Degradation of pyrimidines and pyrimidine analogs—Pathways and mutual influences

Wasternack, Claus

doi:10.1016/0163-7258(80)90079-0

Cited by 114 publications

(71 citation statements)

References 111 publications

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“…The potentiating effect of MISO may be a consequence of competition for catabolic sites with other drugs which are metabolized by microsomal oxidation (Workman & Twentyman, 1982;Siemann, 1983;Workman et al, 1983) but there are conflicting results (Law et al, 1981;Siemann, 1982b). The present study shows that modulation of the pharmacokinetics of cytotoxic drugs by MISO cannot be simply competition for microsomal enzymes, since FU is catabolized at mitochondrial and cytosolic locations (Wasternak, 1979). Clearance values of FU and its primary catabolite, 5'6'-dihydro-5-fluorouracil (DHFU), derived from their concentrations in plasma showed that saturated elimination could be observed within 6 h of drug administration (McDermott et al, 1982).…”

Section: Discussionmentioning

confidence: 72%

Pharmacokinetic rationale for the interaction of 5-fluorouracil and misonidazole in humans

McDermott¹,

Berg²,

Martin³

et al. 1983

Br J Cancer

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Section: Discussionmentioning

confidence: 72%

Pharmacokinetic rationale for the interaction of 5-fluorouracil and misonidazole in humans

McDermott¹,

Berg²,

Martin³

et al. 1983

Br J Cancer

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“…Open circle, vehicle; filled circle, capecitabine; filled triangle, capecitabine ϩ RO0094889 (3.37 mg/kg/day); open triangle, capecitabine ϩ RO0094889 (10.1 mg/kg/day); open square, capecitabine ϩ RO0094889 (33.7 mg/kg/day). The sub-confluent cells of HCT116-pRC and HCT116-DPD were harvested and were used to determine the DPD activities and dThdPase levels- 2 The cells of HCT116-pRC and HCT116-DPD were inoculated into mice. The tumor tissues were resected 16 days after the inoculation and used to determine the DPD activities and dThdPase levels- 3 The ratio of the DPD activities between HCT116-DPD and HCT116-pRC are indicated- 4 The ratio of the dThdPase levels between HCT116-DPD and HCT116-pRC are indicated.…”

Section: Augmentation Of the Antitumor Activity Of Capecitabine By Thmentioning

confidence: 99%

Augmentation of the antitumor activity of capecitabine by a tumor selective dihydropyrimidine dehydrogenase inhibitor, RO0094889

Endo

Miwa

Eda

et al. 2003

Intl Journal of Cancer

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Capecitabine is an orally available fluoropyrimidine and is finally converted to 5-FU selectively in tumor tissues. In our study, we examined whether the antitumor activity of capecitabine is directly affected by a modulation of dihydropyrimidine dehydrogenase (DPD). The modulations were carried out by the overexpression of DPD in tumor cells and by tumor selective DPD inhibition. The DPD-overexpressing cells were obtained by transfection of human DPD cDNA into HCT116 human colorectal cancer cells. The HCT116 cells bearing DPD cDNA expressed about 13 times higher DPD activities than the parental HCT116 cells, and they became significantly less susceptible to capecitabine than the parental cells when transplanted into nude mice. Administration of RO0094889 that is converted to a DPD inhibitor 5-vinyluracil selectively in tumor tissues restored the antitumor activity of capecitabine against the tumor of the HCT116 cells carrying DPD cDNA and various tumors expressing DPD. As compared to 5-ethynyluracil or 5-vinyluracil, which inhibited DPD not only in tumor tissues but also in other non-cancerous tissues, the effective dose range of RO0094889 in augmenting the efficacy of capecitabine was much broader. These results indicate that the antitumor activity of capecitabine is directly affected by DPD activities in tumor tissues and therefore, the combination of capecitabine and a tumor selective DPD inhibitor, RO0094889, will be beneficial to patients who have tumors with high levels of DPD. © 2003 Wiley-Liss, Inc. Key words: dihydropyrimidine dehydrogenase; thymidine phosphorylase; 5-fluorouracil; 5-vinyluracil; prodrug Dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2) is the enzyme responsible for the initial step of pyrimidine catabolism. It is expressed in liver and several types of neoplastic tissues and converts pyrimidines to dihydropyrimidines that are further catabolized to ureidopropionic acid and ␤-alanine by dihydropyrimidinase and ␤-ureidopropionase, respectively. 1,2 Because DPD also degrades 5-fluorouracil (5-FU), the efficacy and toxicity of 5-FU are highly affected by DPD activities. 3-8 Administration of DPD inhibitors, 5-ethynyluracil (5-EU) and 5-chloro-2,4-dihydroxypyridine (CDHP), inhibits DPD activities in liver and increases the concentrations of 5-FU in plasma and many other tissues. 9,10 Furthermore, administration of 5-FU exhibited severe toxicity against patients who are defective in DPD activities, 11-16 and such patients have been thought to be heterozygous or homozygous for a mutated DPD gene. [17][18][19] The DPD deficiency is inherited as an autosomal recessive trait 18 and it is estimated that approximately 3% of the world population to be heterozygous for a mutant DPD gene. 18,20 Therefore, the systemic inhibition of DPD would enhance not only the efficacy but also the toxicity of fluoropyrimidine anticancer drugs. On the other hand, the tumor selective inhibition of DPD may augment the efficacy but not the toxicity of 5-FU.Previously, we developed capecitabine (N 4 -pentyloxyca...

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“…Briefly, a 6-l drop of an equal volume of the protein solution (4.0 -4.5 mg/ml in 50 mM Tris (pH 7.5), 1 mM dithiothreitol, and 100 mM NaCl) and of the reservoir solution was equilibrated against 1 ml of either 0.88 M trisodium citrate, 0.1 M sodium citrate (pH 6.0), and 5% (v/v) dioxane or 1.0 M trisodium citrate, 0.1 M MES (pH 6.5), and 5% (v/v) dioxane. The crystals appeared after 5-7 days and belonged to space group P2 1 .…”

Section: Methodsmentioning

confidence: 99%

“…The structure of Sk␤AS has been determined in two different crystal forms, both belonging to the monoclinic space group P2 1 . Comparison of the final models revealed that the backbone architectures of the subunits are essentially the same, and the observed differences in domain arrangement (discussed below) between the subunits of SeMet-substituted Sk␤AS do not exceed those observed in the crystals of native Sk␤AS.…”

Section: Structure Determinationmentioning

confidence: 99%

“…In the second step, dihydropyrimidinase (EC 3.5.2.2) generates N-carbamyl-␤-alanine and N-carbamyl-␤-aminoisobutyric acid, respectively, via reversible hydrolytic cleavage of the dihydropyrimidine ring. ␤-Alanine synthase (␤AS 1 ; N-carbamoyl-␤-alanine amidohydrolase and ␤-ureidopropionase, EC 3.5.1.6), catalyzes the third and final step: the hydrolysis of the N-carbamylated ␤-amino acids to ␤-alanine or aminoisobutyrate under the release of carbon dioxide and ammonia (1).…”

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confidence: 99%

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Yeast β-Alanine Synthase Shares a Structural Scaffold and Origin with Dizinc-dependent Exopeptidases

Lundgren

Gojković

Piškur

et al. 2003

Journal of Biological Chemistry

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␤-Alanine synthase (␤AS) is the final enzyme of the reductive pyrimidine catabolic pathway, which is responsible for the breakdown of pyrimidine bases, including several anticancer drugs. In eukaryotes, ␤ASs belong to two subfamilies, which exhibit a low degree of sequence similarity. We determined the structure of ␤AS from Saccharomyces kluyveri to a resolution of 2.7 Å. The subunit of the homodimeric enzyme consists of two domains: a larger catalytic domain with a dizinc metal center, which represents the active site of ␤AS, and a smaller domain mediating the majority of the intersubunit contacts. Both domains exhibit a mixed ␣/␤-topology. Surprisingly, the observed high structural homology to a family of dizinc-dependent exopeptidases suggests that these two enzyme groups have a common origin. Alterations in the ligand composition of the metal-binding site can be explained as adjustments to the catalysis of a different reaction, the hydrolysis of an N-carbamyl bond by ␤AS compared with the hydrolysis of a peptide bond by exopeptidases. In contrast, there is no resemblance to the three-dimensional structure of the functionally closely related N-carbamyl-D-amino acid amidohydrolases. Based on comparative structural analysis and observed deviations in the backbone conformations of the eight copies of the subunit in the asymmetric unit, we suggest that conformational changes occur during each catalytic cycle.In most living organisms, the degradation of uracil and thymine is achieved by the three-step reaction sequence of the reductive pyrimidine catabolic pathway. The first and rate-limiting enzyme is dihydropyrimidine dehydrogenase (dihydrouracil dehydrogenase (NADP ϩ ), EC 1.3.1.2), which catalyzes the NADPHdependent reduction of uracil and thymine to the corresponding dihydropyrimidines (Scheme 1). In the second step, dihydropyrimidinase (EC 3.5.2.2) generates N-carbamyl-␤-alanine and N-carbamyl-␤-aminoisobutyric acid, respectively, via reversible

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Degradation of pyrimidines and pyrimidine analogs—Pathways and mutual influences

Cited by 114 publications

References 111 publications

Pharmacokinetic rationale for the interaction of 5-fluorouracil and misonidazole in humans

Pharmacokinetic rationale for the interaction of 5-fluorouracil and misonidazole in humans

Augmentation of the antitumor activity of capecitabine by a tumor selective dihydropyrimidine dehydrogenase inhibitor, RO0094889

Yeast β-Alanine Synthase Shares a Structural Scaffold and Origin with Dizinc-dependent Exopeptidases

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