Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the present study was to clarify the significance of the inhibition of dihydropyrimidine dehydrogenase (DPD) in the modulation of 5-fluorouracil (5-FU) action by 5-ethyl-2'-deoxyuridine (EUdR). Four human cell lines, which differed in their susceptibility to 5-FU and in their DPD activity, were selected as biological objects. Several other enzymes of pyrimidine metabolism, i.e. thymidylate synthase (TS), thymidine kinase (TK) and pyrimidine nucleoside phosphorylase (PNP), which might be involved in the 5-FU action were also studied to elucidate their potential role in the modulation of 5-FU cytotoxicity. Two out of the four cell lines, i.e. COLO1 and SW620, showed low (57 and 28 pmol/min/mg protein) and the other two cell lines, i.e. CAL51 and CAL33, showed high (235 and 184 pmol/min/mg protein) DPD activity, respectively. In our study, contrary to our expectation, no correlation between the DPD and TS activity of the cell lines and their 5-FU sensitivity could be observed. EUdR alone was cytotoxic only on CAL33 cells in a concentration below 1 mM (IC50=194 microM) which might be due to the high TK activity (857 pmol/min/mg protein) measured in this cell line, favoring the formation of the phosphorylated nucleotides EdUMP and EdUTP indispensable for the inhibition of TS and DNA polymerase, respectively. Surprisingly, although EUdR by metabolizing to EUra was able to reduce the high activity of DPD in CAL33 and CAL51 cells by 47 and 55%, respectively, no potentiation of the 5-FU action occurred on these cell lines. On the contrary, enhancement of the 5-FU cytotoxicity was demonstrated on COLO1 and SW620 cells with low DPD activity. Our findings suggest that the 5-FU modulatory action of EUdR may be directed on other molecular targets than DPD as well, i.e. the augmentation of TS inhibition by EdUMP as demonstrated on SW620 cells might be one of these mechanisms.
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PMID:Modulation of 5-fluorouracil by 5-ethyl-2'-deoxyuridine on cell lines expressing different dihydropyrimidine dehydrogenase activities. 1088 4

(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU, Brivudin, Zostex, Zerpex, Zonavir), now more than 20 years after its discovery, still stands out as a highly potent and selective inhibitor of herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) infections. It has been used in the topical treatment of herpetic keratitis and recurrent herpes labialis and the systemic (oral) treatment of herpes zoster (zona, shingles). The high selectivity of BVDU towards HSV-1 and VZV depends primarily on a specific phosphorylation of BVDU to its 5'-diphosphate (DP) by the virus-encoded thymidine kinase (TK). After further phosphorylation (by cellular enzymes), to the 5'-triphosphate (TP), the compound interferes as a competitive inhibitor/alternate substrate with the viral DNA polymerase. The specific phosphorylation by the HSV- and VZV-induced TK also explains the marked cytostatic activity of BVDU against tumor cells that have been transduced by the viral TK genes. This finding offers considerable potential in a combined gene therapy/chemotherapy approach for cancer. To the extent that BVDU or its analogues (i.e., BVaraU) are degraded (by thymidine phosphorylase) to (E)-5-(2-bromovinyl)uracil (BVU), they may potentiate the anticancer potency, as well as toxicity, of 5-fluorouracil. This ensues from the direct inactivating effect of BVU on dihydropyrimidine dehydrogenase, the enzyme that initiates the degradative pathway of 5-fluorouracil. The prime determinant in the unique behavior of BVDU is its (E)-5-(2-bromovinyl) substituent. Numerous BVDU analogues have been described that, when equipped with this particular pharmacophore, demonstrate an activity spectrum characteristic of BVDU, including selective anti-VZV activity.
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PMID:(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU). 1538 33

This Commentary is dedicated to the memory of Dr. Jacques Gielen, the late Editor of Biochemical Pharmacology, whom I have known as both an author and reviewer for the Journal for about 25 years. This is, quite incidentally, about the time it took for bringing brivudin (BVDU) [(E)-5-(2-bromovinyl)-2'-deoxyuridine] from its original description as an antiviral agent to the market place (in a number of European countries, including Germany and Italy) for the treatment of herpes zoster in immunocompetent persons. BVDU is exquisitely active and selective against varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV-1). BVDU owes this high selectivity and activity profile to a specific phosphorylation by the virus-encoded thymidine kinase, followed by a potent interaction with the viral DNA polymerase. The (E)-5-(2-bromovinyl)-substituent can be considered as the hallmark for the activity of BVDU against VZV and HSV-1. Extensive clinical studies have indicated that BVDU as a single (oral) daily dose of 125 mg (for no more than 7 days) is effective in the treatment of herpes zoster, as regards both short-term (suppression of new lesion formation) and long-term effects (prevention of post-herpetic neuralgia). In this sense, BVDU is as efficient and/or convenient, if not more so, than the other drugs (acyclovir, valaciclovir, famciclovir) that have been licensed for the treatment of herpes zoster. There is one caveat; however, BVDU should not be given to patients under 5-fluorouracil therapy, as the degradation product of BVDU, namely (E)-5-(2-bromovinyl)uracil (BVU), may potentiate the toxicity of 5-fluorouracil, due to inhibition of dihydropyrimidine dehydrogenase, the enzyme involved in the catabolism of 5-fluorouracil.
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PMID:Discovery and development of BVDU (brivudin) as a therapeutic for the treatment of herpes zoster. 1554 77