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Peritoneal mesothelioma
Published in Tom Cecil, John Bunni, Akash Mehta, A Practical Guide to Peritoneal Malignancy, 2019
For the more malignant types of mesothelioma, systemic chemotherapy (commonly a platinum-derivative combined with pemetrexed), combined with palliative debulking procedures when necessary, has traditionally been the cornerstone of treatment, often with disappointing results. Early chemotherapy regimens included cisplatin and gemcitabine with a median survival of 6–9 months [13]. Pemetrexed, a multitargeted antifolate, was the first agent approved for the treatment of advanced pleural mesothelioma. In a phase III trial, the combination of pemetrexed with cisplatin improved survival when compared with cisplatin alone, with response rates from 26% to 36% and a median survival of 12.1 months [14]. To date, systemic chemotherapy with or without palliative surgery (for obstructive complications) has shown relatively poor response rates and low median survival rates of approximately 1 year [4].
Personalized Medicine in Lung Cancer
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
Daniela Morales-Espinosa, Silvia Garcá-Román, Rafael Rosell
Pemetrexed (Alimta®, Ely Lilly) is chemically similar to folic acid and belongs to the class of chemotherapy drugs known as folate antimetabolites. It works by inhibiting three enzymes used in purine and pyrimidine synthesis—thymidylate synthase (TS), dihydrofolatereductase (DHFR), and glycinamideribonucleotideformyl transferase (GARFT).21 By inhibiting the formation of precursor purine and pyrimidine nucleotides, pemetrexed prevents the formation of DNA and RNA required for growth and survival of both normal and cancer cells. In 2008, a phase III study by Scagliotti et al. comparing cisplatin/pemetrexed vs. cisplatin/gemcitabine showed for the first time a survival difference in favor of cisplatin/pemetrexed in two histologic groups (adenocarcinoma and large cell carcinoma). The first group had significantly better survival (12.6 vs. 10.9 months),22 something which may be explained by the fact that thymidylate synthase levels are generally lower in adenocarcinoma. Pre-clinical data suggests that overexpression of TS correlates with reduced sensitivity to pemetrexed;23 this is corroborated by a recent meta-analysis. The authors concluded that TS may be a suitable marker of sensitivity to pemetrexed-based chemotherapy in NSCLC patients.24 Nevertheless, this is not yet a standard recommendation for clinical practice.
Lung cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
For patients with non-squamous histology without a sensitizing EGFR mutation, first-line treatment with ciplatin–pemetrexed should be considered. Pemetrexed is a multi-targeted antifolate agent, with a putative major mechanism of action being the inhibition of thymidylate synthase. The toxicity of pemetrexed depends on folate and vitamin B12 nutritional status, and supplementation is mandated within license. The JMDB phase III non-inferiority study compared gemcitabine–cisplatin with pemetrexed-cisplatin in 1725 chemotherapy-naive patients with stage III or IV NSCLC and a PS of 0 to 1.9 The study met the primary endpoint of non-inferiority (OS, 10.3 months), but in a pre-specified subgroup analysis reported superior OS for pemetrexed–cisplatin in patients with non-squamous carcinomas between 1.7 and 3.7 months. Importantly, outcomes for patients with squamous histology were inferior with pemetrexed.
A rare case of pemetrexed-induced diffuse punctal and canalicular stenosis: management by coronary balloon puncto-canaliculoplasty
Published in Orbit, 2022
Abhimanyu Sharma, Monalisa Pattnaik, Mohammad Javed Ali
Chemotherapy-induced epiphora is being increasingly recognized in patients with several malignancies. Chemotherapeutic agents known to cause epiphora include 5-fluorouracil, docetaxel, S-1, panitumumab, radioactive iodine, doxorubicin, capecitabine, imatinib, pentostatin, and mitomycin-C.1,2 The proposed mechanisms causing epiphora are ill-understood.1 Pemetrexed is a chemotherapeutic agent approved for pleural mesothelioma treatment and prolonged maintenance therapy in advanced cases of non-small cell lung carcinoma. It inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, and hence interferes with the folate metabolism.2 Ocular adverse effects of pemetrexed previously described in literature include conjunctivitis3 and eyelid edema.4 Epiphora as a new ocular adverse effect was first reported by Jung et al.2 The patient was successfully treated with three snip punctoplasty (for punctal stenosis) followed by probing (for canalicular stenosis). The present case is the second report to the best of authors’ knowledge, but the first to document dacryoendoscopy findings and report balloon puncto-canaliculoplasty as a minimally-invasive treatment modality for pemetrexed induced punctal and canalicular stenosis.
Development and characterization of cationic solid lipid nanoparticles for co-delivery of pemetrexed and miR-21 antisense oligonucleotide to glioblastoma cells
Published in Drug Development and Industrial Pharmacy, 2018
Berrin Küçüktürkmen, Asuman Bozkır
The antifolate agents, such as methotrexate and 5-fluorouracil (5-FU), have been widely used for decades in the treatment of malignant tumors. Pemetrexed is a novel multi-targeted antifolate agent and has been found to be useful to central nervous system tumors for the development of low resistance. Pemetrexed shows its effect by disrupting folate-dependent metabolic processes, which are essential for cell proliferation. It inhibits key enzymes such as thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase in the purine–pyrimidine pathway [18,19]. Pemetrexed has attracted interest because of its possible use in the brain for treatment of primary brain tumors and the secondary brain tumors, such as lung cancer metastases. However, the penetration of pemetrexed into the central nervous system is limited. It has been suggested that the most important causes of low distribution of pemetrexed in the central nervous system are low permeability due to its hydrophilicity and significant excretion by active reflux pumps [19–21].
The evolving role of pemetrexed disodium for the treatment of non-small cell lung cancer
Published in Expert Opinion on Pharmacotherapy, 2018
Giovanni Rossi, Angela Alama, Carlo Genova, Erika Rijavec, Marco Tagliamento, Federica Biello, Simona Coco, Maria Giovanna Dal Bello, Simona Boccardo, Francesco Grossi
Pemetrexed is a folate analog belonging to the antimetabolites class. The drug interferes with the synthesis of nucleic acids, resulting in a cytotoxic effect on neoplastic cells (Box 1). Pemetrexed competes with reduced folate, thereby significantly inhibiting the activity of multiple folate-requiring enzymes: thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamideribonucleotide formyltransferase (GARFT) [3]. Additionally, another folate-dependent enzyme involved in purine synthesis, aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART), has been reported to be a target for pemetrexed [4]. The primary pharmacologic target of pemetrexed is TS: an essential enzyme involved in DNA replication and cell growth. This enzyme converts deoxyuridylate (dUMP) to deoxythymidylate (dTMP), which is essential for the synthesis of DNA [5]. The TS inhibition reduces dTMP and increases dUTP in cells, causing DNA strand breakage and apoptosis. Some data suggest that low expression of TS could predict responsiveness to pemetrexed in NSCLC patients [6–8]. Pre-clinical data show that pemetrexed is also able to induce the activation of caspase 2, 3, 8, and 9 in NSCLC cell lines, resulting in caspase-dependent apoptosis through the activation of ataxia-telangiectasia mutated (ATM)/p53-dependent and (ATM)/p53-independent signaling pathways [3]. Several mechanisms of resistance to Pemetrexed have been reported: increased intracellular expression of TS, modification in the binding site of TS for the drug, decreased expression of the transporting proteins RFC and PCFT, and reduced polyglutamation of the drug [3,4].