Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with irinotecan hydrochloride on human colorectal and gastric cancer xenografts.
TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluridine and tipiracil hydrochloride at a molar ratio of 1:0.5. TAS-102 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, enhancement of the therapeutic efficacy using a combination therapy of TAS-102 and irinotecan hydrochloride (CPT-11) was evaluated in a colorectal and gastric cancer xenograft-bearing nude mouse model. TAS-102 was orally administered twice a day from day 1 to 14, and CPT-11 was administered intravenously on days 1 and 8. The growth-inhibitory activity was evaluated based on the tumor volume and the growth-delay period, which was estimated based on the period required to reach a tumor volume that was five-times greater than the initial volume (RTV5). The tumor growth-inhibitory activity and the RTV5 of the group receiving TAS-102 with CPT-11 were significantly superior to those of both agents as monotherapy for mice with KM12C, KM12C/5-FU, DLD-1/5-FU, and SC-2 xenografts (p<0.01). No significant decrease in body weight was observed. The present pre-clinical findings indicated that the combination of TAS-102 and CPT-11 is a promising treatment option for colorectal or gastric cancer, not only for chemo-naïve tumors, but also for recurrent tumors after 5-fluorouracil (5-FU)-based chemotherapy.
Translational Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan m-nukatsuka@taiho.co.jp.
Mamoru
M
Nukatsuka
Applied Pharmacology Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Fumio
F
Nakagawa
Applied Pharmacology Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Hitoshi
H
Saito
Applied Pharmacology Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Minoru
M
Sakata
Applied Pharmacology Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Junji
J
Uchida
Translational Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Teiji
T
Takechi
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004338:Drug Combinations; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D011759:Pyrrolidines; D013274:Stomach Neoplasms / Q000188:drug therapy*; D013941:Thymine; D014271:Trifluridine / Q000008:administration & dosage; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D023041:Xenograft Model Antitumor Assays
D004338:Drug Combinations; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D000077146:Irinotecan; D013941:Thymine; D014271:Trifluridine; D005472:Fluorouracil; D002166:Camptothecin
5-FU resistance; TAS-102; colorectal cancer; gastric cancer; irinotecan hydrochloride