem, S. A. King, P. J. O’Dwyer, et al, Biochemistry and clinical activity of N-(phosphonacetyl)-L-aspartate: A review, Cancer Res 48: 4441–4454 (1988).PubMedGoogle Scholar
  40. 40.
    D. S. Martin, and N.E. Kemeny, Overview of PALA + 5-fluorouracil in clinical trials, Semin Oncol 18: 228–233, (1991) (suppl 8).Google Scholar
  41. 41.
    S. H. Harrison, H. D. Giles, and E. P. Denine, Hematologic and histopatholic evaluation of N-(phosphonacetyl)-L-aspartate (PALA) in mice, Cancer Chemother Pharmacol 2: 183–187 (1979).PubMedCrossRefGoogle Scholar
  42. 42.
    N. E. Kemeny, and P. Costa, Phase II trial of PALA and FU in metastatic colorectal carcinoma, Proc Am Soc Clin Oncol 10: (1991).Google Scholar
  43. 43.
    L. D. Nord, R. L. Stolfi, and D. S. Martin, Biochemical modulation of 5-fluorouracil with leucovorin or delayed uridine rescue. Correlation of antitumor activity with dosage and FUra incorporation into RNA, Biochem. Pharmacol 43: 2543–2549 (1992).Google Scholar
  44. 44.
    D. S. Martin, R. L. Stolfi and R. C. Sawyer, Improved therapeutic index with sequential N-phosphonacetyl-L-aspartate plus high-dose methotrexate plus high-dose 5-fluorouracil and appropriate rescue, Cancer Res 43: 4653–4661 (1983).PubMedGoogle Scholar
  45. 45.
    P. J. O’Dwyer, G. Hudes, J. Colofiore, et al, Phase I trial of Fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine riboside dose and schedule through biochemical analysis of sequential tumor biopsy specimens, J Natl Cancer Inst 83: 1235–1240 (1991).PubMedCrossRefGoogle Scholar
  46. 46.
    R. A. Woods, R. M. Henderson, and J. F. Henderson, Consequences of inhibition of purine biosynthesis de novo by 6-methylmercaptopurine ribonucleoside in cultured lymphoma L5178 cells, Eur J Cancer 14: 765–770 (1978).PubMedCrossRefGoogle Scholar
  47. 47.
    G. B. Grindey, J. K. Lowe, A. Y. Direker et al, Potentiation by guanine nucleosides of the growth-inhibitory effects of adenosine analogues on L1210 and Sarcoma 180 cells in culture, Cancer Res 36: 379–383 (1976).PubMedGoogle Scholar
  48. 48.
    D. Hunting, J. Hordern, and J. F. Henderson, Effects of altered ribonucleotide concentrations on ribonucleotide reduction in intact Chinese hamster ovary cells, Can J Biochem 59: 821–829 (1981).PubMedGoogle Scholar
  49. 49.
    N. Kyprianou, and J. T. Isaacs, Thymineless death in androgen-independent prostatic cancer cells, Biochem Biophys Res Commun 165: 73–81 (1989).PubMedCrossRefGoogle Scholar
  50. 50.
    M. A. Barry, C. A. Behnke, and A. Eastman, Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins, and hyperthermia, Biochem Pharmacol 40: 2353–2362 (1990).PubMedCrossRefGoogle Scholar
  51. 51.
    I. U. Schraufstatter, D. B. Hinshaw, P. A. Hyslop, et al, Oxidant injury of cells: DNA strand-breaks activate polyadenosine diphosphate polymerase and lead to depletion of nicotinamide adenine dinucleotide, J Clin Invest 77: 1312–1320 (1986).PubMedCrossRefGoogle Scholar
  52. 52.
    P.A. Hyslop, D.B. Hinslaw, W.A. Halsey, Jr., et al, Mechanisms of oxidant-mediated injury. The glycolytic and mitochondrial pathways of ADP phosphorylation are major intracellular targets inactivated by hydrogen peroxide, J. Biol. Chem., 263: 1665–1675 (1988).PubMedGoogle Scholar
  53. 53.
    A.R. Boobis, DJ. Fawthrop, and D.S. Davies, Mechanism of cell death, Trends Pharmacol. Sci., 10: 275–280 (1989).PubMedCrossRefGoogle Scholar
  54. 54.
    N.A. Berger, S.J. Berger, and S.L. Gerson, DNA repair, ADP ribosylation and pyridine nucleotide metabolism as targets for cancer chemotherapy, Anti-Cancer Drug Design 2: 203–210 (1987).PubMedGoogle Scholar
  55. 55.
    R.L. Stolfi, L.M. Stolfi, R.C. Sawyer, and D.S. Martin, Chemotherapeutic evaluation using clinical criteria in spontaneous, autochthonous murine breast tumors, J. Natl. Cancer Inst., 80: 52–55 (1988).PubMedCrossRefGoogle Scholar
  56. 56.
    R.L. Stolfi, J.R. Colofiore, L.D. Nord, J.A. Koutcher, and D.S. Martin, Biochemical modulation of tumor cell energy: regression of advanced spontaneous murine breast tumors with a 5-fluorouracil-containing drug combination, Cancer Res. 52: 4074–4081 (1992).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Daniel S. Martin
    • 1
    • 2
  1. 1.From Developmental Chemotherapy, Memorial Sloan Kettering Cancer CenterCornell University Medical CollegeNew YorkUSA
  2. 2.Catholic Medical Center of Brooklyn & Queens, Inc.New YorkUSA

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