[Show abstract][Hide abstract] ABSTRACT: Drosophila melanogaster multisubstrate deoxyribonucleoside kinase (Dm-dNK) was applied as a cancer gene therapeutic approach. To improve the antitumor effect of Dm-dNK, a novel suicide gene system based on an oncolytic adenovirus vector was developed to produce therapeutic effects towards colorectal cancer cells. We constructed an oncolytic adenoviral vector (ZD55), which was designed by deletion of the E1B-55 kDa gene for selective replication in tumor cells, containing suicide gene (Dm-dNK) driven by a cytomegalovirus promoter. We analysed the expression and activity of Dm-dNK in colorectal cancer cells (HCT-116 and SW620) via reverse transcription (RT)-PCR and enzyme assay. We assessed selective cytotoxic effects of Dm-dNK with the presence of the analogs (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), difluorodeoxycytidine (dFdC) or 1-β-D-arabinofuranosylthymine (ara-T) by MTT and FACS; the variation of oncolytic adenovirus was detected by titer assay and western blot analysis. Our data showed that ZD55-Dm-dNK mediated high expression of Dm-dNK in HCT-116 and SW620 cancer cell lines and low levels of expression in WI-38 and MRC-5 normal cells, strong cytotoxicity was observed only in tumor cells after ZD55-Dm-dNK infection combined with nucleoside analogs (NA). When ZD55-Dm-dNK was combined with BVDU or dFdC, it produced a synergistic inhibitive effect of adenovirus replication while maintaining specific cancer cell killing activity. The results suggest that the novel oncolytic virus ZD55-Dm-dNK, in combination with NA, has potential as an efficient selective antitumoral agent and may produce synergistic effects in safe control of adenovirus, which is a new promising therapeutic for colorectal cancer.
[Show abstract][Hide abstract] ABSTRACT: Drosophila melanogaster multisubstrate deoxyribonucleoside kinase (Dm-dNK), a novel suicide kinase, was applied as a cancer gene therapeutic approach. To improve the antitumor effect of Dm-dNK and its substrate with the selectivity and safety control in consideration, the conditionally replicative gene-viral system ZD55-dNK, which includes the replicationselective adenovirus ZD55 armed with the Dm-dNK, was used to further explore the potential of this approach. When ZD55-dNK was combined with BVDU it produced a synergistic inhibitive effect of adenovirus replication in vitro while maintaining specific cancer cell killing activity. From a clinical standpoint, this approach is promising for its considerably low toxic side effects.
Full-text · Article · May 2011 · Cancer biology & therapy