title: Metronomic S-1 dosing and thymidylate synthase silencing have synergistic antitumor efficacy in a colorectal cancer xenograft model.
abstract: Metronomic chemotherapy is currently considered an emerging therapeutic option in clinical oncology. S-1, an oral formulation of Tegafur (TF), a prodrug of 5-fluorouracil (5-FU), is designed to improve the antitumor activity of 5-FU in tandem with reducing its toxicity. Clinically, metronomic S-1 dosing has been approved for the standard first- and second-line treatment of metastatic or advanced stage of colorectal (CRC). However, expression of intratumor thymidylate synthase (TS), a significant gene in cellular proliferation, is associated with poor outcome to 5-FU-based chemotherapeutic regimens. In this study, therefore, we examined the effect of a combination of TS silencing by an RNA interfering molecule, chemically synthesized short hairpin RNA against TS (shTS), and 5-FU on the growth of human colorectal cancer cell (DLD-1) both in vitro and in vivo. The combined treatment of both shTS with 5-FU substantially inhibited cell proliferation in vitro. For in vivo treatments, the combined treatment of metronomic S-1 dosing with intravenously injected polyethylene glycol (PEG)-coated shTS-lipoplex significantly suppressed tumor growth, compared to a single treatment of either S-1 or PEG-coated shTS-lipoplex. In addition, the combined treatment increased the proportion of apoptotic cells in the DLD-1 tumor tissue. Our results suggest that metronomic S-1 dosing combined with TS silencing might represent an emerging therapeutic strategy for the treatment of patients with advanced CRC.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt; Department of Pharmaceutics, Faculty of Pharmacy, Hail University, Hail, Saudi Arabia.
authors.forename: Amr S
authors.initials: AS
authors.lastname: Abu Lila
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Moriyoshi
authors.affiliation: Department of Cancer and Metabolism, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fukushima
authors.affiliation: Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Cheng-Long
authors.initials: CL
authors.lastname: Huang
authors.affiliation: Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Wada
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan; Department of Cancer and Metabolism, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan. Electronic address: ishida@tokushima-u.ac.jp.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
mesh_terms: D059250:Administration, Metronomic; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D004338:Drug Combinations; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010094:Oxonic Acid / Q000008:administration & dosage* / Q000378:metabolism; D034622:RNA Interference; D000067492:RNAi Therapeutics / Q000379:methods*; D005641:Tegafur / Q000008:administration & dosage* / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; C000600377:TYMS protein, human; D013940:Thymidylate Synthase
keywords: Colorectal cancer; PEG-coated shRNA-lipoplex; RNAi; S-1; Short hairpin RNA; Thymidylate synthase