title: 5-Fluorouracil prodrug: role of anabolic and catabolic pathway modulation in therapy of colorectal cancer.
abstract: Following p.o. administration to rats bearing advanced colorectal carcinoma, Ftorafur (FT) is converted to 5-fluorouracil (FUra) by microsomal P450 in the liver. To optimize the therapeutic selectivity of the FUra generated from FT, three approaches were utilized: (a) inhibition of FUra degradation to dihydrofluorouracil by uracil as an alternative substrate for uracil reductase in the molar ratio of 4 uracil:1 FT (UFT); (b) modulation of drug inhibition of thymidylate synthase by leucovorin (LV); and (c) by increasing the level of FUra incorporation into cellular RNA by N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate transcarbomylase. The maximum tolerated dose (MTD) of FT and UFT, administered 3 times a day for 28 days, was 150 mg/kg/day and 60 mg/kg/day, respectively. The MTDs were not significantly modified by LV (150 or 600 mg/kg/day), administered by the p.o. route with the drugs, or by PALA (100 mg/kg) administered weekly by the i.v. route. The dose-limiting toxicity of FT alone and in combination with the modulators was stomatitis. The severe alopecia observed with FT alone was reduced significantly by uracil. At the MTD, the antitumor activity of UFT was superior to those of FT and FUra alone and in combination with LV and/or PALA. The 3-month sustained complete tumor regression for UFT, FT, and FUra was 38%, 0%, and 13% (for the weekly schedule), respectively. Although uracil, LV, and PALA individually increased the antitumor activity of FT at its MTD, the combination of the three modulators produced the highest therapeutic efficacy in rats bearing advanced colorectal carcinoma, in which 100% of the treated animals achieved complete and sustained tumor regression. The therapeutic efficacy observed with FT modulation could not be achieved with FUra administered by different schedules, each at its MTD alone or in combination with either LV or PALA. In brief, modulation of FT produced greater therapeutic efficacy and selectivity than FUra. Furthermore, the combined use of modulators capable of inhibiting the degradation pathway of FUra and potentiating the effects of the anabolic metabolites action appears to offer the greatest therapeutic potential.
authors.affiliation: Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263, and Taiho Pharmaceutical Co., Ltd., 216-1 Yaoroshi, Hanno, Saitama 357, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Cao
authors.forename: C
authors.initials: C
authors.lastname: Frank
authors.forename: T
authors.initials: T
authors.lastname: Shirasaka
authors.forename: Y M
authors.initials: YM
authors.lastname: Rustum
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D002955:Leucovorin / Q000627:therapeutic use; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000201:enzymology*; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D005641:Tegafur / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity
chemical_list: D011355:Prodrugs; D005641:Tegafur; D002955:Leucovorin; D005472:Fluorouracil