Biochemical Basis for Fluorouracil Neurotoxicity

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Abstract
THE PYRIMIDINE analog fluorouracil has been used extensively in the chemotherapy of malignant neoplasms since its introduction by Heidelberger and associates in 1957.1The carcinostatic property of fluorouracil seems to be due to anabolic reactions. Although fluorouracil is readily converted to acid-soluble fluorouracil nucleotides, undergoes incorporation into RNA, and interferes with RNA synthesis in mammalian tissues and tumor cells,2its major chemotherapeutic and toxic effects are attributable to an interference with DNA synthesis and cell division. The latter effect is due to inhibition of thymidylate synthetase, the enzyme which catalyzes the conversion of deoxyuridylate of thymidylate, by the fluorouracil derivative fluorodeoxyuridylate (FUDR).2Thus fluorouracil, like other agents which block DNA synthesis, is toxic chiefly to rapidly dividing normal cells, ie, epithelial cells of the alimentary tract and hematopoietic elements of bone marrow and lymphoid tissues.3-5 Recently, Riehl and Brown6described an acute neurological disorder