New drugs in therapy of colorectal cancer: preclinical studies.
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.
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Roswell Park Cancer Institute, Buffalo, NY 14261, USA.
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D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D042943:Dihydrouracil Dehydrogenase (NADP); D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use*; D005493:Folic Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D005641:Tegafur / Q000494:pharmacology / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014498:Uracil / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011355:Prodrugs; D011799:Quinazolines; D013876:Thiophenes; C096910:UFT(R) drug; D003841:Deoxycytidine; D005641:Tegafur; C073482:eniluracil; D014498:Uracil; D000069287:Capecitabine; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; C068874:raltitrexed; D005472:Fluorouracil