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: Mamoru Nukatsuka, Fumio Nakagawa, Teiji Takechi
• Journal: Anticancer research (Anticancer Res) Vol. 35 Issue 9 Pg. 4605-15 (Sep 2015) ISSN: 1791-7530 [Electronic] Greece
• PMID: 26254349 (Publication Type: Journal Article)
• Copyright: Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Chemical References

• Antineoplastic Agents
• Drug Combinations
• Organoplatinum Compounds
• Pyrrolidines
• trifluridine tipiracil drug combination
• Oxaliplatin
• Uracil
• Thymine
• Trifluridine

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Body Weight (drug effects)
• Cell Death (drug effects)
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, pathology)
• Drug Combinations
• HCT116 Cells
• Humans
• Mice, Nude
• Organoplatinum Compounds (pharmacology, therapeutic use)
• Oxaliplatin
• Pyrrolidines
• Stomach Neoplasms (drug therapy, pathology)
• Thymine
• Treatment Outcome
• Trifluridine (administration & dosage, pharmacology, therapeutic use)
• Tumor Burden (drug effects)
• Uracil (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays