NOVEL (E)-5-(2-IODOVINYL)-2'-DEOXYURIDINE DERIVATIVES AS POTENTIAL CYTOSTATIC AGENTS AGAINST HERPES-SIMPLEX VIRUS THYMIDINE KINASE GENE TRANSFECTED TUMORS

(E)-5-lodovinyl)-2'-deoxyuridine (IVDU), its 2'-fluoro-substituted der ivatives IVFRU (with fluorine in the ribo configuration), IVFAU (with fluorine in the ara configuration), and the corresponding 3'-chemical delivery system (CDS), or -methyl-1,4-dihydropyridyl-3-carbonyl)-subst ituted derivatives IVDU-CDS, IVFRU-CDS and IVFAU-CDS were evaluated fo r their cytostatic activity against wild-type (FMSA/O), thymidine kina se (TK)-deficient (FM3A/TK-), and herpes simplex virus type 1 (HSV-1) or HSV-2 thymidine kinase (tk) gene-transfected murine mammary carcino ma FM3A cells (FM3A TK-/HSV-1 TK+ and FM3A TK-/HSV-2 TK+). The test co mpounds proved highly inhibitory to the proliferation of HSVtk gene-tr ansfected FM3A cells. Their cytostatic activity was within the 0.002 t o 0.80 mu M range, a compound concentration that is 1000- to 10 000-fo ld 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 compoun ds for further evaluation for combined gene/chemotherapy of HSVtk gene -transfected tumor cells in animal models