Novel (E)-5-(2-iodovinyl)-2'-deoxyuridine derivatives as potential cytostatic agents against herpes simplex virus thymidine kinase gene transfected tumors.

Abstract

(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.

• Authors: J Balzarini, K W Morin, E E Knaus, L I Wiebe, E De Clercq
• Journal: Gene therapy (Gene Ther) Vol. 2 Issue 5 Pg. 317-22 (Jul 1995) ISSN: 0969-7128 [Print] England
• PMID: 7671107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• 5-(2-iodovinyl)-2'-deoxyuridine
• Thymidine Phosphorylase
• Thymidine Kinase
• Idoxuridine

Topics

• Animals
• Antineoplastic Agents (chemistry, therapeutic use)
• Combined Modality Therapy
• Drug Screening Assays, Antitumor
• Genetic Therapy
• Herpesvirus 1, Human (enzymology, genetics)
• Herpesvirus 2, Human (enzymology, genetics)
• Hydrolysis
• Idoxuridine (analogs & derivatives, chemistry, therapeutic use)
• Mammary Neoplasms, Experimental (genetics, pathology, therapy)
• Mice
• Mice, Inbred C3H
• Substrate Specificity
• Thymidine Kinase (genetics)
• Thymidine Phosphorylase (metabolism)
• Transfection
• Tumor Cells, Cultured