Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1522282 (EMT)
 2,868 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A group of 3'-O- and 5'-O-(3-benzenesulfonylfuroxan-4-yl)-2'-deoxyuridines possessing a variety of substituents (H, Me, I, F, CF(3)) at the C-5 position of the nucleoside moiety were synthesized for evaluation as hybrid anticancer agents that have the ability to simultaneously release cytotoxic nitric oxide (*NO). Incubation of these nitric oxide donor-nucleoside conjugates in the presence of 18 mM L-cysteine released a high percentage of *NO (21-48% at 1 h; 37-86% at 16 h). The release of *NO in the absence of the thiol cofactor was negligible. These hybrid *NO donor-nucleosides exhibited high cellular toxicity (CC(50) = 10(-6)-10(-8) M range) against a battery of tumor cell lines (143B-LTK, 143B, EMT-6, KBALB-STK, and KBALB) and normal human fibroblasts (Hs578Bst). No differences in cytotoxicity between nontransfected (143B, KBALB) and the corresponding transfected (143B-LTK, KBALB-STK) cancer cell lines possessing the herpes simplex virus type 1 (HSV-1) thymidine kinase gene (TK(+)) were observed, indicating that expression of the viral TK enzyme did not provide a gene therapeutic effect.
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PMID:Design and synthesis of 3'- and 5'-O-(3-benzenesulfonylfuroxan-4-yl)-2'-deoxyuridines: biological evaluation as hybrid nitric oxide donor-nucleoside anticancer agents. 1502 76

In vivo transfer of the herpes simplex virus type-1 thymidine kinase (HSV-1 TK) gene, with subsequent administration of antiviral drugs such as ganciclovir, has emerged as a promising gene therapy protocol for treating proliferative disorders. The in vitro cytotoxicities (IC(50)) for two series of 5-iodo- and (E)-5-(2-iodovinyl)-substituted 2'-deoxy- and 2'-deoxy-2'-fluoro-pyrimidine nucleosides ranged from millimolar to low nanomolar concentrations in mammalian tumor cell lines (KBALB; R-970-5; 143B; EMT-6) and their counterparts engineered to express HSV-1 TK (KBALB-STK; 143B-LTK). Their HSV-1 TK selectivity indices ranged from one (nonselective) to one million (highly selective) based on cytotoxicity, with FIRU being the least toxic to all cell lines, and FIAU being most toxic. HSV-1 TK selectivity, based on uptake, ranged from 10 to 140, with IVDU being most selective for HSV-1 TK expressing cells, followed by IVFRU, FIRU, FIAU, IVFAU and finally IUDR. Phosphorylation of [(125)I]FIAU led to incorporation of the radiolabel into nucleic acids, whereas IVFRU and FIRU radioactivity was trapped primarily in the nucleotide pool. These data indicate that cytotoxicity does not depend on initial metabolic trapping (e.g., phosphorylation), but on elaboration of the mononucleotides to more cytotoxic anabolites. Lipophilicities and nucleoside transport rates of the six nucleosides tested were within narrow ranges. This supports the premise that cellular biochemistry, and not cellular bioavailability, is responsible for the observed broad range of cytotoxicity and trapping. In vivo biodistribution studies with 5-[(125)I]iodo-2'-fluoro-2'-deoxyribouridine (FIRU), 5-[(125)I]iodo-2'-fluoro-2'-deoxyarabinouridine (FIAU) and (E)-5-(2-[(125)I]iodovinyl)-2'-fluoro-2'-deoxyuridine (IVFRU) demonstrate selective accumulation of all three radiotracers in HSV-1 TK-expressing KBABK-STK tumors, compared to their very low accumulation in the non-HSV-1 TK-expressing KBALB tumors, in Balb/c mice. In summary, these nucleosides are unpredictably cytotoxic to the various cell lines studied, and this unpredictability extends across the HSV-1 TK expression characteristic; their uptake by cells engineered to express HSV-1 TK is also dependent on the molecular construction of the gene cassette carrying the viral TK gene.
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PMID:Cytotoxicity and cellular uptake of pyrimidine nucleosides for imaging herpes simplex type-1 thymidine kinase (HSV-1 TK) expression in mammalian cells. 1521 81