Tipiracil
(Synonyms: 替吡嘧啶) 目录号 : GC37798
A potent TPase inhibitor
Cas No.:183204-74-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Tipiracil (TPI) is a potent and competitive inhibitor of thymidine phosphorylase (TPase) with an IC50 value of 35 nM for human placental TPase.1 It is selective for TPase over other pyrimidine-metabolizing enzymes (IC50s = >1 mM for UPase, OPRTase, TK, and DPDase). TPI inhibits the phosphorolysis and degradation of trifluorothymidine , a cytotoxic nucleoside, in human breast and colon carcinoma tumor samples. Oral administration of TPI (12.5-50 mg/kg) enhances the anti-tumor activity of trifluorothymidine in a mouse AZ-521 stomach cancer xenograft model. Formulations containing TPI have been used for the treatment of metastatic colorectal cancer.2
1.Fukushima, M., Suzuki, N., Emura, T., et al.Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2'-deoxyribonucleosidesBiochem. Pharmacol.59(10)1227-1236(2000) 2.Trebst, A., Wietoska, H., Draber, W., et al.The inhibition of photosynthetic electron flow in chloroplasts by the dinitrophenylether of bromo-or iodo-nitrothymolZ. Naturforsch. C J. Biosci.33(11-12)919-927(1978)
| Cas No. | 183204-74-2 | SDF | |
| 别名 | 替吡嘧啶 | ||
| Canonical SMILES | O=C1NC(C(Cl)=C(CN2C(CCC2)=N)N1)=O | ||
| 分子式 | C9H11ClN4O2 | 分子量 | 242.66 |
| 溶解度 | Water: 1 mg/mL (4.12 mM); DMSO: < 1 mg/mL (insoluble or slightly soluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.121 mL | 20.605 mL | 41.2099 mL |
| 5 mM | 0.8242 mL | 4.121 mL | 8.242 mL |
| 10 mM | 0.4121 mL | 2.0605 mL | 4.121 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Trifluridine/Tipiracil in the treatment of gastric cancer
Future Oncol 2022 Apr;18(12):1511-1517.PMID:35081748DOI:10.2217/fon-2021-0754.
Trifluridine/Tipiracil is a compound drug, approved in 2015 by the US FDA, and in 2016 by the EMA, for the treatment of chemorefractory metastatic colorectal cancers, after the phase III RECOURSE trial demonstrated significant benefit. Another phase III trial (TAGS) showed significant improvement of overall survival and progression-free survival in refractory gastric cancer and gastroesophageal junction cancer, leading to further approval from the FDA on February 2019, followed by Japan in August 2019 and the EU in September 2019. As promising results have already been observed in the chemorefractory gastric and gastroesophageal-junction cancers, ongoing trials are assessing the use of trifluridine/Tipiracil with other standard of care agents, aiming to further improve the survival rate of these patients.
Trifluridine/Tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial
Lancet Oncol 2018 Nov;19(11):1437-1448.PMID:30355453DOI:10.1016/S1470-2045(18)30739-3.
Background: Trifluridine/Tipiracil showed activity and was well tolerated in a phase 2 study of pretreated patients with advanced gastric cancer done in Japan. We investigated whether the treatment was efficacious compared with placebo in a global population. Methods: TAGS was a randomised, double-blind, placebo-controlled, phase 3 trial done in 110 academic hospitals in 17 countries. Patients aged 18 years or older with histologically confirmed, non-resectable, metastatic gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction) as defined by the American Joint Committee on Cancer staging classification (7th edition) who had received at least two previous chemotherapy regimens and had experienced radiological disease progression were eligible for inclusion. Patients were randomly assigned (2:1) via dynamic randomisation from a centralised interactive voice-response system to receive either oral trifluridine/Tipiracil (35 mg/m2 twice daily on days 1-5 and days 8-12 every 28 days) plus best supportive care or placebo plus best supportive care. Participants were allocated to groups by study-site personnel. Randomisation was stratified by region (Japan vs rest of world), ECOG performance status (0 vs 1), and previous treatment with ramucirumab (yes vs no). Both patients and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy was assessed in the intention-to-treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT02500043. The trial, including follow-up of all participants, has been completed. Findings: Between Feb 24, 2016, and Jan 5, 2018, 507 patients were enrolled and randomly assigned, 337 to the trifluridine/Tipiracil group and 170 to the placebo group. Median overall survival was 5·7 months (95% CI 4·8-6·2) in the trifluridine/Tipiracil group and 3·6 months (3·1-4·1) in the placebo group (hazard ratio 0·69 [95% CI 0·56-0·85]; one-sided p=0·00029, two-sided p=0·00058). Grade 3 or worse adverse events of any cause occurred in 267 (80%) patients in the trifluridine/Tipiracil group and 97 (58%) in the placebo group. The most frequent grade 3 or worse adverse events of any cause were neutropenia (n=114 [34%]) and anaemia (n=64 [19%]) in the trifluridine/Tipiracil group and abdominal pain (n=15 [9%]) and general deterioration of physical health (n=15 [9%]) in the placebo group. Serious adverse events of any cause were reported in 143 (43%) patients in the trifluridine/Tipiracil group and 70 (42%) in the placebo group. One treatment-related death was reported in each group (because of cardiopulmonary arrest in the trifluridine/Tipiracil group and because of toxic hepatitis in the placebo group). Interpretation: Trifluridine/Tipiracil significantly improved overall survival compared with placebo and was well tolerated in this heavily pretreated population of patients with advanced gastric cancer. Trifluridine/Tipiracil could be a new treatment option in this population who represent a high unmet medical need. Funding: Taiho Oncology and Taiho Pharmaceutical.
Trifluridine/Tipiracil for the treatment of metastatic gastric cancer
Expert Rev Gastroenterol Hepatol 2020 Feb;14(2):65-70.PMID:31920125DOI:10.1080/17474124.2020.1715209.
Introduction: Trifluridine/Tipiracil is a novel oral cytotoxic chemotherapy consisting of a thymidine-based nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, Tipiracil. Trifluridine/Tipiracil was approved for the treatment of metastatic colorectal cancer refractory to standard therapies. A phase II trial in Japan demonstrated that this therapy has antitumor activity and is tolerated by patients with advanced gastric cancer (AGC); as a result, the phase III TAGS trial (Trifluridine/Tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer) was initiated.Area covered: Trifluridine/Tipiracil has proved effective for heavily pretreated AGC and has thus been approved for use in the United States in February 2019, Japan in August 2019 and the European Union in September 2019. Detail of the phase III TAGS trial is discussed in this review.Expert opinion: Trifluridine/Tipiracil after at least two previous courses of systemic chemotherapy improved rates of survival of gastric cancer; thus it has become one of the treatment options in affected patients. Currently, several clinical trials of trifluridine/Tipiracil in combination with other anticancer agents such as ramucirumab (an anti-vascular endothelial growth factor receptor 2 monoclonal antibody) for patients with AGC are ongoing.
Trifluridine/Tipiracil: A Review in Metastatic Gastric Cancer
Drugs 2019 Sep;79(14):1583-1590.PMID:31489588DOI:10.1007/s40265-019-01195-w.
Trifluridine/Tipiracil (Lonsurf®) is a fixed-dose combination tablet comprising trifluridine, an antineoplastic nucleoside analogue, and Tipiracil, a thymidine phosphorylase inhibitor. Trifluridine/Tipiracil has recently been granted an additional indication in the USA for the treatment of metastatic gastric cancer, including gastroesophageal junction adenocarcinoma, in patients who have been previously treated with at least two systemic treatment regimens, and has received a positive opinion for this indication in the EU. In the large pivotal phase III TAGS trial, trifluridine/Tipiracil plus best supportive care (BSC) significantly prolonged overall survival (OS; primary endpoint) compared with placebo plus BSC in this patient group. Progression-free survival (PFS) and the disease control rate were also improved with trifluridine/Tipiracil relative to placebo. Health-related quality of life was not adversely affected by the addition of trifluridine/Tipiracil to BSC and time to deterioration of Eastern Cooperative Oncology Group (ECOG) performance status was significantly delayed. The most common adverse events were mainly haematological (neutropenia, leucopenia and anaemia) and gastrointestinal (nausea, vomiting and diarrhoea), and were generally manageable with dosage modifications and/or supportive care. Adverse events ≥ Grade 3 were most frequently haematological in nature. Thus, trifluridine/Tipiracil provides a valuable and much needed treatment option for patients with metastatic gastric or gastroesophageal junction adenocarcinoma that has progressed on at least two prior therapies.
Biomarkers of Trifluridine-Tipiracil Efficacy
J Clin Med 2021 Nov 26;10(23):5568.PMID:34884270DOI:10.3390/jcm10235568.
Trifluridine/Tipiracil (TAS-102) is a newer generation chemotherapy that has been approved for the later-line treatment of metastatic colorectal and gastric/gastroesophageal adenocarcinomas. The oral drug provides a modest benefit of prolongation of survival over placebo in pretreated patients with these cancers with acceptable toxicity. Studies have shown rare objective responses (2-4%), and the disease control rates were 44% in both colorectal and gastric cancer randomized trials. Thus, the majority of patients progress through treatment and are burdened by toxicities. To better characterize the sub-group of patients with a higher probability of benefit from trifluridine/Tipiracil, predictive biomarkers have been sought using data from randomized trials as well as from non-randomized trials and real-world series. Biomarkers examined include clinical characteristics of the patients, laboratory tests, and tumor derived biomarkers. These studies show that early neutropenia on treatment, and ratios of leukocyte subsets, are potential biomarkers able to predict trifluridine/Tipiracil benefit. Combinations of laboratory values and clinical characteristics and proteins involved in trifluridine transport and activation have been examined with initial positive results.