TAS-102 | Trifluridine | Tipiracil | CAS#733030-01-8 | CAS#183204-74-2 | CAS#70-00-8 | Thymidine Phhosphorylase Inhibitor | Cytotoxic Pyrimidine Analog

MedKoo Cat#: 205641 | Name: TAS-102 (Trifluridine/Tipiracil HCl)

Description:

WARNING: This product is for research use only, not for human or veterinary use.

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 Structure

TAS-102 (Trifluridine/Tipiracil HCl)

CAS#733030-01-8

Theoretical Analysis

MedKoo Cat#: 205641

Name: TAS-102 (Trifluridine/Tipiracil HCl)

CAS#: 733030-01-8

Chemical Formula: C19H23Cl2F3N6O7

Exact Mass: 0.0000

Molecular Weight: 575.32

Elemental Analysis: C, 39.67; H, 4.03; Cl, 12.32; F, 9.91; N, 14.61; O, 19.47

Price and Availability

Size	Price	Availability
25mg	USD 150.00	Ready to ship
50mg	USD 250.00	Ready to ship
100mg	USD 450.00	Ready to ship
200mg	USD 650.00	Ready to ship
500mg	USD 850.00	Ready to ship
1g	USD 1,250.00	Ready to ship
2g	USD 2,050.00	Ready to ship
5g	USD 3,950.00	Ready to ship

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Related CAS #

733030-01-8 (183204-72-0 (Tipiracil HCl) 70-00-8 (Trifluridine)

Synonym

TAS102, TAS-102, TAS 102, Trifluridine/tipiracil hydrochloride;

IUPAC/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 Key

PLIXOHWIPDGJEI-OJSHLMAWSA-N

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

SMILES Code

O=C1NC(C(C(F)(F)F)=CN1[C@@H]2O[C@H](CO)[C@@H](O)C2)=O.O=C3NC(C(Cl)=C(CN4C(CCC4)=N)N3)=O.[H]Cl

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

More Info

Since the synthesis of 5-Fluorouracil (5-FU) in 1957, fluoropyrimidines have been a very useful tool in the treatment of many types of cancer. Due to the drawbacks of 5-FU therapy, such as having to be administered over long periods of time via intravenous infusion and the development of resistance in tumors, the need for more convenient and efficacious fluoropyrimidine therapy has been desired. The fluoropyrimidine component of TAS-102, trifluridine, was first synthesized in 1964 by Heidelberger et al. By the late 1960s, Phase I and Phase II clinical trials of intravenous trifluridine alone initially proved to be disappointing. Its pharmacokinetic profile during these clinical trials showed that the drug exhibited a very short half-life while in serum (12 minutes post-injection). In response to its pharmacokinetic properties, adjustments in the dosing regimen demonstrated significant therapeutic benefits in patients with breast cancer and colon cancer; with this new regimen, doses would be given every three hours to total a daily amount of 2.5 mg/kg/day for 8 to 13 days, and as a result, eight out of 23 breast cancer patients were reported to have a therapeutic response while one in six patients with colon cancer showed a near complete response to therapy. Success of trifluridine as an effective anti-cancer agent was short lived, however, due to rapid tumor recurrence upon regression of therapy. Trifluridine therapy in oncology was thus halted. Researchers later found out that trifluridine, when taken orally, was broken down into the inactive metabolites 5-trifluoromethyluracil and 5-trifluoromethyl-2,4(1H,3,H)-pyrimidinedione (FTY) during its extensive first pass metabolism in the liver via the enzyme thymidine phosphorylase (TP). It was then hypothesized that orally administered FTD concentrations could be increased and maintained if the drug was given with a thymidine phosphorylase inhibitor (TPI). (from https://en.wikipedia.org/wiki/TAS-102)

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#MDK50915

QC Data

View QC data: current batch, Lot#MDK50915

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Trifluridine-tipiracil hydrochloride mixture (TAS-102) is a combination drug that consists of an antineoplastic thymidine-based nucleoside analog, trifluorothymidine, and a potent thymidine phosphorylase inhibitor, tipiracil, in a 1:0.5 molar ratio.

In vitro activity:

In Figure 1, TAS-102 treatment also induced apoptosis in the p53-null myeloma cells ARP-1 and JJN3, which indicated that there might be other signaling pathways involved in TAS-102 induced myeloma cell apoptosis. Previous studies have shown that the cytosolic DNA sensing cGAS-STING pathway is greatly important for the cells in response to DNA damage. This pathway can promote cellular apoptosis through the transcriptional activation of apoptotic regulators as well as through a transcription-independent role of IRF3. The expression level of cGAS, STING, the cleaved level of PARP, Caspase 3, and the phosphorylated level of IRF3, TBK1 were upregulated in either wide-type MM.1S myeloma cells or the p53-knockout cells (MM.1S p53 KO), while the level of non-cleaved PARP, Caspase 3, the level of non-phosphorylated TBK1, IRF3 were not changed, and the level of GAPDH protein served as protein loading controls (Figure 3A). STING expression was knocked down in wild type or MM.1S p53 KO myeloma cells using the specific small interfering RNAs (siRNAs) against STING (siSTING). Reduced apoptosis was observed in the siSTING myeloma cells, compared with that in siCtrl cells, after TAS-102 treatment (Figure 3B and 3C). These results indicate an additional mechanism of TAS-102-induced myeloma cell apoptosis through activation of the cGAS-STING pathway. Reference: Am J Cancer Res. 2020; 10(11): 3752–3764. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716153/

In vivo activity:

To investigate the kinetics of FTD (trifluridine) incorporation into DNA, this study followed the process during TAS-102 treatment of mice harboring KM20C human colon cancer xenografts (Fig. 5A and B). TAS-102 treatment (150 mg/kg/day, twice daily for 14 days) was compared to oral administration of S-1 once daily for 14 days. TAS-102 and S-1 had similar antitumor effects (IR of 50.2 and 51.4%, respectively). FTD accumulated in the DNA of KM20C xenografts in a time-dependent manner throughout the administration of TAS-102. Compared to S-1 treatment, the growth suppressive effect of TAS-102 appeared more sustained (Fig. 5A). Reference: Oncol Rep. 2014 Dec; 32(6): 2319–2326. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240496/

	Solvent	mg/mL	mM
Solubility
	DMSO	51.2	88.94
	DMF	20.0	34.76
	Ethanol	100.0	173.82
	Water	32.5	56.49

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 575.32 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Li G, Liu H, He J, Li Z, Wang Z, Zhou S, Zheng G, He Z, Yang J. TAS-102 has a tumoricidal activity in multiple myeloma. Am J Cancer Res. 2020 Nov 1;10(11):3752-3764. PMID: 33294265; PMCID: PMC7716153. 2. Matsuoka K, Nakagawa F, Kobunai T, Takechi T. Trifluridine/tipiracil overcomes the resistance of human gastric 5-fluorouracil-refractory cells with high thymidylate synthase expression. Oncotarget. 2018 Feb 5;9(17):13438-13450. doi: 10.18632/oncotarget.24412. PMID: 29568368; PMCID: PMC5862589. 3. Tanaka N, Sakamoto K, Okabe H, Fujioka A, Yamamura K, Nakagawa F, Nagase H, Yokogawa T, Oguchi K, Ishida K, Osada A, Kazuno H, Yamada Y, Matsuo K. Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models. Oncol Rep. 2014 Dec;32(6):2319-26. doi: 10.3892/or.2014.3487. Epub 2014 Sep 17. PMID: 25230742; PMCID: PMC4240496. 4. Temmink OH, Emura T, de Bruin M, Fukushima M, Peters GJ. Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies. Cancer Sci. 2007 Jun;98(6):779-89. doi: 10.1111/j.1349-7006.2007.00477.x. Epub 2007 Apr 18. PMID: 17441963.

In vitro protocol:

In vivo protocol:

1. Tanaka N, Sakamoto K, Okabe H, Fujioka A, Yamamura K, Nakagawa F, Nagase H, Yokogawa T, Oguchi K, Ishida K, Osada A, Kazuno H, Yamada Y, Matsuo K. Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models. Oncol Rep. 2014 Dec;32(6):2319-26. doi: 10.3892/or.2014.3487. Epub 2014 Sep 17. PMID: 25230742; PMCID: PMC4240496. 2. Temmink OH, Emura T, de Bruin M, Fukushima M, Peters GJ. Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies. Cancer Sci. 2007 Jun;98(6):779-89. doi: 10.1111/j.1349-7006.2007.00477.x. Epub 2007 Apr 18. PMID: 17441963.

1: Tseng KY, Yang MY, Chen WS, Jiang JK, Wang HS, Chang SC, Lan YT, Lin CC, Lin HH, Huang SC, Cheng HH, Yang YW, Lin YZ, Chang CY, Teng HW. Combining moderate dosage of Bevacizumab with TAS-102 provides longer progression-free time in refractory metastatic colorectal Cancer. Int J Colorectal Dis. 2024 Dec 4;39(1):195. doi: 10.1007/s00384-024-04767-9. PMID: 39630293. 2: Huang LZ, Chen YQ, Gu HY, Chen Y. Cost-effectiveness analysis of trifluridine/tipiracil combined with bevacizumab vs. monotherapy for third-line treatment of colorectal cancer. Front Public Health. 2024 Nov 13;12:1465898. doi: 10.3389/fpubh.2024.1465898. PMID: 39606076; PMCID: PMC11599266. 3: Chang YW, Kuo CN, Chang CL, Hsu JC, Ko Y. Effectiveness and Safety of Regorafenib and TAS-102 in Patients with Metastatic Colorectal Cancer: A Nationwide Population-Based Study in Taiwan. Cancer Res Treat. 2024 Nov 18. doi: 10.4143/crt.2024.376. Epub ahead of print. PMID: 39563201. 4: Fumet JD, Roussot N, Bertaut A, Limagne E, Thibaudin M, Hervieu A, Zanetta S, Borg C, Senellart H, Pernot S, Thuillier F, Carnot A, Mineur L, Chibaudel B, Touchefeu Y, Martin-Babau J, Jary M, Labourey JL, Rederstorff E, Lepage C, Ghiringhelli F. Phase I/II study of trifluridine/tipiracil plus XB2001 versus trifluridine/tipiracil in metastatic colorectal cancer. Future Oncol. 2024;20(38):3077-3085. doi: 10.1080/14796694.2024.2415280. Epub 2024 Nov 12. PMID: 39530624. 5: Ying T, Xia R, Zhang Y, Dai J, Wang Y, Xie X. Cost-effectiveness analysis of trifluridine/tipiracil in the treatment of heavily pretreated metastatic gastric cancer from the perspective of Chinese healthcare system. BMJ Open. 2024 Nov 7;14(11):e080846. doi: 10.1136/bmjopen-2023-080846. PMID: 39510786; PMCID: PMC11552601. 6: Saito Y, Takekuma Y, Komatsu Y, Sugawara M. Impact of renal impairment on early development of severe neutropenia with trifluridine/tipiracil treatment for metastatic colorectal cancer. Sci Rep. 2024 Nov 6;14(1):26990. doi: 10.1038/s41598-024-78741-4. PMID: 39506021; PMCID: PMC11541766. 7: Malier M, Laverriere MH, Henry M, Yakoubi M, Bellaud P, Arellano C, Sébillot A, Thomas F, Josserand V, Girard E, Roth GS, Millet A. Tumor-associated macrophages confer resistance to chemotherapy (Trifluridine/Tipiracil) in digestive cancers by overexpressing thymidine phosphorylase. Cancer Lett. 2024 Dec 1;606:217307. doi: 10.1016/j.canlet.2024.217307. Epub 2024 Oct 23. PMID: 39454852. 8: Li B, Yang W, Liu N, Bi D, Yang T, Wu G, Sun Y. Phase II Study of Irinotecan, Trifluridine/tipiracil (TAS-102) plus Bevacizumab as a Later-line Therapy for Patients with Metastatic Colorectal Cancer (mCRC): a prospective single-center explorative study. Br J Cancer. 2024 Dec;131(11):1775-1780. doi: 10.1038/s41416-024-02885-3. Epub 2024 Oct 24. PMID: 39448860; PMCID: PMC11589780. 9: Shin JE, Lim SH, Lee J, Lim HY, Park YS, Kim ST. TAS-102 (trifluridine/tipiracil) plus bevacizumab versus TAS-102 alone as salvage treatment options for metastatic colorectal cancer in routine clinical practice. Front Oncol. 2024 Sep 30;14:1450732. doi: 10.3389/fonc.2024.1450732. PMID: 39403341; PMCID: PMC11471446. 10: Fakih M, Prager GW, Tabernero J, Amellal N, Calleja E, Taieb J. Clinically meaningful outcomes in refractory metastatic colorectal cancer: a decade of defining and raising the bar. ESMO Open. 2024 Nov;9(11):103931. doi: 10.1016/j.esmoop.2024.103931. Epub 2024 Oct 11. PMID: 39395264. 11: Zhu Y, Liu K, Zhu H. TAS-102 with or without bevacizumab treatment for patients with metastatic colorectal cancer: a multi-country cost-effectiveness analysis. Therap Adv Gastroenterol. 2024 Sep 28;17:17562848241284998. doi: 10.1177/17562848241284998. PMID: 39372041; PMCID: PMC11450621. 12: André T, Van Cutsem E, Taieb J, Fakih M, Prager GW, Ciardiello F, Falcone A, Saunders M, Amellal N, Roby L, Tabernero J, Pfeiffer P. Clinical Trial Data Review of the Combination FTD/TPI + Bevacizumab in the Treatment Landscape of Unresectable Metastatic Colorectal Cancer. Curr Treat Options Oncol. 2024 Oct;25(10):1312-1322. doi: 10.1007/s11864-024-01261-w. Epub 2024 Sep 26. PMID: 39325367; PMCID: PMC11485186. 13: Li R, Liu L, Liu Y, Tang J, Li J. Unraveling the Role of PCDH9 in Breast Cancer and Identifying Therapeutic Strategies for PCDH9-Deficient Tumors. Breast Cancer (Dove Med Press). 2024 Sep 9;16:583-593. doi: 10.2147/BCTT.S476083. PMID: 39279908; PMCID: PMC11401061. 14: Hsiao KY, Chen HP, Rau KM, Liu KW, Shia BC, Chang WS, Liang HY, Hsieh MC. Association between sidedness and survival among chemotherapy refractory metastatic colorectal cancer patients treated with trifluridine/tipiracil or regorafenib. Oncologist. 2024 Sep 7:oyae235. doi: 10.1093/oncolo/oyae235. Epub ahead of print. PMID: 39245044. 15: Boland PM, Mukherjee S, Imanirad I, Vijayvergia N, Cohen SD, Gupta M, Iyer RV, Bakin A, Wang J, Chatley S, Cahill B, Vadehra D, Attwood K, Hochster HS, Fountzilas C. TAS-102, Irinotecan, and bevacizumab in pre-treated metastatic colorectal cancer (TABAsCO), a phase II clinical trial. Br J Cancer. 2024 Nov;131(8):1290-1297. doi: 10.1038/s41416-024-02845-x. Epub 2024 Sep 7. PMID: 39244627; PMCID: PMC11473817. 16: Jiang Y, Shao T, Zhao M, Xue Y, Zheng X. A network meta-analysis of efficacy and safety for first-line and maintenance therapies in patients with unresectable colorectal liver metastases. Front Pharmacol. 2024 Jul 26;15:1374136. doi: 10.3389/fphar.2024.1374136. PMID: 39130637; PMCID: PMC11310042. 17: Paly VF, Li S, Khanduri P, Asfaw AA, Zou D, Hernandez L. Budget impact analysis of introducing fruquintinib for metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and biologics in the United States from the payer perspective. J Med Econ. 2024 Jan-Dec;27(1):1076-1085. doi: 10.1080/13696998.2024.2389005. Epub 2024 Aug 19. PMID: 39102473. 18: Peters GJ. Nucleo(s)tide metabolism as basis for drug development; the Anne Simmonds award lecture. Nucleosides Nucleotides Nucleic Acids. 2024;43(8):696-719. doi: 10.1080/15257770.2024.2383681. Epub 2024 Aug 1. PMID: 39087693. 19: Rais T, Riaz R, Siddiqui T, Shakeel A, Khan A, Zafar H. Innovations in colorectal cancer treatment: trifluridine and tipiracil with bevacizumab for improved outcomes - a review. Front Oncol. 2024 Jul 12;14:1296765. doi: 10.3389/fonc.2024.1296765. PMID: 39070141; PMCID: PMC11272516. 20: Jiang Y, Zhao M, Tang W, Zheng X. Comparison of systemic treatments for previously treated patients with unresectable colorectal liver metastases: a systematic review and network meta-analysis. Front Oncol. 2024 Jul 10;14:1293598. doi: 10.3389/fonc.2024.1293598. PMID: 39050571; PMCID: PMC11266080.

1. http://www.china-oncology.com/EN/10.19401/j.cnki.1007-3639.2021.04.008 China Oncology ›› 2021, Vol. 31 ›› Issue (4): 294-301.doi: 10.19401/j.cnki.1007-3639.2021.04.008 A novel strategy of regorafenib in combination with TAS102 against hepatocellular carcinoma ZHANG Jun 1,2 , DONG Yuhua 3 , YANG Ye 1 , ZHANG Mengqi 1 , HE Chang 1,2