title: Combined therapy with a thymidylate synthase-inhibiting vector and S-1 has effective antitumor activity against 5-FU-resistant tumors.
abstract: High levels of intratumoral thymidylate synthase (TS) expression are associated with resistance to 5-fluorourcil (5-FU). In order to establish a new treatment method for 5-FU-resistant tumors, the efficacy of gene therapy was investigated using an adenoviral vector expressing short hairpin RNA (shRNA) targeting TS. A replication-deficient recombinant adenoviral vector expressing shRNA targeting TS was constructed under the control of the human U6 promoter (Ad-shTS). Three 5-FU-resistant cancer cell lines, DLD-1/5FU, KM12C/5FU and NUGC-3/5FU, were used. Transduction with Ad-shTS effectively downregulated TS expression in all three 5-FU-resistant tumor cells. MTT assays demonstrated that treatment with Ad-shTS significantly inhibited the growth of all three 5-FU-resistant tumor cells. Furthermore, combined treatment with Ad-shTS and 5-FU demonstrated significantly greater inhibition of tumor cell growth in comparison to 5-FU treatment alone and Ad-shTS treatment alone. S-1, a combination of tegafur, gimeracil and oteracil potassium, was used for the 5-FU treatment by in vivo experiments. The combined treatment of Ad-shTS and S-1 was found to have the strongest antitumor effect against 5-FU-resistant DLD-1/5FU xenografts in nude mice in comparison to S-1 treatment alone and Ad-shTS treatment alone. Furthermore, the apoptotic index in tumors treated with combined Ad-shTS and S-1 was significantly higher in comparison to that in tumors treated with S-1 alone and that in tumors treated with Ad-shTS alone. Consequently, the combined treatment of the TS-inhibiting adenoviral vector and S-1 has effective antitumor activity against 5-FU-resistant tumors.
authors.affiliation: Department of General Thoracic Surgery, Breast and Endocrinological Surgery, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
authors.forename: Kyuichi
authors.initials: K
authors.lastname: Kadota
authors.forename: Cheng-Long
authors.initials: CL
authors.lastname: Huang
authors.forename: Dage
authors.initials: D
authors.lastname: Liu
authors.forename: Hiroyaseu
authors.initials: H
authors.lastname: Yokomise
authors.forename: Reiji
authors.initials: R
authors.lastname: Haba
authors.forename: Hiromi
authors.initials: H
authors.lastname: Wada
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010094:Oxonic Acid / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D005641:Tegafur / Q000627:therapeutic use*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D013940:Thymidylate Synthase; D005472:Fluorouracil