Biological Activity

• Target

  Thymidylate Synthase Ki:1.3nM

  GARFT Ki:65nM

  DHFR Ki:7.2nM

• DescriptionThe 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].

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

• Clinical Study

• NCT Number	Condition or disease	Phase	Recruitment Status	Estimated Study Completion Date	Locations
  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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