生物活性

• 靶点

  GARFT Ki:65nM

  DHFR Ki:7.2nM

• 描述The biologically active form of folic acid is tetrahydrofolate which is essential for DNA synthesis. Tetrahydrofolate is oxidised to dihydrofolate during DNA synthesis and is regenerated to its active form by the enzyme dihydrofolate reductase. Inhibition of this enzyme prevents DNA synthesis and causes failure of cell renewal. This leads to breaks in epithelial surfaces resulting in oropharyngeal and intestinal ulceration ^[5]. Pemetrexed is a new type of anti-folate and anti-metabolic drug, acting on TS, DHFR and GARFT, with Ki of 1.3nm, 7.2nm and 65nm in cell-free assay, respectively ^[6]. Pemetrexed is used in CCRF-CEM leukemia, GC3/C1 colon cancer, and HCT-8 cecum cancer cells with anti-proliferation activity with IC50 of 25 nM, 34 nM, and 220 nM, respectively. In addition, the combination of thorax and hypoxanthine on the above three cell lines completely reverses the cytotoxicity caused by pemetrexed ^[7]. SOCS-1 (suppressor of cytokine signaling 1, an endogenous inhibitor of intracellular signaling pathways) gene delivery cooperated with cisplatin plus pemetrexed to inhibit cell proliferation, invasiveness and induction of apoptosis in MPM cells ^[8]. Administration of the pemetrexed 6 h prior to administration of 5-fluorouracil resulted in additive growth delay of the MX-1 tumor. In addition, the simultaneous combination of MTA administered daily for 5 days for 2 weeks with administration of gemcitabine resulted in greater-than-additive H460 TGD ^[9].

• 动物研究
  剂量	Rat: 10 mg/kg, 100 mg/kg[3] (i.v.)
  给药途径	i.v.
  动物药代数据	Animal Mice[4] Dogs Dose 20 mg/kg 7.5 mg/kg Administration i.v. or i.p. i.v. AUC0→24h 33 μg·h/ml t1/2α 5 - 20 min Tmax 0.083 h (i.v.) 0.25 h (i.p.) 5 min T1/2β 7.0 h (i.v.) 7.8 h (i.p.) Cmax 41 μg/ml (i.v.) 33 μg/ml (i.p.) t1/2β 2.8 h T1/2α 0083 - 0.5 h (i.v.) AUC 31 μg·h/ml (i.v.) 44 μg·h/ml (i.p.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03655834	Non Small Cell Lung Cancer ... more >> Mesothelioma Collapse <<	Phase 4	Not yet recruiting	September 1, 2021	Netherlands ... more >> Jeroen Bosch Hospital Not yet recruiting 's-Hertogenbosch, Netherlands Contact: Bonne Biesma       b.biesma@jbz.nl    Principal Investigator: Bonne Biesma          Sub-Investigator: Jeroen Derijks          Antoni van Leeuwenhoek Not yet recruiting Amsterdam, Netherlands Contact: Sjaak Burgers       s.burgers@nki.nl    Principal Investigator: Sjaak Burgers          Sub-Investigator: Alwin Huitema          Maastricht University Medical centre Not yet recruiting Maastricht, Netherlands Contact: Anne-Marie Dingemans       a.dingemans@mumc.nl    Principal Investigator: Anne-Marie Dingemans          Radboud university medical centre Not yet recruiting Nijmegen, Netherlands Contact: Rob ter Heine       R.terHeine@radboudumc.nl    Principal Investigator: Rob ter Heine          Sub-Investigator: Nikki de Rouw          Sub-Investigator: Michel van den Heuvel          Erasmus University Medical Centre Not yet recruiting Rotterdam, Netherlands Contact: Joachim Aerts       j.aerts@erasmusmc.nl    Principal Investigator: Joachim Aerts          Sub-Investigator: Ron Mathijsen Collapse <<
  NCT02211833	Carcinoma, Non-Small-Cell Lung	Phase 1	Completed	-	-
  NCT02049060	Malignant Pleural Mesothelioma... more >> Nonsquamous Nonsmall Cell Neoplasm of Lung Collapse <<	Phase 1 Phase 2	Active, not recruiting	December 2017	Italy ... more >> Istituto Clinico Humanitas Rozzano, Milan, Italy, 20089 Collapse <<

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• 参考文献

• [1] Norris RE, Rappaport EF, Adamson PC. Preclinical evaluation of pemetrexed in pediatric solid tumors. Pediatr Blood Cancer. 2011 Dec 15;57(7):1233-5.

  [2] Shih C, Chen VJ, et al. LY231514, a pyrrolo[2,3-d] pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 1997 Mar 15;57(6):1116-23.

  [3] Sørensen JB, et al. Pharmacokinetic evaluation of pemetrexed. Expert Opin Drug Metab Toxicol. 2011 Jul;7(7):919-28.

  [4] LY-231514

  [5] Calcium leucovorin - folinic acid rescue. Drug Ther Bull. 1978 Feb 3;16(3):11-2.

  [6] Shih C LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 1997 Mar 15;57(6):1116-23.

  [7] Shih C. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 1997 Mar 15;57(6):1116-23.

  [8] Iwahori K. SOCS-1 gene delivery cooperates with cisplatin plus pemetrexed to exhibit preclinical antitumor activity against malignant pleural mesothelioma. Int J Cancer. 2013 Jan 15;132(2):459-71. doi: 10.1002/ijc.27611. Epub 2012 May 17.

  [9] Teicher BA. Treatment regimens including the multitargeted antifolate LY231514 in human tumor xenografts. Clin Cancer Res. 2000 Mar;6(3):1016-23.

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