Species-dependent differences in the biochemical effects and metabolism of 5-benzylacyclouridine

Davis, Stephen T.; Joyner, S S; Chandrasurin, Pisal; Baccanari, David P.

doi:10.1016/0006-2952(93)90390-i

Cited by 12 publications

(11 citation statements)

References 15 publications

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“…Metabolic and pharmacokinetic studies [13-15, 22, 35, 38, 40, 42, 46] established PTAU as the best of all known uridine phosphorylase inhibitors in increasing the efficacy and reducing the toxicity of FUra in chemotherapy. All the other inhibitors suffer from limited potency, low bioavailability, and/or poor pharmacokinetic properties [13,15,22,35,36,38,48].…”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of uridine catabolism also prevented the toxic side effects associated with high doses of uridine that resulted from the accumulation of uridine catabolites [18]. However, the effectiveness and bioavailability of the currently available UP inhibitors are limited by metabolism and inadequate pharmacokinetic properties [13,15,22,35,36,38].…”

Section: Introductionmentioning

confidence: 99%

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Potent combination therapy for human breast tumors with high doses of 5-fluorouracil: remission and lack of host toxicity

Safarjalani

Rais²,

Naguib³

et al. 2012

Cancer Chemother Pharmacol

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Potent combination therapy for human breast tumors with high doses of 5-fluorouracil: remission and lack of host toxicity

Safarjalani

Rais²,

Naguib³

et al. 2012

Cancer Chemother Pharmacol

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“…The perturbation of plasma uridine by BAU is speciesdependent, and the rat is a stringent test for the efficacy of UrdPase inhibitors in vivo . 27 When 10j or 11f (90 mg/kg, po) was administered to rats, plasma uridine levels were increased 4-8-fold for 4 h (Figure 2A). The elevation in plasma uridine levels produced by 10j and 11f in rats persisted for at least 1.3 times longer than the elevation produced by one of our best inhibitors reported previously.…”

Section: Chemistry Discussionmentioning

confidence: 99%

Inhibition of Uridine Phosphorylase. Synthesis and Structure−Activity Relationships of Aryl-Substituted 1-((2-Hydroxyethoxy)methyl)-5-(3-phenoxybenzyl)uracil

et al. 1997

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Structure-activity relationship studies on a series of 1-((2-hydroxyethoxy)methyl)-5-(3-(substituted-phenoxy)benzyl)uracils as inhibitors of murine liver uridine phosphorylase have led to compounds with IC50s as low as 1.4 nM. The two most potent compounds, 10j (3-cyanophenoxy) and 11f (3-chlorophenoxy) were tested in vivo for effects on steady-state concentrations of circulating uridine in mice and rats. Both compounds were substantially more efficacious than BAU (5-benzylacyclouridine) both in vitro and in vivo.

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“…Alternatively, co-administration of 5-benzylacyclouridine with 5-azaorotate may rescue the host, but not the parasite, from the possible toxicity of orotate phosphoribosyltransferase inhibitors. 5-Benzylacyclouridine is a potent inhibitor of uridine phosphorylase from various species (Niedzwicki et al, 1982; Park et al, 1986; Naguib et al, 1987; el Kouni et al, 1988; el Kouni et al, 1996), and can alleviate the inhibition of de novo UMP biosynthesis by increasing the plasma levels and salvage of uridine only in the host (Monks et al, 1983; Darnowski and, Handschumacher, 1985; Martin, et al, 1989; Davis et al, 1993; Sommadossi et al, 1995) to overcome pyrimidine starvation. Furthermore, 5-benzylacyclouridine may act synergistically with 5-azaorotate on schistosomes by inhibiting the salvage of uridine by the worms via uridine phosphorylase.…”

Section: Enzymes Of Pyrimidine Salvage Pathwaysmentioning

confidence: 99%

Pyrimidine metabolism in schistosomes: A comparison with other parasites and the search for potential chemotherapeutic targets

Kouni

2017

Comparative Biochemistry and Physiology Part B: Biochemistry an

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Schistosomes are responsible for the parasitic disease schistosomiasis, an acute and chronic parasitic ailment that affects more than 240 million people in 70 countries worldwide. It is the second most devastating parasitic disease after malaria. At least 200,000 deaths per year are associated with the disease. In the absence of the availability of vaccines, chemotherapy is the main stay for combating schistosomiasis. The antischistosomal arsenal is currently limited to a single drug, Praziquantel, which is quite effective with a single-day treatment and virtually no host-toxicity. Recently, however, the question of reduced activity of Praziquantel has been raised. Therefore, the search for alternative antischistosomal drugs merits the study of new approaches of chemotherapy. The rational design of a drug is usually based on biochemical and physiological differences between pathogens and host. Pyrimidine metabolism is an excellent target for such studies. Schistosomes, unlike most of the host tissues, require a very active pyrimidine metabolism for the synthesis of DNA and RNA. This is essential for the production of the enormous numbers of eggs deposited daily by the parasite to which the granulomas response precipitate the pathogenesis of schistosomiasis. Furthermore, there are sufficient differences between corresponding enzymes of pyrimidine metabolism from the host and the parasite that can be exploited to design specific inhibitors or “subversive substrates” for the parasitic enzymes. Specificities of pyrimidine transport also diverge significantly between parasites and their mammalian host. This review deals with studies on pyrimidine metabolism in schistosomes and highlights the unique characteristic of this metabolism that could constitute excellent potential targets for the design of safe and effective antischistosomal drugs. In addition, pyrimidine metabolism in schistosomes is compared with that in other parasites where studies on pyrimidine metabolism have been more elaborate, in the hope of providing leads on how to identify likely chemotherapeutic targets which have not been looked at in schistosomes.

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Species-dependent differences in the biochemical effects and metabolism of 5-benzylacyclouridine

Cited by 12 publications

References 15 publications

Potent combination therapy for human breast tumors with high doses of 5-fluorouracil: remission and lack of host toxicity

Potent combination therapy for human breast tumors with high doses of 5-fluorouracil: remission and lack of host toxicity

Inhibition of Uridine Phosphorylase. Synthesis and Structure−Activity Relationships of Aryl-Substituted 1-((2-Hydroxyethoxy)methyl)-5-(3-phenoxybenzyl)uracil

Pyrimidine metabolism in schistosomes: A comparison with other parasites and the search for potential chemotherapeutic targets

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