Bystander effects of cancer cell lines transduced with the multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster and synergistic enhancement by hydroxyurea

The multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster (D m-dNK) can be expressed in human cells with retained enzymatic activity. Th e cells expressing Dm-dNK exhibit increased sensitivity to several cytotoxi c nucleoside analogs. In this study, we further evaluated Dm-dNK as a poten tial novel suicide gene in combination with (E)-5-(2-bromovinyl)-2'-deoxyur idine (BVDU) as the prodrug. We used two human cancer cell lines transduced with a retrovirus encoding the Dm-dNK cDNA and investigated whether the ce lls expressing the enzyme can induce cell death of untransduced cells, a ph enomenon known as the "bystander effect". A bystander effect was observed i n a thymidine kinase-deficient human osteosarcoma cell line but not in the MIA PaCa-2 human pancreatic adenocarcinoma cell line. The cytotoxicity of B VDU increased in both cell lines when the compound was used in combination with subtoxic concentrations of hydroxyurea. Hydroxyurea also enhanced the bystander effect in the osteosarcoma cells, but not in the MIA PaCa-2 cells , treated with BVDU. These findings indicate that BVDU phosphorylated by Dm -dNK in transduced cancer cells may also induce bystander cell death in cer tain cell lines.