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Blood Cancer Journal Mar 2015Previous data established that plitidepsin, a cyclic depsipeptide, exerted activity in a mouse model of myelofibrosis (MF). New preclinical experiments reported herein...
Evaluation of plitidepsin in patients with primary myelofibrosis and post polycythemia vera/essential thrombocythemia myelofibrosis: results of preclinical studies and a phase II clinical trial.
Previous data established that plitidepsin, a cyclic depsipeptide, exerted activity in a mouse model of myelofibrosis (MF). New preclinical experiments reported herein found that low nanomolar plitidepsin concentrations potently inhibited the proliferation of JAK2V617F-mutated cell lines and reduced colony formation by CD34+ cells of individuals with MF, at least in part through modulation of p27 levels. Cells of MF patients had significantly reduced p27 content, that were modestly increased upon plitidepsin exposure. On these premise, an exploratory phase II trial evaluated plitidepsin 5 mg/m(2) 3-h intravenous infusion administered on days 1 and 15 every 4 weeks (q4wk). Response rate (RR) according to the International Working Group for Myelofibrosis Research and Treatment consensus criteria was 9.1% (95% CI, 0.2-41.3%) in 11 evaluable patients during the first trial stage. The single responder achieved a red cell transfusion independence and stable disease was reported in nine additional patients (81.8%). Eight patients underwent a short-lasting improvement of splenomegaly. In conclusion, plitidepsin 5 mg/m(2) 3-h infusion q4wk was well tolerated but had a modest activity in patients with primary, post-polycythaemia vera or post-essential thrombocythaemia MF. Therefore, this trial was prematurely terminated and we concluded that further clinical trials with plitidepsin as single agent in MF are not warranted.
Topics: Aged; Cell Proliferation; Depsipeptides; Female; Humans; Janus Kinase 2; Male; Middle Aged; Peptides, Cyclic; Polycythemia Vera; Primary Myelofibrosis; Splenomegaly; Thrombocythemia, Essential
PubMed: 25768401
DOI: 10.1038/bcj.2015.5 -
British Journal of Cancer Sep 2013This phase I-II trial compared plitidepsin 1-h infusion alone or combined with dacarbazine (DTIC) 1-h infusion as front-line therapy for advanced melanoma. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This phase I-II trial compared plitidepsin 1-h infusion alone or combined with dacarbazine (DTIC) 1-h infusion as front-line therapy for advanced melanoma.
METHODS
The recommended dose (RD) for plitidepsin/DTIC was defined in the first stage. In the second stage, patients were randomised to receive single-agent plitidepsin 3.2 mg m(-2) (n = 20) on days 1, 8 and 15 every 4 weeks (q4wk) or plitidepsin 2.4 mg m(-2) on days 1, 8 and 15 q4wk combined with DTIC 800 mg m(-2) q4wk (n = 38).
RESULTS
The overall response rate with plitidepsin/DTIC was 21.4%; all responders had normal serum lactate dehydrogenase (LDH) levels and performance status ≤ 1 at baseline. Median progression-free survival (PFS) with plitidepsin/DTIC was 3.3 months in all patients, and 4.3 months in those with baseline normal LDH. No responses occurred with single-agent plitidepsin and median PFS was 1.5 months. Both regimens were well tolerated. Haematological abnormalities were more common and transaminase increases more severe with plitidepsin/DTIC. Treatment-related transaminase increases leading to infusion omission on day 8 were relatively common. No drug-drug pharmacokinetic interactions were found.
CONCLUSION
This plitidepsin/DTIC schedule has antitumour activity and manageable toxicity in advanced melanoma. Further evaluation of plitidepsin 2.4 mg m(-2) fortnightly and DTIC 800 mg m(-2) q4wk is recommended.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Depsipeptides; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Melanoma; Middle Aged; Peptides, Cyclic; Treatment Outcome; Young Adult
PubMed: 23989947
DOI: 10.1038/bjc.2013.477 -
Anti-cancer Drugs Mar 2017This phase I trial evaluated the combination of the marine-derived cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine in advanced cancer...
This phase I trial evaluated the combination of the marine-derived cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine in advanced cancer and lymphoma patients. The study included two treatment arms: a sorafenib/plitidepsin (S/P) and a gemcitabine/plitidepsin (G/P) arm. In the S/P arm, patients were treated orally with sorafenib continuous dosing at two dose levels (DL1: 200 mg twice daily and DL2: 400 mg twice daily) combined with plitidepsin (1.8 mg/m, day 1, day 8, day 15, and, q4wk, intravenously). In the G/P arm, patients with solid tumors or lymphoma were treated at four different DLs with a combination of gemcitabine (DL1: 750 mg/m, DL2-DL4: 1000 mg/m) and plitidepsin (DL1-DL2: 1.8 mg/m; DL3: 2.4 mg/m; DL4: 3 mg/m). Both agents were administered intravenously on day 1, day 8, day 15, and, q4wk. Forty-four patients were evaluable for safety and toxicity. The safety of the combination of plitidepsin with sorafenib or gemcitabine was manageable. Most adverse events (AEs) were mild; no grade 4 treatment-related AEs were reported in any of the groups (except for one grade 4 thrombocytopenia in the gemcitabine arm). The most frequently reported study drug-related (or of unknown relationship) AEs were palmar-plantar erythrodysesthesia, erythema, nausea, vomiting, and fatigue in the S/P arm and nausea, fatigue, and vomiting in the G/P arm. In the S/P arm, one dose-limiting toxicity occurred in two out of six patients treated at the maximum dose tested (DL2): palmar-plantar erythrodysesthesia and grade 2 aspartate aminotransferase/alanine aminotransferase increase that resulted in omission of days 8 and 15 plitidepsin infusions. In the G/P arm, one dose-limiting toxicity occurred in two out of six patients at DL4: grade 2 alanine aminotransferase increase resulted in omission of days 8 and 15 plitidepsin infusions and grade 4 thrombocytopenia. The recommended dose for the combination of plitidepsin with sorafenib was not defined because of a sponsor decision (no expansion cohort to confirm) and for plitidepsin with gemcitabine, it was 2.4 mg/m plitidepsin with 1000 mg/m gemcitabine. In the S/P group, objective disease responses were not observed; however, disease stabilization (≥3months) was observed in four patients. In the gemcitabine group, two lymphoma patients showed an objective response (partial response and complete response) and nine patients showed disease stabilization (≥3months). Combining plitidepsin with gemcitabine and sorafenib is feasible for advanced cancer patients; some objective responses were observed in heavily pretreated lymphoma patients.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Depsipeptides; Dose-Response Relationship, Drug; Female; Humans; Lymphoma; Male; Middle Aged; Neoplasms; Niacinamide; Peptides, Cyclic; Phenylurea Compounds; Prospective Studies; Sorafenib; Young Adult; Gemcitabine
PubMed: 27977433
DOI: 10.1097/CAD.0000000000000457 -
Frontiers in Pharmacology 2021There is an urgent need to identify therapeutics for the treatment of Coronavirus disease 2019 (COVID-19). Although different antivirals are given for the clinical...
There is an urgent need to identify therapeutics for the treatment of Coronavirus disease 2019 (COVID-19). Although different antivirals are given for the clinical management of SARS-CoV-2 infection, their efficacy is still under evaluation. Here, we have screened existing drugs approved for human use in a variety of diseases, to compare how they counteract SARS-CoV-2-induced cytopathic effect and viral replication Among the potential 72 antivirals tested herein that were previously proposed to inhibit SARS-CoV-2 infection, only 18 % had an IC below 25 µM or 10 IU/ml. These included plitidepsin, novel cathepsin inhibitors, nelfinavir mesylate hydrate, interferon 2-alpha, interferon-gamma, fenofibrate, camostat along the well-known remdesivir and chloroquine derivatives. Plitidepsin was the only clinically approved drug displaying nanomolar efficacy. Four of these families, including novel cathepsin inhibitors, blocked viral entry in a cell-type specific manner. Since the most effective antivirals usually combine therapies that tackle the virus at different steps of infection, we also assessed several drug combinations. Although no particular synergy was found, inhibitory combinations did not reduce their antiviral activity. Thus, these combinations could decrease the potential emergence of resistant viruses. Antivirals prioritized herein identify novel compounds and their mode of action, while independently replicating the activity of a reduced proportion of drugs which are mostly approved for clinical use. Combinations of these drugs should be tested in animal models to inform the design of fast track clinical trials.
PubMed: 33841165
DOI: 10.3389/fphar.2021.646676 -
Oncotarget Apr 2019Despite recent progress in its treatment, Multiple Myeloma (MM) remains incurable and its associated bone disease persists even after complete remission. Thus,...
Despite recent progress in its treatment, Multiple Myeloma (MM) remains incurable and its associated bone disease persists even after complete remission. Thus, identification of new therapeutic agents that simultaneously suppress MM growth and protect bone is an unmet need. Herein, we examined the effects of Aplidin, a novel anti-cancer marine-derived compound, on MM and bone cells. In vitro, Aplidin potently inhibited MM cell growth and induced apoptosis, effects that were enhanced by dexamethasone (Dex) and bortezomib (Btz). Aplidin modestly reduced osteocyte/osteoblast viability and decreased osteoblast mineralization, effects that were enhanced by Dex and partially prevented by Btz. Further, Aplidin markedly decreased osteoclast precursor numbers and differentiation, and reduced mature osteoclast number and resorption activity. Moreover, Aplidin reduced Dex-induced osteoclast differentiation and further decreased osteoclast number when combined with Btz. Lastly, Aplidin alone, or suboptimal doses of Aplidin combined with Dex or Btz, decreased tumor growth and bone resorption in bone organ cultures that reproduce the 3D-organization and the cellular diversity of the MM/bone marrow niche. These results demonstrate that Aplidin has potent anti-myeloma and anti-resorptive properties, and enhances proteasome inhibitors blockade of MM growth and bone destruction.
PubMed: 31105871
DOI: 10.18632/oncotarget.26831 -
Cancer Chemotherapy and Pharmacology Jun 2009To characterize the population pharmacokinetics of plitidepsin (Aplidin) in cancer patients. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To characterize the population pharmacokinetics of plitidepsin (Aplidin) in cancer patients.
METHODS
A total of 283 patients (552 cycles) receiving intravenous plitidepsin as monotherapy at doses ranging from 0.13 to 8.0 mg/m(2) and given as 1- or 24-h infusions every week; 3- or 24-h infusion biweekly; or 1-h infusion daily for 5 consecutive days every 21 days were included in the analysis. An open three-compartment pharmacokinetic model and a nonlinear binding to red blood cells model were used to describe the plitidepsin pharmacokinetics in plasma and blood, respectively, using NONMEM V software. The effect of selected covariates on plitidepsin pharmacokinetics was investigated. Model evaluation was performed using goodness-of-fit plots, posterior predictive check and bootstrap.
RESULTS
Plasma clearance and its between subject variability (%) was 13.6 l/h (71). Volume of distribution at steady-state was calculated to be 4791 l (59). The parameters B (max) and C (50) of the non-linear blood distribution were 471 microg/l (56) and 41.6 microg/l, respectively. Within the range of covariates studied, age, sex, body size variables, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, creatinine clearance, albumin, total protein, performance status, co-administration of inhibitors or inducers of CYP3A4 and presence of liver metastases were not statistically related to plitidepsin pharmacokinetic parameters. Bootstrap and posterior predictive check evidenced the model was deemed appropriate to describe the time course of plitidepsin blood and plasma concentrations in cancer patients.
CONCLUSIONS
The integration of phase I/II pharmacokinetic data demonstrated plitidepsin linear elimination from plasma, dose-proportionality up to 8.0 mg/m(2), and time-independent pharmacokinetics. The distribution to red blood cells can be considered linear at doses lower than 5 mg/m(2) administered as 3-h or longer infusion. No clinically relevant covariates were identified as predictors of plitidepsin pharmacokinetics.
Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cytochrome P-450 CYP3A; Depsipeptides; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Models, Biological; Neoplasms; Nonlinear Dynamics; Peptides, Cyclic; Time Factors; Tissue Distribution; Young Adult
PubMed: 18941750
DOI: 10.1007/s00280-008-0841-4 -
Marine Drugs May 2013Plitidepsin is an antitumor drug of marine origin currently in Phase III clinical trials in multiple myeloma. In cultured cells, plitidepsin induces cell cycle arrest or...
Plitidepsin is an antitumor drug of marine origin currently in Phase III clinical trials in multiple myeloma. In cultured cells, plitidepsin induces cell cycle arrest or an acute apoptotic process in which sustained activation of c-Jun N-terminal kinase (JNK) plays a crucial role. With a view to optimizing clinical use of plitidepsin, we have therefore evaluated the possibility of using JNK activation as an in vivo biomarker of response. In this study, we show that administration of a single plitidepsin dose to mice xenografted with human cancer cells does indeed lead to increased phosphorylation of JNK in tumors at 4 to 12 h. By contrast, no changes were found in other in vitro plitidepsin targets such as the levels of phosphorylated-ERK, -p38MAPK or the protein p27KIP1. Interestingly, plitidepsin also increased JNK phosphorylation in spleens from xenografted mice showing similar kinetics to those seen in tumors, thereby suggesting that normal tissues might be useful for predicting drug activity. Furthermore, plitidepsin administration to rats at plasma concentrations comparable to those achievable in patients also increased JNK phosphorylation in peripheral mononuclear blood cells. These findings suggest that changes in JNK activity provide a reliable biomarker for plitidepsin activity and this could be useful for designing clinical trials and maximizing the efficacy of plitidepsin.
Topics: Animals; Antineoplastic Agents; Biomarkers; Cell Line, Tumor; Depsipeptides; Female; Humans; JNK Mitogen-Activated Protein Kinases; K562 Cells; Leukemia; Leukocytes, Mononuclear; Male; Mice; Mice, Nude; Peptides, Cyclic; Phosphorylation; Rats; Rats, Sprague-Dawley; Spleen; Time Factors; Xenograft Model Antitumor Assays
PubMed: 23697951
DOI: 10.3390/md11051677 -
International Journal of Pharmaceutics Apr 2015The focus of this study is to disclose a new delivery carrier intended to improve the pharmacokinetic characteristics of the anticancer drug plitidepsin and to favor its...
The focus of this study is to disclose a new delivery carrier intended to improve the pharmacokinetic characteristics of the anticancer drug plitidepsin and to favor its accumulation within the tumor. These nanocarriers named as nanocapsules, consist of an oily core surrounded by a highly PEGylated polyglutamic acid (PGA-PEG) shell loaded with plitidepsin. They showed a size of around 190 nm, a zeta potential of -24 mV and were able to encapsulate a high percentage (85%) of plitidepsin. In vivo studies, following intravenous injection in healthy mice, indicated that the encapsulation of the drug within PGA-PEG nanocapsules led to an important increase in its area under the curve (AUC) which is related to the important decrease of the clearance, as compared to the values observed for the drug dissolved in a Cremophor(®) EL solution. This improvement of the pharmacokinetic profile of the encapsulated plitidepsin was accompanied by a high increase (2.5-fold) of the maximum tolerated dose (MTD) in comparison to that of plitidepsin Cremophor(®) EL solution. The efficacy study performed in a xenograft tumor mice model evidenced the capacity of PGA-PEG nanocapsules to significantly reduce tumor growth. These promising results highlight the potential of PGA-PEG nanocapsules as an effective drug delivery system for cancer therapy.
Topics: Animals; Antineoplastic Agents; Cell Proliferation; Depsipeptides; Drug Carriers; Drug Delivery Systems; Female; Humans; Injections, Intravenous; Male; Maximum Tolerated Dose; Mice; Mice, Nude; Nanocapsules; Neoplasms, Experimental; Particle Size; Peptides, Cyclic; Polyethylene Glycols; Polyglutamic Acid; Surface Properties; Xenograft Model Antitumor Assays
PubMed: 25681727
DOI: 10.1016/j.ijpharm.2015.02.028 -
Frontiers in Pharmacology 2022The devastating COVID-19 pandemic has caused more than six million deaths worldwide during the last 2 years. Effective therapeutic agents are greatly needed, yet... (Review)
Review
The devastating COVID-19 pandemic has caused more than six million deaths worldwide during the last 2 years. Effective therapeutic agents are greatly needed, yet promising magic bullets still do not exist. Numerous natural products (cordycepin, gallinamide A, plitidepsin, telocinobufagin, and tylophorine) have been widely studied and play a potential function in treating COVID-19. In this paper, we reviewed published studies (from May 2021 to April 2022) relating closely to bioactive natural products (isolated from medicinal plants, animals products, and marine organisms) in COVID-19 therapy to provide some essential guidance for anti-SARS-CoV-2 drug research and development.
PubMed: 36059994
DOI: 10.3389/fphar.2022.926507 -
Journal of Chemotherapy (Florence,... Nov 2009Plitidepsin (Aplidin) is a novel antitumor agent, derived from the mediterranean tunicate Aplidium albicans, and is currently in phase ii clinical trials with evidence...
Plitidepsin (Aplidin) is a novel antitumor agent, derived from the mediterranean tunicate Aplidium albicans, and is currently in phase ii clinical trials with evidence of activity in heavily pretreated multiple myeloma, renal cell carcinoma, melanoma and neuroblastoma patients. As compared to its parental compound didemnin B, plitidepsin has shown a better therapeutic index with less bone marrow toxicity, cardiotoxicity and neurotoxicity in patients and a more potent cytotoxic effect in several tumor cell lines. As sensitivity to the drug varies between cell lines and fresh leukemia samples, we performed studies on transport of plitidepsin in leukemia and lymphoma cell lines to determine the mechanism of uptake. The drug is taken up by an active transport process, i.e. the process is temperature and energy dependent, and has a high-affinity binding site with Kt =212 nM and Vmax = 15 pmoles/min. Importantly, once inside the cell, efflux of plitidepsin is minimum, suggesting that the drug is bound to intracellular macromolecules. Further work showed that plitidepsin binds to G-Protein Coupled Receptors (GPCRs), since GPCR and GRK (GPCR kinases) inhibitors suramin and heparin respectively, markedly reduce the drug uptake and its cytotoxic activity. Signaling via Jak/Stat pathway is inhibited by pharmacological concentrations of plitidepsin, further confirming the relationship between plitidepsin and GPCRs.
Topics: 4-Aminopyridine; Adenosine Triphosphate; Antimetabolites, Antineoplastic; Biological Transport, Active; Cell Proliferation; Cytarabine; Depsipeptides; Heparin; Humans; JNK Mitogen-Activated Protein Kinases; Membrane Microdomains; Peptides, Cyclic; Potassium Channel Blockers; Potassium Channels; Receptors, G-Protein-Coupled; STAT Transcription Factors; Subcellular Fractions; Suramin; Time Factors; Tumor Cells, Cultured
PubMed: 19933047
DOI: 10.1179/joc.2009.21.5.550