Enhancement of 5‐fluorouracil cytotoxicity by human thymidine‐phosphorylase expression in cancer cells: In vitro and In vivo study

• Published in: International journal of cancer Vol. 80; no. 3; pp. 465 - 470
• Main Authors: Evrard, Alexre, Cuq, Pierre, Robert, Bruno, Vian, Laurence, Pèlegrin, André, Cano, Jean‐Paul
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 29.01.1999; Wiley-Liss
• Subjects: Animals; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic agents; Biological and medical sciences; Carcinoma - drug therapy; Carcinoma - genetics; Carcinoma - therapy; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - therapy; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Drug Synergism; Floxuridine - metabolism; Floxuridine - pharmacology; Fluorouracil - pharmacology; Humans; Medical sciences; Mice; Mice, Inbred BALB C; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Pharmacology. Drug treatments; Thymidine Phosphorylase - genetics; Thymidine Phosphorylase - metabolism; Transfection; Adenocarcinoma; Antineoplastic agent; Immunohistochemistry; Cell culture; Glycosyltransferases; Cytotoxicity; Established cell line; Immunoblotting assay; Sensitization; Colon; Thymidine phosphorylase; Fluorouracil; Enzyme; Transferases; Fluoropyrimidine derivatives; Rodentia; Implantation; Malignant tumor; In vitro; Colonic disease; Pathology; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Digestive diseases; Pyrimidine derivatives; Molecular biology; Gene therapy; Pentosyltransferases
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/(SICI)1097-0215(19990129)80:3<465::AID-IJC21>3.0.CO;2-6

Transferring a gene into cancer cells in order to sensitize them to drugs is an important approach in human cancer gene‐therapy research. Thymidine phosphorylase (TP) is the first enzyme in the metabolic activation pathway of 5‐fluorouracil (5‐FU) to fluorodeoxyribonucleotides, thus, it could be used to increase the sensitivity of cancer cells to this anti‐pyrimidine agent. In this study, an expression vector containing the human TP cDNA was transfected into C26 murine colon‐carcinoma cells. Stable transfectants were selected; all showed increased TP activity, ranging from 2‐ to 10‐fold when compared with wild‐type cells. The in vitro sensitivity of transfectants to 5‐FU and 5′‐deoxy‐5‐fluorouridine (5′‐DFUR) was enhanced, in agreement with the observed increase in TP activity. Then, tumors were generated by s.c. injection of TP‐transfected or wild‐type C26 cells in syngeneic BALB/c mice. 5‐FU (25 mg/kg, i.p.) induced a growth delay of TP‐transfected C26 tumors as compared with C26 wild‐type tumors. These data suggest that TP could be transfected in tumor cells to increase the sensitivity to 5‐FU for subsequent cancer gene therapy. Int. J. Cancer 80:465–470, 1999. © 1999 Wiley‐Liss, Inc.