TAS-102 (Trifluridine/Tipiracil HCl)
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MedKoo CAT#: 205641

CAS#: 733030-01-8

Description: 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

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TAS-102 (Trifluridine/Tipiracil HCl)
CAS# 733030-01-8
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 205641
Name: TAS-102 (Trifluridine/Tipiracil HCl)
CAS#: 733030-01-8
Chemical Formula: C19H23Cl2F3N6O7
Exact Mass: 0.00
Molecular Weight: 575.323
Elemental Analysis: C, 39.67; H, 4.03; Cl, 12.32; F, 9.91; N, 14.61; O, 19.47

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Size Price Availability Quantity
25mg USD 150 Ready to ship
50mg USD 250 Ready to ship
100mg USD 450 Ready to ship
200mg USD 650 Ready to ship
500mg USD 850 Ready to ship
1g USD 1250 Ready to ship
2g USD 2050 Ready to ship
5g USD 3950 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)

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/

Solubility Data

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

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.

Recalculate based on batch purity %
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: 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.
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.

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  1: 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.

2: 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.

3: 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.

4: 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.

5: 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.

6: Mayor S. TAS-102 prolongs overall survival in refractory colorectal cancer, study shows. BMJ. 2015 May 14;350:h2620. doi: 10.1136/bmj.h2620. PubMed PMID: 25979138.

7: Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19. doi: 10.1056/NEJMoa1414325. PubMed PMID: 25970050.

8: Aiba K, Natori K. [Advance of salvage chemotherapy for colorectal cancer]. Gan To Kagaku Ryoho. 2015 Apr;42(4):394-7. Japanese. PubMed PMID: 25963685.

9: Sakamoto K, Yokogawa T, Ueno H, Oguchi K, Kazuno H, Ishida K, Tanaka N, Osada A, Yamada Y, Okabe H, Matsuo K. Crucial roles of thymidine kinase 1 and deoxyUTPase in incorporating the antineoplastic nucleosides trifluridine and 2'-deoxy-5-fluorouridine into DNA. Int J Oncol. 2015 Jun;46(6):2327-34. doi: 10.3892/ijo.2015.2974. Epub 2015 Apr 20. PubMed PMID: 25901475; PubMed Central PMCID: PMC4441292.

10: Takahashi K, Yoshisue K, Chiba M, Nakanishi T, Tamai I. Involvement of Concentrative Nucleoside Transporter 1 in Intestinal Absorption of Trifluridine Using Human Small Intestinal Epithelial Cells. J Pharm Sci. 2015 Sep;104(9):3146-53. doi: 10.1002/jps.24455. Epub 2015 Apr 21. PubMed PMID: 25900515.

11: Tsukihara H, Nakagawa F, Sakamoto K, Ishida K, Tanaka N, Okabe H, Uchida J, Matsuo K, Takechi T. Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts. Oncol Rep. 2015 May;33(5):2135-42. doi: 10.3892/or.2015.3876. Epub 2015 Mar 23. PubMed PMID: 25812794; PubMed Central PMCID: PMC4391594.

12: Lee HJ, Oh SJ, Lee EJ, Chung JH, Kim Y, Ryu JS, Kim SY, Lee SJ, Moon DH, Kim TW. Positron emission tomography imaging of human colon cancer xenografts in mice with [18F]fluorothymidine after TAS-102 treatment. Cancer Chemother Pharmacol. 2015 May;75(5):1005-13. doi: 10.1007/s00280-015-2718-7. Epub 2015 Mar 17. PubMed PMID: 25776904.

13: Nukatsuka M, Nakagawa F, Saito H, Sakata M, Uchida J, Takechi T. Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with irinotecan hydrochloride on human colorectal and gastric cancer xenografts. Anticancer Res. 2015 Mar;35(3):1437-45. PubMed PMID: 25750295.

14: Matsuoka K, Iimori M, Niimi S, Tsukihara H, Watanabe S, Kiyonari S, Kiniwa M, Ando K, Tokunaga E, Saeki H, Oki E, Maehara Y, Kitao H. Trifluridine Induces p53-Dependent Sustained G2 Phase Arrest with Its Massive Misincorporation into DNA and Few DNA Strand Breaks. Mol Cancer Ther. 2015 Apr;14(4):1004-13. doi: 10.1158/1535-7163.MCT-14-0236. Epub 2015 Feb 19. PubMed PMID: 25700705.

15: Kotani D, Fukuoka S, Yoshino T. [Efficacy of TAS-102]. Gan To Kagaku Ryoho. 2015 Jan;42(1):1-5. Review. Japanese. PubMed PMID: 25596673.

16: Yasui H, Tsurita G, Imai K. DNA synthesis inhibitors for the treatment of gastrointestinal cancer. Expert Opin Pharmacother. 2014 Nov;15(16):2361-72. doi: 10.1517/14656566.2014.958074. Epub 2014 Sep 26. Review. PubMed PMID: 25256052.

17: 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. PubMed PMID: 25230742; PubMed Central PMCID: PMC4240496.

18: El-Naggar M, Ebbing E, Bijnsdorp I, van den Berg J, Peters GJ. Radiosensitization by thymidine phosphorylase inhibitor in thymidine phosphorylase negative and overexpressing bladder cancer cell lines. Nucleosides Nucleotides Nucleic Acids. 2014;33(4-6):413-21. doi: 10.1080/15257770.2014.892127. PubMed PMID: 24940699.

19: Peters GJ. Novel developments in the use of antimetabolites. Nucleosides Nucleotides Nucleic Acids. 2014;33(4-6):358-74. doi: 10.1080/15257770.2014.894197. Review. PubMed PMID: 24940694.

20: Utsugi T. New challenges and inspired answers for anticancer drug discovery and development. Jpn J Clin Oncol. 2013 Oct;43(10):945-53. doi: 10.1093/jjco/hyt131. Epub 2013 Sep 5. PubMed PMID: 24014883; PubMed Central PMCID: PMC3787805.

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