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(Ftorafur) to 5-Fluorouracil by Soluble Enzymes1

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(Ftorafur) to 5-Fluorouracil by Soluble Enzymes1 [CANCER RESEARCH 43, 4039-4044, September 1983] Metabolic Activation of RS-1-(Tetrahydro-2-furanyl)-5-fluorouracil (Ftorafur) to 5-Fluorouracil by Soluble Enzymes1 Yousry M. El Sayed2 and Wolfgang Sadée3 Departments of Pharmacy and Pharmaceutical Chemistry, School at Pharmacy, University of California, San Francisco, California 94143 ABSTRACT the N-1—C-2' bond of ftorafur to yield 4-hydroxybutanal as the intermediate which is further metabolized to GBL or GHB. There are two major fl,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) activation pathways to 5-fluorouracil, one that is me diated by microsomal cytochrome P-450 oxidation at C-5' of the MATERIALS AND METHODS tetrahydrofuran moiety and one that is mediated by soluble All chemicals and reagents were of spectroquality or analytical grade. enzymes. This report demonstrates that the soluble enzyme Ftorafur was supplied by the Chemical and Drug Procurement Section, pathway proceeds via enzymatic cleavage (possibly hydrolytic) of the N-1—C-2' bond to yield 5-fluorouracil and 4-hydroxybu- Division of Cancer Treatment, National Cancer Institute, Bethesda, Md. NADPH and NADH were purchased from the Sigma Chemical Co. (St. tanal, which is immediately further metabolized to 7-butyrolac- Louis, Mo.). Alcohol dehydrogenase from horse liver (specific activity, tone or -y-hydroxybutyric acid. The soluble activation pathway about 2.7 units/mg) was purchased from Boehringer Mannheim, Indian was present in liver, small intestine, and brain. Because of the apolis, Ind. Because of their chemical instabilities, 4-hydroxybutanal and limited distribution of cytochrome P-450 in body tissues and succinaldehyde had to be synthesized immediately preceding their use. because of the lack of redistribution of 5-fluorouracil via the 4-Hydroxybutanal was generated from the precursor 2,3-dihydrofuran systemic circulation after ftorafur administration, we propose (Aidrich Chemical Co., Milwaukee, Wis.) under acidic conditions (21). Succinaldehyde was generated from 2,5-dimethoxytetrahydrofuran (Aid- that the soluble enzyme pathway is at least in part responsible rich Chemical Co.) under acidic conditions (17). for organ toxicity and possibly antitumor effect. Distinction of the microsomal (C-5') and the soluble enzyme (C-2') activation path Tissue Homogenate Preparations and in Vitro Incubations. Male Dutch rabbits were stunned and decapitated. The liver, brain, and small ways can be exploited in the design of more selective prodrug intestine were excised and rinsed in ice-cold isotonic (1.15%) KCI. Each analogues. organ tissue was homogenized in ice-cold 0.01 M potassiunrsodium phosphate buffer (pH 7.4):1.15% KCI (1:2, w/v) using a Potter-Elvehjem Teflon-pestle homogenizer. The homogenates were centrifuged at INTRODUCTION 10,000 g for 20 min at 0-4° to yield the 10,000 g supernatant fraction. The pyrimidine antimetabolite ftorafur4 has shown activity The supernatant fractions were recentrifuged at 100,000 g for 1 hr at 0- 4°. The 100,000 g supernatant fraction may be used immediately or against several adenocarcinomas with less myelotoxicity but frozen at -20° until use. more central nervous sytem toxicity than those of 5-fluorouracil (29). Ftorafur is considered a prodrug of 5-fluorouracil, and it is Several experiments were carried out with dialyzed 100,000 g liver homogenates. The dialysis tubes containing the homogenates were slowly metabolized to 5-fluorouracil by several metabolic path incubated in 200 volumes of 100 mM Tris buffer, pH 7.4, for 5 hr at 4°. ways (3, 4, 10). A high concentration of Tris buffer was chosen to accelerate solute Recently, we identified 2 major in vitro pathways of ftorafur exchange; moreover, the buffer was replaced every hr. activation to 5-fluorouracil that do not involve the known ftorafur All in vitro incubations were earned out at pH 7.4 at 37°for 1 hr. Final metabolites (that retain the tetrahydrofuran moiety), one occur concentration of all preparations was standardized to 1 g tissue (wet ring in the 100,000 g supernatant fraction (soluble enzymes) of weight) per 2 ml incubation mixture. Chemical reagents and cofactors liver homogenate and one in the 100,000 g microsomal pellet (3, were added at the concentrations indicated. The concentrations of 10). The microsomal pathway involving cytochrome P-450 pro NADPH and NADH were 1 mM each. When incubations were performed duces succinaldehyde and 5-fluorouracil via oxidation at the C- for more than 1 hr, additional amounts of NADPH and NADH were added 5' position of ftorafur (10). In contrast, GBL or its ring open every hr (yielding concentration increments of 1 mw each) in order to prevent cofactor depletion. Higher concentrations of NADPH and NADH congener GHB was isolated as a major metabolite in the super failed to increase the rate of product formation. The rate of GBL or GHB natant soluble enzyme fractions. Chart 1 shows the potential formation from ftorafur was linear over at least 4 hr. activation pathways that can occur at either position C-2' or C- GG Assay for GBL or GHB, 4-Hydroxybutanal, and 1,4-Butanediol. 5' of ftorafur with GBL or GHB as the possible common end GBL or GHB, 4-hydroxybutanal, and 1,4-butanediol were measured by product. the previously published GC assay of GBL or GHB (3) with the following Precise knowledge of the activation mechanisms of ftorafur modifications. The column, injector, and detector temperatures were may lead to the development of more selective 5-fluorouracil 145,190, and 210°,respectively. GC retention times for GBL, 4-hydroxy butanal, and 1,4-butanediol were 3.2, 1.5, and 9.5 min, respectively. prodrugs. In this report, we provide evidence that the soluble There was no detectable conversion of 4-hydroxybutanal and succinal- enzyme pathway of ftorafur activation proceeds via cleavage of dehyde to GBL or GHB under the assay conditions. Sensitivity for GBL 1This work was supported by National Cancer Institute Grant CA 27866. was approximately 0.5 ¿/g/mltissue homogenates. Standard curves were 2 Recipient of a scholarship from the Egyptian Government, in partial support of linear over the range of 0.5 to 200 /<g/ml. There is no measurable this work. 3 To whom requests for reprints should be addressed. decomposition of ftorafur to GBL at concentrations up to 200 jig/ml 4 The abbreviations used are: ftorafur, fl,S-1-<tetrahydro-2-furanyl)-5-fluorouracil; during the assay procedures. GBL, -,-butyroiactone: GHB, -y-hydroxybutyric acid; GC, gas chromatography. High-Pressure Liquid Chromatographie Assay of 5-Fluorouracil. 5- Received February 17.1983; accepted May 26.1983. Fluorouradl was measured in the in vitro incubates with a modified high- SEPTEMBER 1983 4039 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1983 American Association for Cancer Research. Y. M. El Sayed and W. Sadée Chart 2 shows the percentage of conversion of succinaldehyde (500 MM)to GBL or GHB in rabbit liver homogenates (100,000 g C-2' IIIMTMI supernatant fraction). The addition of NADPH or NADH greatly O°^ enhanced the conversion of succinaldehyde to GBL or GHB, en tu while incubation without any cofactor added to the soluble enzyme preparation generated only 12% GBL or GHB. In addi tion, incubations without enzyme and only with phosphate buffer did not generate any detectable GBL or GHB. Acid treatment of o— succinaldehyde which is part of the GC assay procedure did not 4-11 1,4-10 produce any detectable amounts of GBL:GHB, thereby ruling out any procedural artifacts. Incubation of lower concentrations of succinaldehyde (50 Õ/M)gave similar yields of GBL or GHB. Incubations of succinaldehyde (500 A/M)with the 100,000 g supernatants in the presence of NADPH and hydrazine (2 mw) O«/* COOH _HO<X\ f00*1 produced an 80% inhibition of GBL or GHB product formation SSI S.ccinic feM (Chart 2). Hydrazine was chosen because it was expected to Chart 1. Three possible activation pathways of ftorafur (FT) that lead to 5- form a cyclic bis(hydrazone) with succinaldehyde (17). In con fluorouracil (FUra) and the expected products of the tetrahydrofuran moiety. Poten trast, pyrazole (2 HIM)(an alcohol dehydrogenase inhibitor) (22), tial interconversion among these products is also indicated. 4-HB, 4-hydroxybu- A/-ethylmaleimide (1 mw) (an inactivator of sulfhydryl groups) (8), tanal; 1,4-BD. 1.4-butanediol: SA. succinaldehyde; SSA. succinic semialdehyde. and semicarbazide (2 mw) (an aldehyde-trapping reagent), did not produce a significant change in the yield of GBL or GHB. pressure liquid Chromatographie assay (30) using prepurifìcationof ex Chart 3 shows the percentage of conversion of 4-hydroxybu- tracts by column chromatography for sufficient sensitivity (100 ng/ml). tanal (50 ^M) to GBL or GHB under different liver 100,000 g The column chromatography afforded separation of 5-fluorouracil from homogenate incubation conditions. Most strikingly, 4-hydroxy- the endogenous interferences present in the tissue homogenates. To 1 butanal is very rapidly and quantitatively converted to GBL or ml of the in vitro incubation of ftorafur (2 mw) with the soluble enzyme GHB without any cofactor added. NADPH slightly reduced the of the 100,000 g supernatant, 0.1 ml of 0.5 M NaH2PO4 and 5 /¿gof5- yield of GBL or GHB, while hydrazine had very little effect on the bromouracil:50 n\ methanol as internal standard were added. Samples reaction. However, the conversion to GBL or GHB was inhibited were then extracted with 2 x 10 ml ethyl acetate, and the ethyl acetate layers were evaporated to dryness under nitrogen gas at 60°. The by 80% with NADH plus horse liver alcohol dehydrogenase residue was dissolved in a small volume (100 /tl) of methanol and added to the 100,000 g supernatant fractions. NADH and horse subjected to column chromatography (14 x 0.9 cm, inside diameter; silica liver alcohol dehydrogenase were selected for this experiment, gel, 100 to 200 mesh; Bio-Rad, Richmond, Calif.), eluting with 10 ml since they were expected to reduce 4-hydroxybutanal to 1,4- acetonitrile:chloroform:water (40:4:1) (20).
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