Abstract
For years, 5-fluorouracil (5-FU) was the only chemotherapeutic agent for the treatment of patients with advanced colorectal cancer. Based on laboratory data, modulation of 5-FU by leucovorin (LV) was proven to be an active alternative. In addition, a number of 5-FU prodrugs and antifolate antimetabolites became available for preclinical and clinical evaluation. With the 5-FU prodrugs, the overall aim was to improve the therapeutic efficacy and selectivity of 5-FU and to provide an oral form of therapy. In preclinical systems, several of the 5-FU prodrugs, eg, capecitabine, uracil/ ftorafur (UFT)/LV, and S- , are active and offer significant therapeutic advantages over 5-FU/LV. A direct and specific new thymidylate synthase (TS) inhibitor, Tomudex (raltitrexed, ZDI694; Zeneca Pharmaceuticals, Macclesfield, UK), is active in several preclinical and clinical settings. The major focus of this report will be on the preclinical development of selected fluoropyrimidine prodrugs.
Publication types
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Research Support, U.S. Gov't, P.H.S.
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Review
MeSH terms
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Animals
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Antimetabolites, Antineoplastic / pharmacology
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Antimetabolites, Antineoplastic / therapeutic use*
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Capecitabine
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Colorectal Neoplasms / drug therapy*
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Deoxycytidine / analogs & derivatives
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Deoxycytidine / pharmacology
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Deoxycytidine / therapeutic use
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Dihydrouracil Dehydrogenase (NADP)
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Drug Combinations
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use*
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Fluorouracil / pharmacology
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Fluorouracil / therapeutic use*
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Folic Acid Antagonists / pharmacology
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Folic Acid Antagonists / therapeutic use*
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Humans
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Oxidoreductases / antagonists & inhibitors
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Prodrugs / pharmacology
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Prodrugs / therapeutic use*
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Quinazolines / pharmacology
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Quinazolines / therapeutic use*
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Tegafur / pharmacology
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Tegafur / therapeutic use
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Thiophenes / pharmacology
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Thiophenes / therapeutic use*
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Thymidine Phosphorylase / antagonists & inhibitors
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Thymidylate Synthase / antagonists & inhibitors
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Uracil / analogs & derivatives
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Uracil / pharmacology
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Uracil / therapeutic use
Substances
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Antimetabolites, Antineoplastic
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Drug Combinations
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Enzyme Inhibitors
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Folic Acid Antagonists
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Prodrugs
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Quinazolines
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Thiophenes
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UFT(R) drug
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Deoxycytidine
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Tegafur
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eniluracil
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Uracil
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Capecitabine
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Oxidoreductases
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Dihydrouracil Dehydrogenase (NADP)
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Thymidylate Synthase
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Thymidine Phosphorylase
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raltitrexed
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Fluorouracil