Oncolytic virotherapy with the adenovirus mutant dl 1520 in combination with chemotherapy has shown clinical response. Approaches to cancer gene therapy involving delivery of enzymes to activate the prodrugs CB 1954 and 5-FC are currently being tested in clinical trials. We hypothesised that the combination of an adenoviral vector equivalent to dl1520 with activation ofCB 1954or 5-FC and the combination of CB 1954 activation with 5-FU may further improve the antitumour effects for colorectal cancer therapy. The initial in vitro data showed that the combination of dl 1520 with CB 1954 activation or 5-FU (metabolite of 5-FC activation) and the combination of CB 1954 activation with 5-FU led to an additive or synergistic cytotoxicity. Subsequent data showed that the incorporation of Ntr or CD-UPRT genes into replicating oncolytic adenoviruses (ROAds) resulted in enhanced Ntr expression or CD-UPRT activity and augmented cytotoxic effects in tissue culture, surpassing the levels and cytotoxic effects mediated by the corresponding replication-defective vectors. When tested in subcutaneous human colon cancer xenografis, Ntr expression mediated by the ROAd was apparently higher than the level mediated by replication-defective CTLI02. Importantly, the antitumoural efficacy of CB 1954 activation mediated by ROAd is significantly superior to that mediated by CTLI 02 (p = 0.01). The ROAds displayed viral replication and oncolysis in vitro and in vivo and these attributes can contribute to the increased gene expression level and enhanced efficacy. Overall, the data suggested that the use of ROAds improved Ntr or CD-UPRT expression and antitumoural efficacy in the presence of corresponding prodrugs and may have the potential to achieve clinical significance in the treatment for colorectal cancer.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:273724 |
| Date | January 2003 |
| Creators | Chen, Ming-Jen |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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