Animal models

Xenograft-bearing nude mouse models of colorectal and gastric cancers

Dosage form

150 mg/kg/day (combination of Trifluridine and Tipiracil Hydrochloride); p.o.; b.i.d., for 14 days

Applications

The tumor growth-inhibitory activity and RTV5 in mice administered TAS-102 (consisting of Trifluridine and Tipiracil Hydrochloride) with Oxaliplatin were significantly superior to those associated with either monotherapy in mice with colorectal (HCT 116 and SW-48 cells) and gastric (SC-2 and MKN74 cells) cancers. In vivo, TAS-102 alone was effective in MKN74/5FU cells, and its anti-tumor activity was substantially enhanced in combination with Oxaliplatin. No significant decrease in body weight or toxicity was observed compared to either monotherapy.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

Tipiracil is an inhibitor of Thymidine phosphorylase (TP).

Thymidine phosphorylase (TP)is a key enzyme in the pyrimidine nucleoside salvage pathway. It catalyses the reversible phosphorylation of thymidine, and thereby generate thymine and 2-deoxy-D-ribose-1-phosphate.

Tipiracil (TPI) and trifluridine (FTD) are active components of TAS-102 at a molecular ratio of 1:0.5, which is a novel oral nucleoside antitumor agent in clinical trials. Oral administered TPI and FTD co-treatment may differ from that of i.v. administration of FTD alone. [1] When FTD is administered orally, it is rapidly degraded to its inactive form in the intestines and the liver (first-pass effect) [2], but the combination with TPI helps to maintain adequate FTD plasma concentrations [3]. TPI thus, potentiates the antitumor activity of FTD, and the optimal molecular ratio of FTD to TPI has been proven to be 1:0.5. [3]

References:
1. Tsukihara H1, Nakagawa F2, Sakamoto K et al.  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.
2.  Dexter DL, Wolberg WH, Ansfield FJ, Helson L and Heidelberger C: The clinical pharmacology of 5-trifluoro-methyl-2'-deoxyuridine. Cancer Res 32: 247-253, 1972.
3.  Fukushima M, Suzuki N, Emura T et al. Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2'-deoxyribonucleosides. biochem Pharmacol 59: 1227-1236, 2000.