TAS-102

TAS-102 is an investigational drug candidate for metastatic colorectal cancer. It contains trifluridine (TFT) and Tipiracil hydrochloride (TTP) in a molar ratio of 1;0.5. Trifluridine is a nucleoside analog, and tipiracil hydrochloride is a thymidine phosphorylase inhibitor, which prevents rapid metabolism of trifluiridine, increasing the bioavailability of trifluiridine. After oral administration of TAS-102, TFT is phosphorylated to the active monophosphate form TF-TMP, which binds covalently to the active site of thymidylate synthase, thereby reducing the nucleotide pool levels required for DNA replication. Furthermore, the triphosphate form TF-TTP can be incorporated into DNA, which induces DNA fragmentation and leads to the inhibition of tumor growth. TPI exhibits a dual effect: 1) an anti-angiogenic effect mediated through the inhibition of thymidine phosphorylase, which plays an important role in nucleotide metabolism and a variety of development processes, including angiogenesis, 2) increased bioavailability of the normally short-lived antimetabolite TFT by preventing its degradation into the inactive form trifluorothymine (TF-Thy). The synergistic effect of the components in TAS-102 may demonstrate antitumor activity in 5-FU-resistant cancer cells.

Product information

CAS Number: 733030-01-8

Molecular Weight: 575.32

Formula: C19H23Cl2F3N6O7

Synonym:

TAS 102

TAS102

Trifluridine/tipiracil hydrochloride

Chemical Name:  4-hydroxy-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyrimidin-2(1H)-one compound with 5-chloro-6-((2-iminopyrrolidin-1-yl)methyl)pyrimidine-2,4-diol (1:1) hydrochloride

Smiles: Cl.N=C1CCCN1CC1NC(=O)NC(=O)C=1Cl.O[C@H]1C[C@@H](O[C@@H]1CO)N1C=C(C(=O)NC1=O)C(F)(F)F

InChiKey: PLIXOHWIPDGJEI-OJSHLMAWSA-N

InChi: InChI=1S/C10H11F3N2O5.C9H11ClN4O2.ClH/c11-10(12,13)4-2-15(9(19)14-8(4)18)7-1-5(17)6(3-16)20-7;10-7-5(12-9(16)13-8(7)15)4-14-3-1-2-6(14)11;/h2,5-7,16-17H,1,3H2,(H,14,18,19);11H,1-4H2,(H2,12,13,15,16);1H/t5-,6+,7+;;/m0../s1

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Soluble in DMSO, not in water

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥360 days if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

TAS-102 (Trifluridine-tipiracil hydrochloride mixture), a novel antimetabolite combination chemotherapy agent, consists of a rediscovered antimetabolite agent, trifluorothymidine (trifluridine, FTD) combined with the metabolic inhibitor of thymidine phosphorylase, tipiracil (TPI), in a 1:0.5 molar ratio. FTD is the active antitumor component of TAS-102 (Trifluridine-tipiracil hydrochloride mixture); its monophosphate form inhibits thymidylate synthase, and its triphosphate form is incorporated into DNA in tumor cells. The incorporation into DNA is known to have antitumor effects, since the inhibition of thymidylate synthase caused by oral FTD rapidly disappears after the drug's elimination. When FTD is administered orally, it is rapidly degraded to its inactive form by thymidine phosphorylase in the intestines and liver (first-pass effect). Consequently, TPI is synthesized to maintain adequate plasma concentrations of orally-administered FTD and to potentiate the antitumor activity of FTD.

In Vivo:

TAS-102 (Trifluridine-tipiracil hydrochloride mixture) and CPT-11 is a promising treatment option for colorectal or gastric cancer. Trifluridine-tipiracil hydrochloride mixture monotherapy has a significant antitumor activity against KM12C/5-FUFU-bearing nude mice. The combination-treated (CPT-11-and Trifluridine-tipiracil hydrochloride mixture) group is significantly superior to monotherapy. FTD systemic exposure in plasma increaseS dose-dependently. The tumor growth rate and body weight gain decreaseS dose-dependently, but FTD concentrations in the DNA of tumor tissues and white blood cells increases dose-dependently. FTD inhibits colony formation of bone marrow cells in a concentration-dependent manner.

References:

1. Cleghorn S. TAS-102 for metastatic refractory colorectal cancer. Lancet Oncol. 2015 Jul;16(7):e314. doi: 10.1016/S1470-2045(15)70246-9. Epub 2015 May 21. PubMed PMID: 26004375.
2. Drug Improves Survival in Refractory Colorectal Cancer. Cancer Discov. 2015 Jul;5(7):OF3. doi: 10.1158/2159-8290.CD-NB2015-077. Epub 2015 Jun 4. PubMed PMID: 26045012.
3. Doi T, Yoshino T, Fuse N, Boku N, Yamazaki K, Koizumi W, Shimada K, Takinishi Y, Ohtsu A. Phase I study of TAS-102 and irinotecan combination therapy in Japanese patients with advanced colorectal cancer. Invest New Drugs. 2015 Jul 12. [Epub ahead of print] PubMed PMID: 26163340.

Products are for research use only. Not for human use.