title: Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, TAS-102, with Oxaliplatin on Human Colorectal and Gastric Cancer Xenografts.
abstract: TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluridine (FTD) and the thymidine phosphorylase inhibitor tipiracil hydrochloride (at a molar ratio of 1:0.5) that was approved in Japan in 2014 for the treatment of unresectable advanced or recurrent colorectal cancer. In the present study, the enhancement of therapeutic efficacy using a combination of TAS-102 and oxaliplatin was evaluated in a xenograft-bearing nude mouse model of colorectal and gastric cancer. TAS-102 was orally administered twice-a-day from day 1 to 14, and oxaliplatin was administered intravenously on days 1 and 8. The in vivo growth-inhibitory activity was evaluated based on the tumor volume and the growth-delay period, was estimated based on the period required to reach a tumor volume five-times greater than the initial volume (RTV5). The tumor growth-inhibitory activity and RTV5 in mice administered TAS-102 with oxaliplatin were significantly superior to those associated with either monotherapy in mice with colorectal (HCT 116, SW-48; p<0.001) and gastric cancer (SC-2, MKN74; p<0.001). MKN74/5FU, a 5-fluorouracil-resistant MKN74 sub-line, was sensitive to both FTD and oxaliplatin in vitro. In vivo, TAS-102 alone was effective in MKN74/5FU, and its anti-tumor activity was significantly enhanced in combination with oxaliplatin (p<0.001). No significant decrease in body weight or toxicity was observed compared to either monotherapy. The present pre-clinical findings indicate that combination of TAS-102 and oxaliplatin is a promising treatment option for colorectal or gastric cancer, and can be utilized in both chemo-naïve tumors and recurrent tumors after 5-fluorouracil treatment.
authors.affiliation: Translational Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan m-nukatsuka@taiho.co.jp.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Nukatsuka
authors.affiliation: Applied Pharmacology Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakagawa
authors.affiliation: Translational Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Teiji
authors.initials: T
authors.lastname: Takechi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004338:Drug Combinations; D045325:HCT116 Cells; D006801:Humans; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000077150:Oxaliplatin; D011759:Pyrrolidines; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013941:Thymine; D016896:Treatment Outcome; D014271:Trifluridine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D009944:Organoplatinum Compounds; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D000077150:Oxaliplatin; D014498:Uracil; D013941:Thymine; D014271:Trifluridine
keywords: 5-FU resistance; TAS-102; colorectal cancer; gastric cancer; oxaliplatin