Abstract
Interest in the use of antimetabolites as chemotherapeutic agents was stimulated by the demonstration of a competitive relationship between the sulfonamides and para-aminobenzoic acid in the de novo synthesis of folate co-factors in bacteria (1, 2). Shive relied extensively on the competitive interactions between metabolites and antimetabolites in his studies on intermediary metabolism of bacteria and the role of B vitamins in purine and pyrimidine biosynthesis (3, 4). He introduced the term “inhibition analysis” to refer to that area of research which utilized metabolite-antimetabolite interactions as probes in the study of biochemical reactions. Goldin (5) has demonstrated that it is possible to conduct quantitative studies of metabolite-antimetabolite relationships in the whole animal. By applying the principles of inhibition analysis to these investigations it may be possible to establish a relationship between basic biochemical studies and growth studies in vivo which may be relevant to cancer research and therapy. As outlined by Goldin (1), such investigations may raise several important questions including: 1) whether an observed inhibition of a specific enzyme by an antimetabolite in vitro will occur in vivo; 2) what will be the overall effect of this enzyme inhibition on the intact organism; 3) can an investigation of metabolite-antimetabolite relationships in vivo reveal metabolic pathways in the whole organism which may prove useful in the design of future therapy; and 4) whether knowledge concerning the action of the inhibitor can provide information regarding the host-tumor relationship which may be used to increase the therapeutic response. In cancer chemotherapy there is currently considerable interest in the use of metabolite-antimetabolite combinations to enhance tumor cell kill and to increase the overall therapeutic selectivity of the cytotoxic agent. The successful use of leucovorin to reverse host toxicity to methotrexate (MTX) clearly demonstrates the potential clinical utility of this concept (6).
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© 1986 Martinus Nijhoff Publishing, Boston
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Rustum, Y.M., Campbell, J. (1986). Metabolic Modulation of Ara-C. In: Valeriote, F.A., Baker, L.H. (eds) Biochemical Modulation of Anticancer Agents: Experimental and Clinical Approaches. Developments in Oncology, vol 47. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-2331-0_8
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DOI: https://doi.org/10.1007/978-1-4613-2331-0_8
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