TAS-102, a novel antitumor agent: a review of the mechanism of action.

Abstract

Inhibition of nucleoside metabolism is an important principle in cancer therapy as evidenced by the role of fluoropyrimidines, such as 5-fluorouracil (5-FU), and antifolates in the treatment of many cancers. TAS-102 is an oral combination therapy consisting of trifluridine (FTD), a thymidine-based nucleoside analog, plus tipiracil hydrochloride (TPI), a novel thymidine phosphorylase inhibitor that improves the bioavailability of FTD. TAS-102 has demonstrated efficacy in 5-FU-refractory patients based on a different mechanism of action and has been approved for the treatment of metastatic colorectal cancer in Japan. This review describes the mechanism of action of TAS-102, highlighting key differences between TAS-102 and 5-FU-based therapies. While both FTD and 5-FU inhibit thymidylate synthase (TS), a central enzyme in DNA synthesis, sufficient TS inhibition by FTD requires continuous infusion; therefore, it is not considered a clinically relevant mechanism with oral dosing. Instead, the primary cytotoxic mechanism with twice-daily oral dosing, the schedule used in TAS-102 clinical development, is DNA incorporation. FTD incorporation into DNA induces DNA dysfunction, including DNA strand breaks. Uracil-based analogs such as 5-FU may also be incorporated into DNA; however, they are immediately cleaved off by uracil-DNA glycosylases, reducing their ability to damage DNA. Moreover, the TPI component may enhance the durability of response to FTD. With its distinct mechanism of action and metabolism, TAS-102 is a promising treatment option for patients resistant to or intolerant of 5-FU-based fluoropyrimidines.

• Authors: Heinz-Josef Lenz, Sebastian Stintzing, Fotios Loupakis
• Journal: Cancer treatment reviews (Cancer Treat Rev) Vol. 41 Issue 9 Pg. 777-83 (Nov 2015) ISSN: 1532-1967 [Electronic] Netherlands
• PMID: 26428513 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2015. Published by Elsevier Ltd.

Chemical References

• Drug Combinations
• Pyrrolidines
• trifluridine tipiracil drug combination
• Uracil
• Thymine
• Trifluridine

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Clinical Trials as Topic
• Drug Combinations
• Humans
• Neoplasms (drug therapy)
• Pyrrolidines
• Thymine
• Trifluridine (pharmacology)
• Uracil (analogs & derivatives, pharmacology)