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.
Chemical Formula: C19H23Cl2F3N6O7
Molecular Weight: 575.3232
Elemental Analysis: C, 39.67; H, 4.03; Cl, 12.32; F, 9.91; N, 14.61; O, 19.47
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
InChi Code: 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
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
Trifluridine-tipiracil hydrochloride mixture (TAS-102), 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 Trifluridine-tipiracil hydrochloride mixture (TAS-102); 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.
Trifluridine-tipiracil hydrochloride mixture (TAS-102) 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.
Nukatsuka M, Nakagawa F, Takechi T. Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, TAS-102, with Oxaliplatin on Human Colorectal and Gastric Cancer Xenografts. Anticancer Res. 2015 Sep;35(9):4605-15. PubMed PMID: 26254349.
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.
Yamashita F, Komoto I, Oka H, Kuwata K, Takeuchi M, Nakagawa F, Yoshisue K, Chiba M. Exposure-dependent incorporation of trifluridine into DNA of tumors and white blood cells in tumor-bearing mouse. Cancer Chemother Pharmacol. 2015 Aug;76(2):325-33. doi: 10.1007/s00280-015-2805-9. Epub 2015 Jun 18. PubMed PMID: 26084259.
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.
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.
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