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Drug Delivery and Translational Research Oct 2022Malignant pleural mesothelioma (MPM) is a rare malignancy with poor prognosis, for which chemotherapy with pemetrexed (PEM) is among the few clinical treatments. PEM...
Malignant pleural mesothelioma (MPM) is a rare malignancy with poor prognosis, for which chemotherapy with pemetrexed (PEM) is among the few clinical treatments. PEM suffers, however, fast clearance, moderate drug exposure, and dose-limiting toxicities. Here, we report on epidermal growth factor receptor (EGFR)-targeted disulfide-crosslinked biodegradable chimaeric polymersomes (EGFR-CPs) to firmly load PEM and boost chemotherapy of MPM. EGFR-CPs encapsulating 8.7-16.4 wt.% PEM (EGFR-CPs-PEM) showed diameters of 62-65 nm and reduction-responsive drug release property. EGFR-CPs-PEM was more efficiently taken up by EGFR-overexpressed MSTO-211H cells, inducing about 4.7-fold enhanced anticancer activity compared with non-targeted CPs-PEM control. Intriguingly, the in vivo experiments in MSTO-211H xenograft mouse model revealed that EGFR-CPs-PEM brought about superior tumor deposition and penetration to CPs-PEM, and significantly more potent tumor repression than CPs-PEM and free PEM. This polymersome-enabled EGFR-targeted delivery of PEM offers an appealing therapeutic strategy for MPM.
Topics: Animals; Cell Line, Tumor; ErbB Receptors; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mice; Pemetrexed
PubMed: 34802094
DOI: 10.1007/s13346-021-01094-2 -
Drug Development and Industrial Pharmacy Jan 2023Due to the complexity of the pathophysiology of non-small cell lung cancer (NSCLC) and the susceptibility of single chemotherapy to drug resistance, the combination of...
Due to the complexity of the pathophysiology of non-small cell lung cancer (NSCLC) and the susceptibility of single chemotherapy to drug resistance, the combination of drugs and small interfering RNA (siRNA) may produce a desired therapeutic effect on NSCLC through the action of multiple pathways. We designed to develop poly-γ-glutamic acid-modified cationic liposomes (γ-PGA-CL) to co-deliver pemetrexed disodium (PMX) and siRNA to treat NSCLC. Firstly, γ-PGA was modified on the surface of PMX and siRNA co-loaded cationic liposomes by electrostatic interaction (γ-PGA modified PMX/siRNA-CL). In order to evaluate whether the prepared γ-PGA modified PMX/siRNA-CL could be taken up by tumor cells and exert significant anti-tumor effects, and studies were performed, with A549 cells and LLC-bearing BABL/c mice as experimental models, respectively. The particle size and potential of γ-PGA modified PMX/siRNA-CL was (222.07 ± 1.23) nm and (-11.38 ± 1.44) mV. A preliminary stability experiment showed the complex could protect siRNA from degradation. cell uptake experiment indicated the complex group exerted stronger fluorescence intensity and expressed higher flow detection value. Cytotoxicity study showed the cell survival rate of γ-PGA-CL was (74.68 ± 0.94)%. Polymerase chain reaction (PCR) analysis and western blot technology displayed that the complex could inhibit the expression of Bcl-2 mRNA and protein to promote cell apoptosis. anti-tumor experiments represented the complex group showed a significant inhibitory effect on tumor growth, while the vector showed no obvious toxicity. Therefore, the current studies proved the feasibility of combining PMX and siRNA by γ-PGA-CL as a potential strategy for the treatment of NSCLC.
Topics: Animals; Mice; Pemetrexed; Liposomes; Carcinoma, Non-Small-Cell Lung; Glutamic Acid; RNA, Small Interfering; Lung Neoplasms; Cell Line, Tumor
PubMed: 36803267
DOI: 10.1080/03639045.2023.2182125 -
Recent Patents on Anti-cancer Drug... 2021Pemetrexed is a folate analogue metabolic inhibitor for mammalian cells. Pemetrexed is toxic to several cancer cells by interfering with their new biosynthesis of... (Review)
Review
BACKGROUND
Pemetrexed is a folate analogue metabolic inhibitor for mammalian cells. Pemetrexed is toxic to several cancer cells by interfering with their new biosynthesis of nucleotides, thus causing cell apoptosis. Presently, Pemetrexed is given to patients with Non-Small Cell Lung Cancer (NSCLC).
OBJECTIVE
This review focuses on the recent patents of Pemetrexed. This assessment includes patents grouped in segments like crystalline form patent, composition related patents, product patents, as well as a method of treatment. The aim of this review is to simplify inventors with existing patents in a single place.
METHODS
Data were searched from several available databases, including paid databases which include Orbit® and SciFinder®. Free databases include Worldwide Espacenet® (EPO), Patentscope® (WIPO), InPASS (Indian patent database) and Google Patents.
RESULTS
Some new polymorph and composition-related inventions of Pemetrexed have been recently patented as its orange-book listed patents will soon expire in May 2022. Further, because of the problem of oxidation through the development and continuing storage of Pemetrexed composition, several excipients are experimented with within these patents to stabilize the same. Nevertheless, there is a need for further development of an improved composition of Pemetrexed with improved characteristics.
CONCLUSION
Wide research has been conducted on different processes for preparing Pemetrexed and formulation thereof. Such type of active research may clear the track for the generic companies in the United States, producing the formulation at low prices and providing universal health care at economical prices.
Topics: Adenocarcinoma of Lung; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Folic Acid Antagonists; Humans; Lung Neoplasms; Patents as Topic; Pemetrexed
PubMed: 33494684
DOI: 10.2174/1574892816666210120113256 -
Journal of Investigative Medicine : the... Mar 2022This article aimed to investigate the effects of the administration method of pemetrexed and cisplatin on the efficacy and safety of treating non-small cell lung cancer...
This article aimed to investigate the effects of the administration method of pemetrexed and cisplatin on the efficacy and safety of treating non-small cell lung cancer (NSCLC) and the intrinsic molecular mechanism. Subcutaneous injection of A549 cells into BALB/C nude mice was used to explore the efficacy of different administration methods of pemetrexed and cisplatin in vivo. Immunogenic cell death (ICD) was evaluated by ATP secretion, ecto-CALR expression, and high mobility group protein 1 release. Western blot, qRT-PCR, and immunohistochemical staining were applied to detect the expression of apoptosis, cell cycle, and stimulator of interferon genes (STING) pathway-related markers. Immune microenvironment was evaluated by secretion of cytokines, infiltration of CD8 T cells, and expression of programmed death molecular ligand-1 (PD-L1). Sequential treatment with pemetrexed and cisplatin inhibited A549 cell-driven tumor formation in nude mice and regulated the expression of apoptosis and cell cycle-related genes. STING pathway and ICD were further activated by sequential treatment with pemetrexed and cisplatin. This sequential administration method increased the levels of interferon β, tumor necrosis factor α, interleukin 12, and C-X-C motif chemokine ligand 10, enhanced the infiltration of CD8 T cells, and upregulated the expression of PD-L1. Sequential administration of pemetrexed and cisplatin in the treatment of mouse NSCLC model may have a better effect than combination of drugs, providing theoretical basis and potential guidance for clinical medication.
Topics: Animals; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cisplatin; Humans; Ligands; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Pemetrexed; Programmed Cell Death 1 Receptor; Tumor Microenvironment
PubMed: 34872935
DOI: 10.1136/jim-2021-002159 -
Expert Opinion on Drug Metabolism &... 2016Despite many clinical efforts, non-small-cell lung cancer (NSCLC) has a dismal 5-year survival rate of 16%, and high incidence of recurrence. The success of biologically... (Review)
Review
Despite many clinical efforts, non-small-cell lung cancer (NSCLC) has a dismal 5-year survival rate of 16%, and high incidence of recurrence. The success of biologically targeted agents, as well as the activity of well-established chemotherapeutic regimens, has been limited by inherited/acquired resistance, and biomarkers to adapt the prescription of anticancer drugs to patients' features are urgently warranted. Areas covered. In oncology, pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best match the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity. The present review summarizes the main findings on NSCLC pharmacogenetics, critically reappraising the most important studies on polymorphisms correlated with outcome of pemetrexed and EGFR-inhibitors, and provides perspective on clinical application of genomic tests for treatment decision-making. Expert Opinion. A major challenge in NSCLC is the identification of subgroups of diseases/patients that will truly benefit from specific treatments. Ideally, convenient and minimally invasive tests to decipher biomarkers of chemosensitivity/resistance and toxicity should be developed alongside novel anticancer treatments. Integration with the latest generation of whole-genome analyses and liquid biopsies as well as prospective validation in large cohorts of patients will overcome the limitations of the traditional pharmacogenetic approaches.
Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Patient Selection; Pemetrexed; Pharmacogenetics; Survival Rate
PubMed: 26761638
DOI: 10.1517/17425255.2016.1141894 -
Cancer Genomics & Proteomics 2021Cisplatin combined with pemetrexed disodium heptahydrate (pemetrexed) is considered the standard treatment for patients with advanced, non-squamous, non-small-cell lung...
BACKGROUND/AIM
Cisplatin combined with pemetrexed disodium heptahydrate (pemetrexed) is considered the standard treatment for patients with advanced, non-squamous, non-small-cell lung cancer. However, its growth-inhibitory effects on KRAS-dependent lung cancer as monotherapy and combination therapy are not well understood. The aim of this study was to compare the effects of cisplatin and pemetrexed on A549 cells as mono- and combination therapies and elucidate the underlying mechanisms.
MATERIALS AND METHODS
For in vitro studies, A549 cells were exposed to cisplatin with/without pemetrexed for 72 h. The results were then evaluated by cell viability, apoptosis, reactive oxygen species, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and western blotting assays.
RESULTS
Our results revealed that cisplatin monotherapy was most cytotoxic to A549 cells, while cisplatin plus pemetrexed combination had an intermediate effect, and pemetrexed monotherapy induced a minimal cytotoxic effect on A549 cells. This effect was evidenced by cell viability results, inhibition of KRAS proto-oncogene, GTPase (KRAS)/Raf proto-oncogene, serine/threonine kinase/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways and apoptosis induction triggered by reactive oxygen species-mediated DNA damage. The immunoblotting result of conversion of microtubule-associated protein 1 light chain 3 alpha (LC3)-I to -II indicated that the greatest inducer of autophagy was combined treatment with cisplatin plus pemetrexed, while pemetrexed monotherapy had the lowest effect on autophagy induction, with cisplatin monotherapy having an intermediate effect. We found that the AKT serine/threonine kinase 1/mechanistic target of rapamycin kinase (mTOR) and AMP-activated protein kinase/mTOR signaling pathways were associated with autophagy activation. Interestingly, combination therapy with cisplatin plus pemetrexed was the primary eliminator of cellular senescence; cisplatin monotherapy had an intermediate effect, while pemetrexed monotherapy increased cellular senescence of A549 cells, as assessed by the expression of β-galactosidase protein.
CONCLUSION
Cisplatin monotherapy may be more effective than pemetrexed monotherapy or cisplatin plus pemetrexed combination therapy against KRAS-dependent lung cancer.
Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Autophagy; Cell Survival; Cellular Senescence; Cisplatin; DNA Damage; Extracellular Signal-Regulated MAP Kinases; Humans; Lung Neoplasms; Mitogen-Activated Protein Kinase Kinases; Pemetrexed; Proto-Oncogene Mas; Proto-Oncogene Proteins c-raf; Proto-Oncogene Proteins p21(ras); Reactive Oxygen Species; Signal Transduction
PubMed: 34183390
DOI: 10.21873/cgp.20282 -
British Journal of Clinical Pharmacology Feb 2022Pemetrexed is a cytotoxic drug for first-line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical...
Pemetrexed is a cytotoxic drug for first-line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin-related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P = .196) or volume of distribution (+7% change, P = .002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Humans; Lung Neoplasms; Pemetrexed
PubMed: 34374116
DOI: 10.1111/bcp.15031 -
Revue Des Maladies Respiratoires Apr 2018Malignant pleural mesothelioma (MPM) is a quite rare cancer, but with increasing incidence, that is usually induced by previous asbestos exposure. Its prognosis is poor... (Review)
Review
INTRODUCTION
Malignant pleural mesothelioma (MPM) is a quite rare cancer, but with increasing incidence, that is usually induced by previous asbestos exposure. Its prognosis is poor and there is no validated curative therapy to date. Surgery of MPM, done only by few expert teams within a multimodal treatment is of limited and still disputed value. The standard treatment of MPM, relying on first-line chemotherapy by combined cisplatin-pemetrexed is often poorly effective, even if combination with bevacizumab anti-VEGF antibodies has slightly improved the results. Moreover, no second line treatment is recommended in case of failure of this chemotherapy. Therefore, the search of new therapies or strategies is crucial and the recruitment of patients in clinical trials is highly encouraged.
BACKGROUND
Among the treatments under investigation, various anti-tumour immunotherapies, in particular immune checkpoints inhibitors (ICI), currently exhibit the most promising preliminary results. First data from the phase II, randomized "IFCT MAPS-2", recently presented during the 2017 ASCO meeting, confirmed the value of ICI in MPM patients in cases of chemotherapy failure.
OUTLOOK AND CONCLUSIONS
However, several exciting immunotherapies other than ICI are presently being evaluated in MPM and are reported in this article. Moreover, many questions still need to be answered about immunotherapy: what is its potential value as first line treatment? How to target the best candidates for these treatments? Which combinations between immunotherapy and standard chemotherapy, targeted therapies, surgery or radiotherapy? Finally, it is now essential that every clinician has sufficient knowledge about the possible toxicities of immunotherapy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cisplatin; Combined Modality Therapy; Humans; Immunotherapy; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Pemetrexed; Pleural Neoplasms
PubMed: 29415822
DOI: 10.1016/j.rmr.2017.07.025 -
Journal of Thoracic Oncology : Official... Jan 2020
Topics: Biomarkers; ErbB Receptors; Gefitinib; Humans; Lung Neoplasms; Mutation; Pemetrexed
PubMed: 31864546
DOI: 10.1016/j.jtho.2019.10.017 -
Anticancer Research Sep 2023No standard treatment is currently recommended for advanced biliary tract cancer (BTC) after first-line therapy with gemcitabine plus cisplatin. We aimed to evaluate the...
Pemetrexed and Erlotinib as a Salvage Treatment in Patients With Metastatic Biliary Tract Cancer Who Failed Gemcitabine-containing Chemotherapy: A Phase II Single-arm Prospective Study.
BACKGROUND/AIM
No standard treatment is currently recommended for advanced biliary tract cancer (BTC) after first-line therapy with gemcitabine plus cisplatin. We aimed to evaluate the efficacy and safety of a pemetrexed and erlotinib combination in patients with BTC previously treated with gemcitabine.
PATIENTS AND METHODS
This phase II, open-label, single-arm study enrolled patients with BTC who had previously failed gemcitabine-based first-line chemotherapy. Patients were treated with pemetrexed as a 500 mg/m intravenous infusion on day 1 for three weeks and erlotinib 100 mg daily until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate (ORR).
RESULTS
The study enrolled 20 patients with BTC, including 12 (60%) with intrahepatic cholangiocarcinoma (IHCC), 3 (15%) with extrahepatic cholangiocarcinoma (EHCC), and 5 (25%) with gallbladder cancer (GBC). The ORR was 5%, and the disease control rate (DCR) was 55%. As of the cutoff point of March 31, 2023, the median progression-free survival (PFS) was 2.3 months [95% confidence interval (CI)=0.00-4.74] and the median overall survival (OS) was 5.6 months (95%CI=2.28-8.87). Patients with EHCC showed longer PFS and OS compared to patients with IHCC or GBC, but the differences were not significant. A baseline CEA greater than the upper normal limit was the only significant prognostic factor for a worse OS rate. The only treatment-related adverse event (TRAE) with severity grade ≥3 was anemia (5%).
CONCLUSION
Salvage chemotherapy with pemetrexed plus erlotinib was well-tolerated and showed marginal clinical activity in BTC patients after failure to gemcitabine-based chemotherapy.
Topics: Humans; Salvage Therapy; Gemcitabine; Erlotinib Hydrochloride; Pemetrexed; Prospective Studies; Bile Duct Neoplasms; Carcinoma in Situ; Cholangiocarcinoma; Gallbladder Neoplasms; Bile Ducts, Intrahepatic
PubMed: 37648323
DOI: 10.21873/anticanres.16607