Trifluridine/tipiracil

Trifluridine/tipiracil
Combination of
Trifluridine Cytotoxin
Tipiracil Thymidine phosphorylase inhibitor
Clinical data
Trade names Lonsurf
Pregnancy
category
  • Can cause fetal harm
Legal status
Identifiers
CAS Number 733030-01-8

Trifluridine/tipiracil (trade name Lonsurf, code name TAS-102) is a combination drug for the treatment of metastatic colorectal cancer. It is a combination of two active pharmaceutical ingredients: trifluridine, a nucleoside analog, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor. Tipiracil hydrochloride prevents rapid metabolism of trifluridine, increasing the bioavailability of trifluridine.

Trifluridine/tipiracil was approved by the U.S. Food and Drug Administration on September 22, 2015, for use as a third- or fourth-line treatment in metastatic colorectal cancer which has already received both conventional chemotherapy and biologic therapy.[1][2]

Mechanism of action

TAS-102 – trifluridine and tipiracil mechanism of action

TAS-102 consists of the cytotoxin trifluridine and the thymidine phosphorylase inhibitor (TPI) tipiracil.[3] Trifluridine is incorporated into DNA during DNA synthesis and inhibits tumor cell growth. Trifluridine (TFT) is incorporated into DNA by phosphorylation by thymidylate kinase (TK) to TF-TMP;[4] TF-TMP then covalently binds to tyrosine 146 of the active site of thymidylate synthase (TS) inhibiting the enzyme's activity.[4] TS is vital to the synthesis of DNA because it is an enzyme involved in the synthesis of the deoxynucleotide, dTTP.[4] Inhibition of TS depletes the cell of dTTP and causes accumulation of dUMP, which increases the likelihood that uracil gets misincorporated into the DNA.[4] Also, subsequent phosphorylations of TF-TMP cause an increased level of TF-TTP within the cell, which results in it being incorporated into DNA.[4] Even though the exact mechanism of how TFT causes DNA damage is not completely understood, it is hypothesized that the incorporation TF-TTP in DNA leads to DNA strand break formation.[4]

In addition to the effects TAS-102 has on DNA synthesis, the thymidine phosphorylase inhibitor (TPI) prevents the degradation of trifluridine via thymidine phosphorylase (TP) when taken orally and also has antiangiogenic properties.[5][6][4][7] Not only has thymidine phosphorylase been shown to be identical to platelet-derived endothelial cell growth factor (PD-ECGF), which is an endogenous factor involved in the formation of new vasculature, but also the products of the enzyme may contribute to the stimulation of endothelial cell chemotaxis.[7]

Physical and chemical properties

TAS-102 has two active pharmaceutical ingredients: a nucleoside analog trifluridine (α,α,α-trifluorothymidine; 5-trifluromethyl-2′-deoxyuridine ; FTD5-trifluoro-2′-deoxythymidine; TFT; CF3dUrd; FTD; F3TDR; F3Thd) and a thymidine phosphorylase inhibitor (TPI), tipiracil hydrochloride[2](5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4 (1H,3H)-pyrimidinedione hydrochloride).[6][4]

The molar concentrations of FTD and TPI in the formulation of TAS-102 is 1.0 to 0.5, respectively.[8]

History

Since the synthesis of 5-fluorouracil (5-FU) in 1957,[9] fluoropyrimidines have been a useful tool in the treatment of many types of cancer.[8] 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, more convenient and efficacious fluoropyrimidine therapy has been desired.[8] The fluoropyrimidine component of TAS-102, trifluridine, was first synthesized in 1964 by Heidelberger et al.[8] By the late 1960s, Phase I and Phase II clinical trials of intravenous trifluridine alone initially proved to be disappointing.[8] Its pharmacokinetic profile during these clinical trials showed that the drug exhibited a very short half-life while in serum (12 minutes post-injection).[8] In response to its pharmacokinetic properties, adjustments in the dosing regimen demonstrated significant therapeutic benefits in patients with breast cancer and colon cancer;[8] 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.[8] Success of trifluridine as an effective anti-cancer agent was short lived, however, due to rapid tumor recurrence upon regression of therapy.[8] Trifluridine therapy in oncology was thus halted.[8]

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).[6][8] 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).[8]

References

  1. ↑ "FDA approves new oral medication to treat patients with advanced colorectal cancer" (Press release). Silver Spring, MD. U.S. Food and Drug Administration. 2015-09-22. Retrieved 2015-09-23.
  2. 1 2 "Taiho Oncology's TAS-102 Meets Primary Endpoint of Improving Overall Survival in Global Phase III RECOURSE Trial in Refractory Metastatic Colorectal Cancer". Taiho Pharma. 12 May 2014. Retrieved 2 December 2014.
  3. ↑ "A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA.". Sep 2004.
  4. 1 2 3 4 5 6 7 8 Temmink, Olaf (June 2007). "Therapeutic potential of the dual‐targeted TAS‐102 formulation in the treatment of gastrointestinal malignancies". Cancer science 98 (6): 779–789. doi:10.1111/j.1349-7006.2007.00477.x.
  5. ↑ "New Drug for Colorectal Cancer Shows Promise in Phase II Trial". 28 Aug 2012.
  6. 1 2 3 Peters, Godefridus (December 2012). "TAS-102: more than an antimetabolite". The Lancet Oncology 13 (12): e518–e519. doi:10.1016/s1470-2045(12)70426-6.
  7. 1 2 Matsushita, Shigeto (15 April 1999). "The Effect of a Thymidine Phosphorylase Inhibitor on Angiogenesis and Apoptosis in Tumors". Cancer Research 59 (8): 1911–1916.
  8. 1 2 3 4 5 6 7 8 9 10 11 12 Hong, David (15 September 2006). "Phase I Study to Determine the Safety and Pharmacokinetics of Oral Administration of TAS-102 in Patients With Solid Tumors". Cancer 107 (6): 1383–1390. doi:10.1002/cncr.22125.
  9. ↑ Hoff, P. M. (1 August 2001). "The Evolution of Fluoropyrimidine Therapy: From Intravenous to Oral". The Oncologist 6 (90004): 3–11. doi:10.1634/theoncologist.6-suppl_4-3.


This article is issued from Wikipedia - version of the Thursday, January 28, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.