Abstract
The critical point for us to develop therapeutic strategies for advanced cancer is how we can achieve cytotoxic effects which are specific for tumor cells. Genetic transduction technology provides us with various approaches to this goal. Specific antitumor cytocidal effect could be achieved by several strategies. (A) The use of tissue-specific promoters to drive suicide genes : We developed adenoviral vectors expressing suicide genes under the control of tissue-specific promoters (i. e., promoters for AFP, CEA, PSA). With these recombinant adenoviruses, we attained specific killing of the tumor cells from certain tissue origins (i. e., hepatocellular carcinoma, gastric and pancreas cancer, and prostate cancer). We characterized ganciclovir/HSV-TK and 5-FC/E. coli cytosine deaminase systems as prodrug/enzyme therapies. E. coli upp gene for uracil phosphoribosyl transferase, UPRTase, in combination with 5-FU is also an interesting system. We showed that adenovirus-mediated upp gene transduction resulted in 10 to 100-fold enhancement of the therapeutic effect of 5-FU toxicity for cancer cells. Upp gene transduction is a hopeful modality to overcome the 5-FU resistance which is often seen in patients with cancers from various tissue origins. (B) The use of tumor-specific mutations such as p53 tumor suppressor gene : Our recombinant adenoviruses with deficient E1B55K (AxE1AdB) was demonstrated to efficiently replicate in and kill tumor cells deficient in p53 gene activity. Since mutations in p53 are the most common type of genetic abnormality in cancer occurring in more than 50 percent of human cancer cases, this approach will have a wide applicability in specific tumor cell-targeting. (C) The use of targetable viral vectors : We have established a system of constructing recombinant adenoviruses with mutant fiber knob or penton base proteins, which are responsible for virus-host cell interaction. Now it is feasible to develop mutant viral vectors which could be targetable for specific cancer cells.
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