Sugar Analogs and 5-Fluorouridine in Combination Chemotherapy

Abstract

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 2.1.1.45) 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.