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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 -
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 Treatment Reviews Oct 2014Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on... (Review)
Review
Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on historical regimens for aggressive B-cell lymphomas, have resulted in insufficient patient outcomes. The majority of patients relapse rapidly, and current 5-year overall survival rates are only 10-30%. It is evident that new approaches to treat patients with PTCL are required. In recent years, prospective studies in PTCL have been initiated, mainly in patients with relapsed/refractory disease. In some of these, selected histologic subtypes have been evaluated in detail. As a consequence, numerous new therapies have been developed and shown activity in PTCL, including: agents targeting the immune system (e.g. brentuximab vedotin, alemtuzumab, lenalidomide); histone deacetylase inhibitors (romidepsin, belinostat); antifolates (pralatrexate); fusion proteins (denileukin diftitox); nucleoside analogs (pentostatin, gemcitabine); and other agents (e.g. alisertib, plitidepsin, bendamustine, bortezomib). A variety of interesting novel combinations is also emerging. It is hoped that these innovative approaches, coupled with a greater understanding of the clinicopathologic features, pathogenesis, molecular biology, and natural history of PTCL will advance the field and improve outcomes in this challenging group of diseases. This review summarizes the currently available clinical evidence on the various approaches to treating relapsed/refractory PTCL, including the role of stem cell transplantation, with an emphasis on potential new drug therapies.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Cyclophosphamide; Depsipeptides; Diphtheria Toxin; Doxorubicin; Folic Acid Antagonists; Histone Deacetylase Inhibitors; Humans; Immunoconjugates; Interleukin-2; Lenalidomide; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Peptides, Cyclic; Prednisolone; Recombinant Fusion Proteins; Stem Cell Transplantation; Thalidomide; Topoisomerase Inhibitors; Vincristine
PubMed: 25199959
DOI: 10.1016/j.ctrv.2014.08.001 -
Marine Drugs Jan 2014The prevailing paradigm states that cancer cells acquire multiple genetic mutations in oncogenes or tumor suppressor genes whose respective activation/up-regulation or... (Review)
Review
The prevailing paradigm states that cancer cells acquire multiple genetic mutations in oncogenes or tumor suppressor genes whose respective activation/up-regulation or loss of function serve to impart aberrant properties, such as hyperproliferation or inhibition of cell death. However, a tumor is now considered as an organ-like structure, a complex system composed of multiple cell types (e.g., tumor cells, inflammatory cells, endothelial cells, fibroblasts, etc.) all embedded in an inflammatory stroma. All these components influence each other in a complex and dynamic cross-talk, leading to tumor cell survival and progression. As the microenvironment has such a crucial role in tumor pathophysiology, it represents an attractive target for cancer therapy. In this review, we describe the mechanism of action of trabectedin and plitidepsin as an example of how these specific drugs of marine origin elicit their antitumor activity not only by targeting tumor cells but also the tumor microenvironment.
Topics: Animals; Antineoplastic Agents; Aquatic Organisms; Cell Death; Cell Survival; Depsipeptides; Dioxoles; Disease Progression; Humans; Molecular Targeted Therapy; Neoplasms; Peptides, Cyclic; Tetrahydroisoquinolines; Trabectedin; Tumor Microenvironment
PubMed: 24473171
DOI: 10.3390/md12020719 -
Pharmaceutical Research Apr 2014Plitidepsin is an antineoplasic currently in clinical evaluation in a phase III trial in multiple myeloma (ADMYRE). Presently, the hydrophobic drug plitidepsin is...
PURPOSE
Plitidepsin is an antineoplasic currently in clinical evaluation in a phase III trial in multiple myeloma (ADMYRE). Presently, the hydrophobic drug plitidepsin is formulated using Cremophor®, an adjuvant associated with unwanted hypersensitivity reactions. In search of alternatives, we developed and tested two nanoparticle-based formulations of plitidepsin, aiming to modify/improve drug biodistribution and efficacy.
METHODS
Using nanoprecipitation, plitidepsin was loaded in polymer nanoparticles made of amphiphilic block copolymers (i.e. PEG-b-PBLG or PTMC-b-PGA). The pharmacokinetics, biodistribution and therapeutic efficacy was assessed using a xenograft renal cancer mouse model (MRI-H-121 xenograft) upon administration of the different plitidepsin formulations at maximum tolerated multiple doses (0.20 and 0.25 mg/kg for Cremophor® and copolymer formulations, respectively).
RESULTS
High plitidepsin loading efficiencies were obtained for both copolymer formulations. Considering pharmacokinetics, PEG-b-PBLG formulation showed lower plasma clearance, associated with higher AUC and Cmax than Cremophor® or PTMC-b-PGA formulations. Additionally, the PEG-b-PBLG formulation presented lower liver and kidney accumulation compared with the other two formulations, associated with an equivalent tumor distribution. Regarding the anticancer activity, all formulations elicited similar efficacy profiles, as compared to the Cremophor® formulation, successfully reducing tumor growth rate.
CONCLUSIONS
Although the nanoparticle formulations present equivalent anticancer activity, compared to the Cremophor® formulation, they show improved biodistribution profiles, presenting novel tools for future plitidepsin-based therapies.
Topics: Animals; Depsipeptides; Drug Carriers; Female; Kidney Neoplasms; Mice; Mice, Nude; Nanoparticles; Peptides, Cyclic; Tissue Distribution; Treatment Outcome; Xenograft Model Antitumor Assays
PubMed: 24287622
DOI: 10.1007/s11095-013-1220-3 -
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 -
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 -
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 -
Journal of Controlled Release :... Jul 2013A critical objective in cancer therapy is to reduce the systemic toxicity through the modification of the biodistribution of anticancer drugs. Herein, we disclose a new...
A critical objective in cancer therapy is to reduce the systemic toxicity through the modification of the biodistribution of anticancer drugs. Herein, we disclose a new biodegradable nanocarrier, polyglutamic acid (PGA) nanocapsules, and present the in vivo pharmacokinetics/toxicity proof-of-concept for the anticancer drug plitidepsin. These novel nanocapsules were prepared using a modified solvent displacement technique where the polyamino acid was electrostatically deposited onto the lipid core. The nanocapsules exhibited an average size of 200 nm, a negative zeta potential and a great capacity for the encapsulation of plitidepsin (encapsulation efficiency above 90%). In addition, the nanocapsules could be freeze-dried and showed an adequate stability profile upon storage. Finally, the in vivo proof-of-concept studies performed in mice indicated that the encapsulation provided the drug with a prolonged blood circulation and a significantly reduced toxicity. In fact, the maximum tolerated dose of the nanoencapsulated drug was more than 3 times that of the reference formulation (Cremophor® EL plitidepsin solution). Overall, beyond the value of this specific formulation, the work reported here represents the evidence of the potential of polyamino acid nanocapsules in nano-oncological therapy.
Topics: Animals; Antineoplastic Agents; Depsipeptides; Male; Mice; Models, Molecular; Nanocapsules; Peptides, Cyclic; Polyglutamic Acid
PubMed: 23591661
DOI: 10.1016/j.jconrel.2013.03.037 -
Haematologica Mar 2013This phase II clinical trial evaluated the efficacy, safety and pharmacokinetics of plitidepsin 3.2 mg/m(2) administered as a 1-hour intravenous infusion weekly on days...
This phase II clinical trial evaluated the efficacy, safety and pharmacokinetics of plitidepsin 3.2 mg/m(2) administered as a 1-hour intravenous infusion weekly on days 1, 8 and 15 every 4 weeks in 67 adult patients with relapsed/refractory aggressive non-Hodgkin's lymphoma. Patients were divided into two cohorts: those with non-cutaneous peripheral T-cell lymphoma (n=34) and those with other lymphomas (n=33). Efficacy was evaluated using the International Working Group criteria (1999). Of the 29 evaluable patients with non-cutaneous peripheral T-cell lymphoma, six had a response (overall response rate 20.7%; 95% confidence interval, 8.0%-39.7%), including two complete responses and four partial responses. No responses occurred in the 30 evaluable patients with other lymphomas (including 27 B-cell lymphomas). The most common plitidepsin-related adverse events were nausea, fatigue and myalgia (grade 3 in <10% of cases). Severe laboratory abnormalities (lymphopenia, anemia, thrombocytopenia, and increased levels of transaminase and creatine phosphokinase) were transient and easily managed by plitidepsin dose adjustments. The pharmacokinetic profile did not differ from that previously reported in patients with solid tumors. In conclusion, plitidepsin monotherapy has clinical activity in relapsed/refractory T-cell lymphomas. Combinations of plitidepsin with other chemotherapeutic drugs deserve further evaluation in patients with non-cutaneous peripheral T-cell lymphoma. (clinicaltrials.gov identifier: NCT00884286).
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Depsipeptides; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Peptides, Cyclic; Recurrence; Treatment Outcome; Tumor Burden; Young Adult
PubMed: 23065525
DOI: 10.3324/haematol.2012.069757