Selectivity of CF and 5-Fluorouracil: Critical Role of Polyglutamylation
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Earlier studies from these laboratories have indicated that in human colon adenocarcinoma xenografts, the mechanism of intrinsic resistance to 5-fluoropyrimidines may be a consequence of low levels of CH2-H4PteGlu in tumor cells. Thus, after administration of FUra or FdUrd, the inhibitory complex between FdUMP, CH2-H4PteGlu and TS may form relatively slowly, or may dissociate quite rapidly (1,2). Due to the influence of CH2-H4PteGlu on the stability of the ternary complex, leucovorin, a stable form of reduced folate, has been used in cultured cells (3) and clinically (4,5) to attempt to increase the pool of CH2-H4PteGlu, the stability of the ternary complex, and the inhibition of TS. However, preclinical studies that document the fate of leucovorin in neoplastic tissues are currently lacking.
KeywordsBolus Injection Ternary Complex Excess Formaldehyde Combine Pool Polyglutamate Form
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