Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We exploited the ability of lentiviral vectors to govern the stable transduction of cells irrespective of their cycling status to induce the reversible immortalization of human primary cells. First, bicistronic HIV-derived lentiviral vectors expressing GFP- and the HSV1 thymidine kinase and containing the LoxP sequence in their LTR (HLox) were used to transduce HeLa cells. Cre expression led to efficient proviral deletion, and unexcised cells could be eliminated by ganciclovir treatment. A human liver biopsy was then exposed to a combination of HLox vectors that harbored either the SV40 large T (TAg) or the human telomerase (hTERT) DNAs in place of GFP. This led to the isolation of liver sinusoidal endothelial cell (LSEC) clones that exhibited an immortalized phenotype while retaining most of the features of primary hLSEC. Complete growth arrest of these cells was observed in 2 days of Cre expression, and the resulting stationary culture could be kept for at least 2 weeks. Transduction of human adult pancreatic islets with HLox vectors coding for Tag and Bmi-1 also induced the proliferation of insulin-positive cells. These results indicate that lentivectors can be used to mediate the reversible immortalization of primary nondividing cells and should allow for the production of large supplies of a wide variety of human cells for both therapeutic and research purposes.
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PMID:Reversible immortalization of human primary cells by lentivector-mediated transfer of specific genes. 1102 Mar 57

We have previously produced transgenic (TG) mice expressing the mouse inhibin alpha-subunit promoter/Simian virus 40 T-antigen (Inhalpha/Tag) fusion gene. The mice develop gonadal somatic cell tumors at the age of 5-7 months; the ovarian tumors originate from granulosa cells, and those of the testes from Leydig cells. In the present study another TG mouse line was produced, expressing under the same inh-alpha promoter the herpes simplex virus thymidine kinase gene (Inhalpha/TK). Crossbreeding of the two TG mouse lines resulted in double TG mice (Inhalpha/TK-Inhalpha/Tag), which also developed gonadal tumors. The single (Inhalpha/Tag) and double TG (Inhalpha/TK-Inhalpha/Tag) mice, both bearing gonadal tumors, were treated at the age of 5.5-6.5 months with ganciclovir (GCV, 150 mg/kg body weight twice daily i.p.) for 14 days, or with aciclovir (ACV, 300-400 mg/kg body weight per day perorally) for 2 months. During GCV treatment, the total gonadal volume including the tumor, decreased in double TG mice by an average of 40% (P<0.05), while in single TG mice, there was a concomitant increase of 60% in gonadal size (P<0.05). GCV was also found to increase apoptosis in gonads of the double TG mice. Peroral treatment with ACV was less effective, it did not reduce significantly the gonadal volume. We also analyzed the in vitro efficacy of ACV and GCV treatments in transiently HSV-TK-transfected KK-1 murine granulosa tumor cells, originating from a single-positive Inhalpha/Tag mouse. GCV proved to be more effective and more specific than ACV in action. These results prove the principle that targeted expression of the HSV-TK gene in gonadal somatic cell tumors is potentially useful for tumor ablation by antiherpes treatment. The findings provide a lead for further development of somatic gene therapy for gonadal tumors.
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PMID:Gonadal tumors of mice double transgenic for inhibin-alpha promoter-driven simian virus 40 T-antigen and herpes simplex virus thymidine kinase are sensitive to ganciclovir treatment. 1143 Nov 40