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  • Title: Selection of HSV-1 TK gene-transfected murine mammary carcinoma cells resistant to (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and ganciclovir (GCV).
    Author: Degrève B, De Clercq E, Balzarini J.
    Journal: Gene Ther; 2000 Sep; 7(18):1543-52. PubMed ID: 11021592.
    Abstract:
    We evaluated the molecular mechanism of resistance in herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) gene-transfected murine mammary carcinoma (FM3ATK-/HSV-1 TK+) cells, that were selected for resistance against (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and ganciclovir (GCV) by prolonged exposure of the cell cultures to dose-escalating concentrations of these compounds. Drug-resistant FM3ATK-/HSV-1 TK+ cells showed marked differences in their sensitivity spectrum to a series of antiherpetic nucleoside analogues. BVDU-resistant FM3ATK-/HSV-1 TK+ cells displayed the same sensitivity profile as wild-type FM3A/0 cells. In contrast, GCV-resistant FM3ATK-/HSV-1 TK+ cells were still sensitive to BVDU, (E)5-(2-iodovinyl)-2'-deoxyuridine (IVDU) and (E)-5-(2bromovinyl)-2'-deoxycytidine (BVDC), a typical feature of FM3A TK cells lacking cytosolic TK. Southern blot and PCR analysis revealed that HSV-1 TK genes were not deleted from the genome of the drug-resistant FM3ATK-/HSV-1 TK+ cells. However, the TK genes in drug-resistant FM3ATK-/HSV-1 TK+ cells were shown to be heavily methylated. Accordingly, RT-PCR demonstrated the complete abrogation of TK mRNA production resulting in a complete loss of TK enzyme activity in drug-resistant FM3A TK-/HSV-1 TK+ cells.
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