Virus-directed enzyme/prodrug therapy (VDEPT). Selectively engineering drug sensitivity into tumors.
A gene therapy approach has been described that generates a tumor-selective qualitative difference in the metabolic capability in tumor cells. This is the result of the selective expression of a nonmammalian enzyme in tumor cells. Selective expression is achieved by utilization of a chimeric gene composed of the TRS from a tumor-associated marker gene linked to the coding domain of a gene encoding a nonmammalian enzyme. We have described the application of this approach for the treatment of metastatic CRC. This approach involves creation of a chimeric gene composed of the CEA TRS linked to the coding domain of the CD gene. Selective expression of CD in the tumor cells will allow the selective conversion of the prodrug 5-FCyt to 5-FCyt in the tumor while sparing normal cells. Most importantly, delivery and expression of CD into a small fraction of tumor cells may be sufficient to achieve a significant antitumor effect.
Division of Cell Biology, Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
B E
BE
Huber
C A
CA
Richards
E A
EA
Austin
D000818:Animals; D001426:Bacterial Proteins / Q000008:administration & dosage; D002272:Carcinoembryonic Antigen / Q000008:administration & dosage / Q000235:genetics; D002277:Carcinoma / Q000628:therapy; D003001:Cloning, Molecular; D015179:Colorectal Neoplasms / Q000628:therapy*; D043525:Cytosine Deaminase; D004798:Enzymes / Q000008:administration & dosage*; D018014:Gene Transfer Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D051379:Mice; D009700:Nucleoside Deaminases / Q000008:administration & dosage / Q000235:genetics; D011355:Prodrugs / Q000378:metabolism*
D001426:Bacterial Proteins; D002272:Carcinoembryonic Antigen; D004798:Enzymes; D011355:Prodrugs; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase