Novel (E)-5-(2-iodovinyl)-2'-deoxyuridine derivatives as potential cytostatic agents against herpes simplex virus thymidine kinase gene transfected tumors.
(E)-5-(2-Iodovinyl)-2'-deoxyuridine (IVDU), its 2'-fluoro-substituted derivatives IVFRU (with fluorine in the ribo configuration), IVFAU (with fluorine in the ara configuration), and the corresponding 3'-chemical delivery system (CDS), or 3'-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)- substituted derivatives IVDU-CDS, IVFRU-CDS and IVFAU-CDS were evaluated for their cytostatic activity against wild-type (FM3A/O), thymidine kinase (TK)-deficient (FM3A/TK-), and herpes simplex virus type 1 (HSV-1) or HSV-2 thymidine kinase (tk) gene-transfected murine mammary carcinoma FM3A cells (FM3A TK-/HSV-1 TK+ and FM3A TK-/HSV-2 TK+). The test compounds proved highly inhibitory to the proliferation of HSVtk gene-transfected FM3A cells. Their cytostatic activity was within the 0.002 to 0.80 microM range, a compound concentration that is 1000- to 10,000-fold lower than that required to inhibit proliferation of wild-type FM3A/O cells. The target for the cytostatic activity of the test compounds is the cellular thymidylate synthase. In contrast to the parent IVDU compound, IVFRU and IVFAU and their CDS-substituted derivatives proved resistant to phosphorolytic cleavage by human and bacterial thymidine phosphorylase and should be considered as promising candidate compounds for further evaluation for combined gene/chemotherapy of HSVtk gene-transfected tumor cells in animal models.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Morin
K W
KW
Knaus
E E
EE
Wiebe
L I
LI
De Clercq
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004354:Drug Screening Assays, Antitumor; D015316:Genetic Therapy; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics*; D018258:Herpesvirus 2, Human / Q000201:enzymology / Q000235:genetics; D006868:Hydrolysis; D007065:Idoxuridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008809:Mice, Inbred C3H; D013379:Substrate Specificity; D013937:Thymidine Kinase / Q000235:genetics*; D013939:Thymidine Phosphorylase / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C030360:5-(2-iodovinyl)-2'-deoxyuridine; D013939:Thymidine Phosphorylase; D013937:Thymidine Kinase; D007065:Idoxuridine