title: Mechanism of cytostatic action of novel 5-(thien-2-yl)- and 5-(furan-2-yl)-substituted pyrimidine nucleoside analogues against tumor cells transfected by the thymidine kinase gene of herpes simplex virus.
abstract: Several novel 5-substituted 2'-deoxyuridine (dUrd) analogues were evaluated as substrates for highly purified herpes simplex virus type 1 (HSV-1)-encoded thymidine kinase (TK) derived from HSV-1 TK gene-transfected murine mammary carcinoma FM3A cells, and human platelet thymidine (dThd) phosphorylase. The Ki of 5-(furan-2-yl)-dUrd, 5-(thien-2-yl)-dUrd and 5-(thien-2-yl)-dCyd for HSV-1 TK was 0.94, 0.71, and 1.32 microM, respectively. Inhibition was competitive with respect to the natural substrate dThd. With dCyd as substrate, the Ki of 5-(thien-2-yl)-dCyd for HSV-1 TK was 4.5 microM (Ki/Km = 0.17). In striking contrast with (E)-5-(2-bromovinyl)-dUrd, the 5-(thien-2-yl)- and 5-(furan-2-yl)-dUrd derivatives were not substrates for human dThd phosphorylase. 5-(Thien-2-yl)-dUrd, 5-(furan-2-yl)-dUrd and 5-(thien-2-yl)-dCyd were at least 100-fold more cytostatic to the HSV TK gene-transfected FM3A tumor cells than wild-type FM3A/0 cells. The viral TK expressed in the HSV-1 TK gene-transfected tumor cells merely acts as an activating enzyme, whereas thymidylate synthase serves as the target enzyme for the cytostatic action of the compounds. The novel 5-substituted dUrd analogues should be further pursued as candidate drugs in the treatment of HSV TK gene-transfected tumors.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Bohman
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: P
authors.initials: P
authors.lastname: Wigerinck
authors.forename: A
authors.initials: A
authors.lastname: Van Aerschot
authors.forename: P
authors.initials: P
authors.lastname: Herdewijn
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002845:Chromatography; D002846:Chromatography, Affinity; D002852:Chromatography, Ion Exchange; D003600:Cytosol / Q000201:enzymology; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D017886:Durapatite; D005260:Female; D018259:Herpesvirus 1, Human / Q000201:enzymology* / Q000235:genetics; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008809:Mice, Inbred C3H; D011741:Pyrimidine Nucleosides / Q000633:toxicity*; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000302:isolation & purification; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D011741:Pyrimidine Nucleosides; D017886:Durapatite; D013937:Thymidine Kinase