Enhanced growth suppression in esophageal carcinoma cells using adenovirus-mediated fusion gene transfer (uracil phosphoribosyl transferase and herpes simplex virus thymidine kinase).
Advanced esophageal cancers are highly malignant and frequently resistant to 5-fluorouracil (5-FU). Escherichia coli uracil phosphoribosyltransferase (UP) is a pyrimidine salvage enzyme that alters 5-FU metabolism and sensitivity. A recombinant adenovirus encoding the UP gene (AxCA.UP) has been applied in gastric cancer gene therapy to sensitize cancer cells to lower concentrations of 5-FU. We have generated a recombinant adenovirus (AxCA.UT) encoding UP and herpes simplex virus thymidine kinase fusion protein (UT) to examine whether it would enhance the antitumor activity of AxCA.UP treatment. AxCA.UT treatment significantly enhanced the sensitivity of human esophageal cancer cells to and significantly enhanced the growth inhibition effects of UP gene therapy in vitro. Moreover, both 5-FU and ganciclovir showed bystander effects on growth inhibition. In an in vivo study, the therapeutic outcome of AxCA.UT treatment significantly enhanced the antitumor activity of AxCA.UP treatment. These observations suggest that AxCA.UT may be useful in esophageal cancer gene therapy.
Shimizu
T
T
Department of Surgery, Chiba University School of Medicine, Chiba, Japan.
Shimada
H
H
Ochiai
T
T
Hamada
H
H
D000256:Adenoviridae / Q000235:genetics*; D000998:Antiviral Agents / Q000494:pharmacology; D015153:Blotting, Western; D002277:Carcinoma / Q000628:therapy*; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000201:enzymology; D004938:Esophageal Neoplasms / Q000628:therapy*; D015774:Ganciclovir / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D010430:Pentosyltransferases / Q000235:genetics*; D018139:Simplexvirus / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*; D013997:Time Factors; D014161:Transduction, Genetic; D001616:beta-Galactosidase / Q000378:metabolism
D000998:Antiviral Agents; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D013937:Thymidine Kinase; D001616:beta-Galactosidase; D015774:Ganciclovir