Phosphorolysis of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and other 5-substituted-2'-deoxyuridines by purified human thymidine phosphorylase and intact blood platelets

Des̀granges, Claude; Razaka, G; Rabaud, M.; Bricaud, H; Balzarini, Jan; Clercq, Erik De

doi:10.1016/0006-2952(83)90307-6

Cited by 145 publications

(75 citation statements)

References 34 publications

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“…29 Phosphorylase activity is present in many mammalian tissues, especially in platelets and in the liver. 30 To determine whether speciesspecific differences in the BVDU metabolism could be responsible for the discrepancies between the results obtained on mice and rats, BVDU clearance following i.v.…”

Section: In Vivo Bvdu Degradation In Mice and Ratsmentioning

confidence: 99%

Comparative in vitro and in vivo cytotoxic activity of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) and its arabinosyl derivative, (E)-5-(2-bromovinyl)-1-β-D-arabinofuranosyluracil (BVaraU), against tumor cells expressing either the Varicella zoster or the Herpes simplex virus thymidine kinase

Grignet¹,

Cool²,

Baudson³

et al. 2000

Cancer Gene Ther

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The inhibitory effects of (E)-5-(2-bromovinyl)-2Ј-deoxyuridine (BVDU) and its arabinosyl derivative (E)-5-(2-bromovinyl)-1-␤-Darabinofuranosyluracil (BVaraU) on the growth of both MDA-MB-435 human breast carcinoma and 9L rat gliosarcoma cells expressing the thymidine kinase (tk)-encoding gene of the Varicella zoster virus (VZV) or the Herpes simplex virus (HSV) were evaluated. In vitro, BVDU and BVaraU effectively killed both cell types expressing VZVtk, with 50% inhibitory concentration values ranging from 0.06 to 0.4 M, whereas ganciclovir (GCV) lacked activity. On HSVtk ϩ cells, BVDU had high cytotoxic activity, with 50% inhibitory concentration values that were similar to those of GCV, whereas BVaraU was inactive. In vivo, BVDU applied intraperitoneally caused a 50% tumor growth inhibition in nude mice inoculated subcutaneously with VZVtk ϩ as well as HSVtk ϩ mammary tumor cells. In mice and at variance with the in vitro results, BVaraU had very little activity against the VZVtk ϩ mammary cells; GCV had the highest activity on the HSVtk ϩ cells, resulting in a 50% eradication of the tumors. With the 9L rat gliosarcoma model, the VZVtk/BVDU system completely failed to inhibit the development of VZVtk ϩ glioma tumors induced subcutaneously in syngeneic rats, although BVDU had a similar 45-minute half-life in both rats and mice. Factors other than degradation of the prodrug and related to the mode of action of these analogs are possibly involved in the observed discrepancies between the in vitro and in vivo results. Cancer Gene Therapy (2000) 7, 215-223

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Section: In Vivo Bvdu Degradation In Mice and Ratsmentioning

confidence: 99%

Comparative in vitro and in vivo cytotoxic activity of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) and its arabinosyl derivative, (E)-5-(2-bromovinyl)-1-β-D-arabinofuranosyluracil (BVaraU), against tumor cells expressing either the Varicella zoster or the Herpes simplex virus thymidine kinase

Grignet¹,

Cool²,

Baudson³

et al. 2000

Cancer Gene Ther

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“…In this system it was previously found that several 5-substituted 2h-deoxyuridines are degraded by TP, a fact that limits their potential therapeutic activity [15]. To compare the susceptibility of 4h-oxy-and 4h-thio-2h-deoxyuridines in this system, we incubated intact human blood platelet with…”

Section: H-thio-2h-deoxyuridines Are Resistant To Phosphorolysis By mentioning

confidence: 99%

Anti-(herpes simplex virus) activity of 4′-thio-2′-deoxyuridines: a biochemical investigation for viral and cellular target enzymes

Verri

Focher

Duncombe

et al. 2000

Biochemical Journal

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The antiviral activity of several nucleoside analogues is often limited by their rapid degradation by pyrimidine nucleoside phosphorylases. In an attempt to avoid this degradation, several modified nucleosides have been synthesized. A series of 4h-thio2h-deoxyuridines exhibits an anti-[herpes simplex virus (HSV)] activity significantly higher (20-600 times) than that shown by the corresponding 4h-oxy counterpart. We investigated the mode of action of these compounds and we found that : (i) several 4h-thio-2h-deoxyuridines are phosphorylated to the mono-and diphosphates by HSV-1 thymidine kinase (TK) more efficiently than their corresponding 4h-oxy counterpart ; (ii) both are inhibitors of cellular thymidylate synthase ; (iii) 4h-thio-2h-deoxyuridines are resistant to phosphorolysis by human thymidine phosphorylase ; (iv) both 4h-oxy-and 4h-thio-2h-deoxyuridines are phosphorylated to deoxyribonucleotide triphosphate in HSV-1-infected cells and are incorporated into viral DNA ; (v) 4h-thio-

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“…TP not only recognizes natural 2 0 -deoxynucleosides but is also able to catalyze the phosphorolysis of several nucleoside analogues endowed with antiviral or antitumor activity, such as 5-trifluorothymidine (TFT), 5-(E)-(2-bromovinyl)-2 0 -deoxyuridine (BVDU) and 5-fluoro-2 0 -deoxyuridine [2][3][4]. In addition to its catabolic role in the nucleoside salvage pathway, TP is also implicated in tumor progression as it has been shown to stimulate angiogenesis [5][6][7][8] and protect tumor cells from apoptosis [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Identification of aspartic acid-203 in human thymidine phosphorylase as an important residue for both catalysis and non-competitive inhibition by the small molecule “crystallization chaperone” 5′-O-tritylinosine (KIN59)

Bronckaers

Aguado

Negri

et al. 2009

Biochemical Pharmacology

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Phosphorolysis of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and other 5-substituted-2'-deoxyuridines by purified human thymidine phosphorylase and intact blood platelets

Cited by 145 publications

References 34 publications

Comparative in vitro and in vivo cytotoxic activity of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) and its arabinosyl derivative, (E)-5-(2-bromovinyl)-1-β-D-arabinofuranosyluracil (BVaraU), against tumor cells expressing either the Varicella zoster or the Herpes simplex virus thymidine kinase

Comparative in vitro and in vivo cytotoxic activity of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) and its arabinosyl derivative, (E)-5-(2-bromovinyl)-1-β-D-arabinofuranosyluracil (BVaraU), against tumor cells expressing either the Varicella zoster or the Herpes simplex virus thymidine kinase

Anti-(herpes simplex virus) activity of 4′-thio-2′-deoxyuridines: a biochemical investigation for viral and cellular target enzymes

Identification of aspartic acid-203 in human thymidine phosphorylase as an important residue for both catalysis and non-competitive inhibition by the small molecule “crystallization chaperone” 5′-O-tritylinosine (KIN59)

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