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Anti-cancer Drugs Mar 2015Cyclic depsipeptides are polypeptides in which one or more amino acid is replaced by a hydroxy acid, resulting in the formation of at least one ester bond in the core... (Review)
Review
Cyclic depsipeptides are polypeptides in which one or more amino acid is replaced by a hydroxy acid, resulting in the formation of at least one ester bond in the core ring structure. Many natural cyclic depsipeptides possessing intriguing structural and biological properties, including antitumor, antifungal, antiviral, antibacterial, anthelmintic, and anti-inflammatory activities, have been identified from fungi, plants, and marine organisms. In particular, the potent effects of cyclic depsipeptides on tumor cells have led to a number of clinical trials evaluating their potential as chemotherapeutic agents. Although many of the trials have not achieved the desired results, romidepsin (FK228), a bicyclic depsipeptide that inhibits histone deacetylase, has been shown to have clinical efficacy in patients with refractory cutaneous T-cell lymphoma and has received Food and Drug Administration approval for use in treatment. In this review, we discuss antitumor cyclic depsipeptides that have undergone clinical trials and focus on their structural features, mechanisms, potential applications in chemotherapy, and pharmacokinetic and toxicity data. The results of this study indicate that cyclic depsipeptides could be a rich source of new cancer therapeutics.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Depsipeptides; Histone Deacetylase Inhibitors; Humans; Lactams; Lactones; Lymphoma, T-Cell, Cutaneous; Peptides, Cyclic
PubMed: 25419631
DOI: 10.1097/CAD.0000000000000183 -
Cancer Chemotherapy and Pharmacology Sep 2018Plitidepsin absorption, distribution, metabolism and excretion characteristics were investigated in a mass balance study, in which six patients received a 3-h...
PURPOSE
Plitidepsin absorption, distribution, metabolism and excretion characteristics were investigated in a mass balance study, in which six patients received a 3-h intravenous infusion containing 7 mg C-plitidepsin with a maximum radioactivity of 100 µCi.
METHODS
Blood samples were drawn and excreta were collected until less than 1% of the administered radioactivity was excreted per matrix for two consecutive days. Samples were pooled within-patients and between-patients and samples were screened for metabolites. Afterwards, metabolites were identified and quantified. Analysis was done using Liquid Chromatography linked to an Ion Trap Mass Spectrometer and offline Liquid Scintillation Counting (LC-Ion Trap MS-LSC).
RESULTS
On average 4.5 and 62.4% of the administered dose was excreted via urine over the first 24 h and in faeces over 240 h, respectively. Most metabolites were found in faeces.
CONCLUSION
Plitidepsin is extensively metabolised and it undergoes dealkylation (demethylation), oxidation, carbonyl reduction, and (internal) hydrolysis. The chemical formula of several metabolites was confirmed using high resolution mass data.
Topics: Carbon Radioisotopes; Chromatography, Liquid; Clinical Trials, Phase I as Topic; Depsipeptides; Feces; Humans; Neoplasms; Peptides, Cyclic; Tandem Mass Spectrometry
PubMed: 29974200
DOI: 10.1007/s00280-018-3637-1 -
Infectious Diseases (London, England) Jul 2024To study the effect of plitidepsin antiviral treatment in immunocompromised COVID-19 patients with underlying haematological malignancies or solid tumours, particularly... (Observational Study)
Observational Study
Outcomes and clinical characteristics of the compassionate use of plitidepsin in COVID-19 patients with solid tumours, haematological malignancies or anti-CD20 antibody treatment.
OBJECTIVE
To study the effect of plitidepsin antiviral treatment in immunocompromised COVID-19 patients with underlying haematological malignancies or solid tumours, particularly those who have undergone anti-CD20 therapies.
DESIGN
We conducted a retrospective observational study, involving 54 adults treated with plitidepsin on compassionate use as an antiviral drug. Our analysis compared outcomes between patients with solid tumours and those with haematological malignancies, and a cohort of cases treated or not with anti-CD20 monoclonal antibodies.
RESULTS
Patients with a history of anti-CD20 therapies showed a prolonged time-to-negative RT-PCR for SARS-CoV-2 infection compared to non-treated patients (33 d (28;75) vs 15 (11;25); = .002). Similar results were observed in patients with solid tumours in comparison to those with haematological malignancies (13 (10;16) vs 26 (17;50); < .001). No serious adverse events were documented.
CONCLUSIONS
Patients with haematological malignancies appear to be at a heightened risk for delayed SARS-CoV-2 clearance and subsequent clinical complications. These findings support plitidepsin as a well-tolerated treatment in this high-risk group. A phase II clinical trial (NCT05705167) is ongoing to evaluate plitidepsin as an antiviral drug in this population.KEY POINTSHaematological patients face an increased risk for severe COVID-19.Anti-CD20 therapies could increase fatal outcomes in COVID-19 patients.Persistent viral replication is increased in immunocompromised patients.Plitidepsin does not lead to new serious adverse events in immunocompromised patients.
Topics: Humans; Male; Female; Retrospective Studies; Middle Aged; Hematologic Neoplasms; Aged; Depsipeptides; Neoplasms; COVID-19 Drug Treatment; Peptides, Cyclic; SARS-CoV-2; COVID-19; Antiviral Agents; Treatment Outcome; Adult; Compassionate Use Trials; Immunocompromised Host; Antigens, CD20; Aged, 80 and over
PubMed: 38743059
DOI: 10.1080/23744235.2024.2351043 -
Lung Cancer (Amsterdam, Netherlands) Apr 2009To evaluate the antitumor activity and safety profile of plitidepsin administered as a 1h weekly intravenous (i.v.) infusion of 3.2mg/m(2) to patients with small cell...
OBJECTIVE
To evaluate the antitumor activity and safety profile of plitidepsin administered as a 1h weekly intravenous (i.v.) infusion of 3.2mg/m(2) to patients with small cell lung cancer (SCLC) who relapsed or progressed after one line of chemotherapy.
PATIENTS AND METHODS
This was a multicenter, open-label, single-arm, exploratory, phase II clinical trial. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. Objective response rate (primary efficacy endpoint) was evaluated according to response evaluation criteria in solid tumors (RECIST). The rate of stable disease (SD) lasting for at least 6 months and time-to-event variables were secondary endpoints of efficacy. Toxicity was assessed using National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0.
RESULTS
Twenty pretreated SCLC patients (median age, 60 years) with extensive (n = 13) or limited-stage disease (n = 7) received a total of 24 treatment cycles (median, one cycle per patient; range, 1-2). Objective tumor responses were not observed and only one of the 17 evaluable patients had SD. With a median follow-up of 11.8 months, the progression-free survival and the median overall survival were 1.3 months and 4.8 months, respectively. The most troubling or common toxicities were fatigue, muscle weakness, lymphopenia, anemia (no patients showed neutropenia), and asymptomatic, non-cumulative increase of transaminases levels and alkaline phosphatase.
CONCLUSION
This clinical trial shows that a cycle of 1h weekly i.v. infusion of plitidepsin (3.2mg/m(2)) was generally well tolerated other than fatigue and muscle weakness in patients with pretreated SCLC. One patient died due to multi-organ failure. The absence of antitumor activity found here precludes further studies of this plitidepsin schedule as second-line single-agent treatment of SCLC.
Topics: Adrenal Gland Neoplasms; Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Depsipeptides; Female; Humans; Infusions, Intravenous; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Peptides, Cyclic; Prognosis; Salvage Therapy; Skin Neoplasms; Small Cell Lung Carcinoma; Survival Rate; Treatment Outcome
PubMed: 18692272
DOI: 10.1016/j.lungcan.2008.06.017 -
Turkish Journal of Medical Sciences Dec 2021Currently there is not an effective antiviral treatment for COVID-19, but a large number of drugs have been evaluated since the beginning of the pandemic, and many of... (Review)
Review
BACKGROUND/AIM
Currently there is not an effective antiviral treatment for COVID-19, but a large number of drugs have been evaluated since the beginning of the pandemic, and many of them have been used for the treatment of COVID-19 despite the preliminary or conflicting results of the clinical trials. We aimed to review and summarize all of the current knowledge on the antivirals for COVID-19
RESULTS
There are 2 main drug groups for SARS-CoV-2: agents that target proteins or RNA of the virus or interfere with proteins or biological processes in the host that support the virus. The main drug groups include inhibitors of viral entry into the human cell (convalescent plasma, monoclonal antibodies, nanobodies, mini proteins, human soluble ACE-2, camostat, dutasteride, proxalutamide, bromhexin, hydroxychloroquine, umifenovir nitazoxanid, niclosamide, lactoferrin), inhibitors of viral proteases (lopinavir/ritonavir, PF-07321332, PF-07304814, GC376), inhibitors of viral RNA (remdesivir, favipiravir, molnupiravir, AT-527, merimepodib, PTC299), inhibitors of host proteins supporting virus (plitidepsin, fluvoxamine, ivermectin), and agents supporting host natural immunity (Interferons).
CONCLUSION
When taking into account the results of all the available laboratory and clinical trials on the subject, monoclonal antibodies seem to be the most effective treatment for COVID-19 at the moment, and high-titer convalescent plasma also could be effective when administered during the early phase of the disease. As lopinavir/ritonavir, hydroxychloroquine, merimepodib, and umifenovir were found to be ineffective in RCTs, they should not be used. Additional studies are needed to define the role of remdesivir, favipiravir, interferons, ivermectin, dutasteride, proxulutamide, fluvoxamine, bromhexine, nitazoxanide, and niclosamid in the treatment of COVID-19. Finally, the results of phase trials are waited to learn whether or not the newer agents such as molnupiravir, PF-07321332, PF-07304814, plitidepsin and AT-527 are effective in the treatment of COVID-19.
Topics: Antiviral Agents; COVID-19; Humans; Immunization, Passive; Pandemics; SARS-CoV-2; COVID-19 Serotherapy; COVID-19 Drug Treatment
PubMed: 34391321
DOI: 10.3906/sag-2106-250 -
Marine Drugs 2009This randomized phase II study evaluated two schedules of the marine compound Plitidepsin with or without co-administration of L-carnitine in patients with renal cell... (Randomized Controlled Trial)
Randomized Controlled Trial
This randomized phase II study evaluated two schedules of the marine compound Plitidepsin with or without co-administration of L-carnitine in patients with renal cell carcinoma. Patients had adequate performance status and organ function. The primary endpoint was the rate of disease control (no progression) at 12 weeks (RECIST). Other endpoints included the response rate and time dependent efficacy measures. The trial also assessed the efficacy of L-carnitine to prevent Plitidepsin-related toxicity. The two regimes given as 24 hour infusion every two weeks showed hints of antitumoral activity. Disease control at 12 weeks was 15.8% in Arm A (5mg/m2, no L-carnitine) and 11,1% in Arm B (7 mg/m2 with L-carnitine). Two partial responses were observed in Arm A (19 patients), none in Arm B (20 patients). Both schedules had the same progression-free interval (2.1 months). The median overall survival was 7.0 and 7.6 months. The safety profile was similar in both arms of the trial and adverse events were mainly mild to moderate (NCI CTC version 2.0). Increasing the dose to 7 mg/m2 did not increase the treatment efficacy but the incidence of transaminase and CPK elevations and serious AEs. Coadministration of L-carnitine did not prevent muscular toxicity or CPK-elevation associated with Plitidepsin.
Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Carnitine; Creatine Kinase; Depsipeptides; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Kidney Neoplasms; Male; Middle Aged; Peptides, Cyclic; Transaminases
PubMed: 19370171
DOI: 10.3390/md7010057 -
Science (New York, N.Y.) Feb 2021
Topics: Depsipeptides; Host-Pathogen Interactions; Humans; Peptides, Cyclic; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33632832
DOI: 10.1126/science.abg6837 -
Lung Cancer (Amsterdam, Netherlands) Jun 2008To evaluate the progression-free rate (PFR) at 3 months (13+/-1 weeks), antitumor response, time-to-event efficacy endpoints, and toxicity profile of plitidepsin...
OBJECTIVE
To evaluate the progression-free rate (PFR) at 3 months (13+/-1 weeks), antitumor response, time-to-event efficacy endpoints, and toxicity profile of plitidepsin administered as a 3-h continuous i.v. infusion at a dose of 5mg/m(2), every 2 weeks, to patients with chemotherapy pretreated advanced non-small cell lung cancer (NSCLC).
PATIENTS AND METHODS
This was a multicenter, non-randomized, exploratory, phase II study. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. PFR (primary efficacy endpoint) and objective response rate (secondary efficacy endpoint) were evaluated according to RECIST, while the toxic profile of plitidepsin was assessed using the NCI-CTC, version 2.0.
RESULTS
A total of 21 patients with a median age of 61 years and with locally advanced or metastatic non-resectable NSCLC, who had previously received only one line of chemotherapy in an advanced setting, received a total of 54 cycles of treatment (median of two cycles per patient; range: 1-8). Antitumor activity was seen in 3 (1 PR, 2 SD) out of 17 evaluable patients according to RECIST. One patient was responder for the primary (PFR at 13+/-1 weeks) and secondary efficacy endpoint (stable disease according to RECIST). Other two patients were non-responders for the primary efficacy endpoint, but had stable disease (not confirmed at weeks 13+/-1 due to previous withdrawal due to adverse events). With a median follow-up of 12.3 months, the median time to progression (TTP) and the median overall survival (OS) were 1.2 months and 4.3 months, respectively. The incidence of plitidepsin-related toxicities was low and most of them were mild-to-moderate in severity. The most common side effects were anemia, and asymptomatic and non-cumulative increases of gamma-glutamyltransferase (GGT) and liver transaminase levels.
CONCLUSION
This study shows that plitidepsin 3-h continuous i.v. infusion (5mg/m(2)) every 2 weeks, was feasible and well tolerated in patients with pretreated NSCLC. The lack of evidence of antitumor activity precludes further studies with this plitidepsin schedule in this tumor setting.
Topics: Adult; Aged; Anemia; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Depsipeptides; Disease Progression; Disease-Free Survival; Female; Humans; Infusions, Intravenous; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Peptides, Cyclic; Transaminases; Urochordata; gamma-Glutamyltransferase
PubMed: 18054408
DOI: 10.1016/j.lungcan.2007.10.019 -
Journal of Biomedical Nanotechnology Nov 2015Encapsulating chemotherapy drugs in targeted nanodelivery systems is one of the most promising approaches to tackle cancer disease, avoiding side effects of common...
Encapsulating chemotherapy drugs in targeted nanodelivery systems is one of the most promising approaches to tackle cancer disease, avoiding side effects of common treatment. In the last decade, several nanocarriers with different nature have been tested, but polypeptide-based copolymers have attracted considerable attention for their biocompatibility, controlled and slow biodegradability as well as their low toxicity. In this work, we synthesized, characterized and evaluated poly(trimethylene carbonate)-bock-poly(L-glutamic acid) derived polymersomes, targeted to epidermal growth factor receptor (EGFR), loaded with plitidepsin and ultimately tested in HT29 and LS174T colorectal cancer cell lines for specificity and efficacy. Furthermore, morphology, physico-chemical properties and plitidepsin loading were carefully investigated. A thorough in vitro cytotoxicity analysis of the unloaded polymersomes was carried out for biocompatibility check, studying viability, cell membrane asymmetry and reactive oxygen species levels. Those cytotoxicity assays showed good biocompatibility for plitidepsin-unloaded polymersomes. Cellular uptake and cytotoxic effect of EGFR targeted and plitidepsin loaded polymersome indicated that colorectal cancer cell lines were.more sensitive to anti-EGFR-drug-loaded than untargeted drug-loaded polymersomes. Also, in both cell lines, the use of untargeted polymersomes greatly reduced plitidepsin cytotoxicity as well as the cellular uptake, indicating that the use of this targeted nanocarrier is a promising approach to tackle colorectal cancer disease and avoid the undesired effects of the usual treatment. Furthermore, in vivo assays support the in vitro conclusions that EGFR targeted polymersomes could be a good drug delivery system. This work provides a proof of concept for the use of encapsulated targeted drugs as future therapeutic treatments for cancer.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Depsipeptides; Dioxanes; Drug Carriers; ErbB Receptors; Female; HT29 Cells; Humans; Mice; Mice, Nude; Necrosis; Peptides, Cyclic; Polyglutamic Acid; Polymers; Xenograft Model Antitumor Assays
PubMed: 26554161
DOI: 10.1166/jbn.2015.2148 -
Chemical Reviews Aug 2013
Review
Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Aquatic Organisms; Aza Compounds; Carbazoles; Chemistry, Pharmaceutical; Depsipeptides; Furans; Humans; Indoles; Naphthyridines; Peptides, Cyclic; Phosphoinositide-3 Kinase Inhibitors; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Pyrimidines; Staurosporine; Terpenes
PubMed: 23679846
DOI: 10.1021/cr300410v