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Article
August 1970

Biochemical Basis for Fluorouracil NeurotoxicityThe Role of Krebs Cycle Inhibition by Fluoroacetate

Author Affiliations

Chicago
From the Neurology Service, Veterans Administration Research Hospital, and the Department of Neurology, Northwestern University Medical School, Chicago.

Arch Neurol. 1970;23(2):155-160. doi:10.1001/archneur.1970.00480260061008
Abstract

THE PYRIMIDINE analog fluorouracil has been used extensively in the chemotherapy of malignant neoplasms since its introduction by Heidelberger and associates in 1957.1 The 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,2 its 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).2 Thus 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 Brown6 described an acute neurological disorder

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