Sugar Analogs and 5-Fluorouridine in Combination Chemotherapy
One of the possible approaches to tumor chemotherapy involves the elimination of the malignant cells by means of cytostatic or cytocidal drugs that should be as selective as possible for a given tumor. The comparatively high degree of selective toxicity induced by the antibacterial chemotherapeutic agents has not been achieved with the antitumor drugs since their selectivity must be based on minor metabolic differences between the normal and the malignant cells and tissues. Many of the effective drugs in cancer chemotherapy are antimetabolites that inhibit enzymes of essential metabolic pathways on the basis of a structural similarity with physiological intermediates, interfering thereby with cellular growth and proliferation. This may be exemplified by the blockade of thymidylate synthase (EC 22.214.171.124) by 5-f luorodeoxyuridine 5’-monophosphate, a metabolite of the pyrimidine analogs 5-fluorouracil, 5-f luorodeoxyuridine, or 5-fluorouridine (1). Inhibition of thymidylate synthase can lead to a depletion of thymine nucleotides and result in DNA synthesis inhibition due to substrate deficiency.
KeywordsHepatoma Cell Pyrimidine Synthesis Morris Hepatoma Substrate Deficiency Uridine Kinase
Unable to display preview. Download preview PDF.
- 1.C. Heidelberger, P. V. Danenberg, and R. G. Moran, Fluorinated Pyrimidines and Their Nucleosides, Adv. Enzymol. 54: 57 (1983).Google Scholar
- 4.A. Holstege and D. Keppler, Effects of D-Glucosamine and 6-Azauridine on Nucleotide Contents, 5-Fluorouridine Uptake, and Cytotoxicity in TA3 Mammary Tumor Cells, J. Nat. Cancer Inst., in press (1986).Google Scholar
- 8.D. Keppler and W. Kaiser, Enzymatic Analysis of Guanine Nucleotides in Tissues and Cells, Anal. Biochem. 86: 147 (1978).Google Scholar
- 11.S. Bayne, Aldosuloses (Osones), in: “Methods in Carbohydrate Chemistry,” Volume 2, R. L. Whistler and M. L. Wolf rom, eds., Academic Press, New York (1963).Google Scholar
- 15.W. Reutter and C. Bauer, Terminal Sugars in Glycoconjugates: Metabolism of Free and Protein-bound L-Fucose, N-Acetyl-neuraminic Acid and D-Galactose in Liver and Morris Hepatomas, in: “Morris Hepatomas,” H. P. Morris and W. E. Criss, eds., Plenum Press, New York (1978).Google Scholar
- 18.D. Keppler and A. Holstege, Pyrimidine Nucleotide Metabolism and its Compartmentation, in: “Metabolic Compartmentation,” H. Sies, ed., Academic Press, London (1982).Google Scholar