title: Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts.
abstract: TAS-102 is a novel oral nucleoside antitumor agent that consists of trifluridine (FTD) and tipiracil hydrochloride (TPI) at a molecular ratio of 1:0.5, and was approved in Japan in March 2014 for the treatment of patients with unresectable advanced or recurrent colorectal cancer that is refractory to standard therapies. In the present study, we used colorectal cancer xenografts to assess whether the efficacy of TAS-102 could be improved by combining it with bevacizumab, cetuximab or panitumumab. TAS-102 was orally administered twice a day from day 1 to 14, and bevacizumab, cetuximab and panitumumab were administered intraperitoneally twice a week for 2 weeks. Growth inhibitory activity was evaluated based on the relative tumor volume (RTV) after 2 weeks of drug administration and time taken for the relative tumor volume to increase five-fold (RTV5). Tumor growth inhibition and RTV5 with TAS-102 and bevacizumab combination treatment were significantly better than those with TAS-102 or bevacizumab alone in the SW48 and HCT116 tumor models, and the concentration of phosphorylated FTD in tumors determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was higher in the TAS-102 and bevacizumab combination group than in the TAS-102 monotherapy group. The combination of TAS-102 and cetuximab or panitumumab was also significantly more effective than either monotherapy in the SW48 tumor model. There was no significant difference in the body weight between the mice treated with TAS-102 monotherapy and any of the combination therapies on day 29. Our preclinical findings indicate that the combination therapy of TAS-102, bevacizumab and cetuximab or panitumumab is a promising treatment option for colorectal cancer.
authors: Translational Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Kawauchi-Cho, Tokushima-shi, Tokushima 771-0194, Japan.
authors: Hiroshi
authors: H
authors: Tsukihara
authors: Applied Pharmacology Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Kawauchi-Cho, Tokushima-shi, Tokushima 771-0194, Japan.
authors: Fumio
authors: F
authors: Nakagawa
authors: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Okubo, Tsukuba, Ibaraki 300-2611, Japan.
authors: Kazuki
authors: K
authors: Sakamoto
authors: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Okubo, Tsukuba, Ibaraki 300-2611, Japan.
authors: Keiji
authors: K
authors: Ishida
authors: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Okubo, Tsukuba, Ibaraki 300-2611, Japan.
authors: Nozomu
authors: N
authors: Tanaka
authors: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Okubo, Tsukuba, Ibaraki 300-2611, Japan.
authors: Hiroyuki
authors: H
authors: Okabe
authors: Applied Pharmacology Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Kawauchi-Cho, Tokushima-shi, Tokushima 771-0194, Japan.
authors: Junji
authors: J
authors: Uchida
authors: Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Okubo, Tsukuba, Ibaraki 300-2611, Japan.
authors: Kenichi
authors: K
authors: Matsuo
authors: Translational Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Kawauchi-Cho, Tokushima-shi, Tokushima 771-0194, Japan.
authors: Teiji
authors: T
authors: Takechi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000068258:Bevacizumab / Q000008:administration & dosage; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage; D002853:Chromatography, Liquid; D015179:Colorectal Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D004338:Drug Combinations; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000077544:Panitumumab; D011759:Pyrrolidines; D053719:Tandem Mass Spectrometry; D013941:Thymine; D014271:Trifluridine / Q000008:administration & dosage*; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D004338:Drug Combinations; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D000068258:Bevacizumab; D014498:Uracil; D000077544:Panitumumab; D000068818:Cetuximab; D013941:Thymine; D014271:Trifluridine