TAS-102: A Novel Antimetabolite for the 21st Century

Abstract

TAS-102, a novel antimetabolite combination chemotherapy agent, consists of a rediscovered antimetabolite agent, trifluorothymidine (trifluridine) combined with the metabolic inhibitor of thymidine phosphorylase, tipiracil, in a 1:0.5 molar ratio. Mechanism of action studies suggest that this agent works by incorporation into DNA. Both preclinical and clinical studies demonstrate that this agent is noncross-resistant with 5-fluorouracil. Tipiracil may also have antiangiogenic effects through inhibition of thymidine phosphorylase. Recent randomized Phase II and III trials demonstrate clinical activity (improved progression-free survival, time to decrease in performance status, prolonged overall survival) in metastatic colorectal cancer refractory to all standard agents. Monotherapy with TAS-102 has now been approved for this indication in Japan and in the USA.

Selective therapeutic strategy for p53-deficient cancer by targeting dysregulation in DNA repair

“…Our data demonstrate that fluorinated and ethynyl-deoxyuridine analogues selectively induced DNA damage in p53mt cancer cells. Fluorinated uridine antimetabolites (FdUrd and 5FU) have been in clinical practice for several decades and their pharmacology is well studied 54 , 55 . The main mechanism of action for these analogues involves inhibition of thymidylate synthase (TS) by a common metabolite FdUMP, leading to a reduction of dTTP levels and promoting the incorporation of dUTP and FdUTP into the genome 46 , 55 .…”

Radiosynthesis of the anticancer nucleoside analogue Trifluridine using an automated 18F-trifluoromethylation procedure

“…Furthermore, defluorination can be directly connected to the mode of action of TFT. Although DNA incorporation of tri-phosphorylated TFT is considered the main mechanism by which it exerts anticancer properties, 39 , 40 mono-phosphorylated TFT also covalently binds to and inhibits thymidylate synthase (TS). 41 Several reports have determined that this covalent linkage results in a stepwise loss of the three fluorine substituents of TFT, 42 – 44 which in the case of [ 18 F]TFT, would result in bone uptake of free [ 18 F]fluoride in the PET scans.…”

Getting Lost in the Cell–Lysosomal Entrapment of Chemotherapeutics

“…Inhibits de novo purine synthesis Produces genotoxic thioguanine nucleotides that inhibit DNA and RNA synthesis and alter their subsequent metabolism [7,9] Thymidine phophorylase inhibitor Tipiracil Hydrochloride (TAS-102) Induces cell cycle arrest at G2 phase and DNA double-strand breaks with enhanced drug potency. [135,136] Antifolate Methotrexate, Pemetrexed…”