plitidepsin and Neoplasms

Among the diseases that afflict the human population, cancer is one for which many drug treatments are not yet known or effective. Moreover, the pharmacological treatments used often create serious side effects in sick patients and for this reason, it is essential to find effective and less harmful treatments. To date, marine biodiversity is a real source of metabolites with antitumoral activity and among invertebrates' ascidians have been the main source to obtain them. Mediterranean area is the richest in biodiversity and contains several ascidian species used in drugs development during the years. However, many more Mediterranean ascidian species have not been studied and could be a source of useful bioactive compounds. This review aims to summarize the scientific studies that analyzed the antitumor compounds obtained from different Mediterranean ascidians species, encouraging them to search further compounds in other new species to improve pharmacological treatments and human population life.

Topics: Animals; Antineoplastic Agents; Biological Products; Depsipeptides; Humans; Mediterranean Sea; Neoplasms; Peptides, Cyclic; Trabectedin; Urochordata

Plitidepsin is a cyclic depsipeptide that was first isolated from a Mediterranean marine tunicate (

Topics: Animals; Antineoplastic Agents, Phytogenic; Depsipeptides; Drug Design; Humans; Neoplasms; Peptides, Cyclic

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

Natural cyclopeptides are hot spots in chemical and pharmaceutical fields because of the wide spreading bio-resources, complex molecular structures and various bioactivities. Bio-producers of cyclopeptides distribute over almost every kingdom from bacteria to plants and animals. Many cyclopeptides contain non-coded amino acids and non-pepditic bonds. Most exciting characteristic of cyclopeptides is a range of interesting bioactivities such as antibiotics gramicidin-S (2), vancomycin (3) and daptomycin (4), immunosuppressive cyclosporin-A (1) and astin-C (8), and anti-tumor aplidine (5), RA-V (6) and RA-VII (7). Compounds 1-4 are being used in clinics; compounds 5-8 are in the stages of clinical trial or as a candidate for drug research. In this review, the progress in chemical and bioactive studies on these important natural bioactive cyclopeptides 1-8 are introduced, mainly including discovery, bioactivity, mechanism, QSAR and synthesis.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Cyclosporine; Daptomycin; Depsipeptides; Gramicidin; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Molecular Structure; Neoplasms; Peptides, Cyclic; Quantitative Structure-Activity Relationship; Vancomycin

To characterize the population pharmacokinetics of plitidepsin (Aplidin) in cancer patients.. 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.. 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.. 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

The marine ecosystem that has contributed to the discovery of cytarabine and its fluorinated derivative gemcitabine is now considered the most productive toll to acquire new natural derived anticancer entities. Few marine anticancer agents have entered clinical development, including bryostatin-1, dolastatin 10, LU103793, ET-743, kahalalide F, didemnin B and aplidine. The marine plitidepsin aplidine derived from the mediterranean tunicate Aplidium albicans is a synthetically produced anticancer agent that is structurally related to didemnins. Aplidine's mechanism of action involves several pathways, including cell cycle arrest, inhibition of protein synthesis and antiangiogenic activity. Phase I studies have been reported for a number of several schedules including 1-hour, 3-hour and 24-hour infusion. Evidences of antitumor activity and clinical benefit of aplidine in several tumor types were noted across phase I trials, particularly in advanced medullar thyroid carcinoma. Phase II studies are underway. Within the entire phase I program, dose-limiting toxicities of aplidine were neuromuscular toxicity, asthenia, skin toxicity, and diarrhea. Interestingly, no hematological toxicity was observed. Aplidine displayed a very peculiar delayed neuromuscular toxicity that was found to be closely related to the symptoms described in the adult form of carnitine palmitoyl transferase deficiency type 2, which is a genetic disease treated with L-carnitine. Consistently, concomitant administration of L-carnitine allowed to improve aplidine-induce neuromuscular toxicity. In summary, aplidine is a novel marine anticancer agent with a very particular delayed neuromuscular toxicity that requires careful follow-up with promising antitumor activity.

Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Depsipeptides; Humans; Marine Toxins; Neoplasms; Neuromuscular Diseases; Peptides, Cyclic

Naturally derived anticancer agents continue to be instrumental in the systemic therapeutic intervention against solid tumors and hematological malignancies. Such compounds now have a relevant role in contemporary models of combination with targeted agents, thus providing a rationale to consider nature as a valid tool to discover new innovative anticancer agents. The marine ecosystem has increasingly been the focus of interest for new discoveries in the field that are expected to be of significant therapeutic impact in cancer patients. A critical review of the integrated data generated in our marine-derived anticancer program seems to confirm such expentancies. ET-743 (Yondelis) represents the first new agent developed against advanced pretreated soft tissue sarcoma in the past 25 years, and also harbors activity in women bearing pretreated ovarian cancer and a solid potential in combination therapy. The lack of cumulative toxicities makes this compound suitable for long-lasting therapies, reversible transaminitis being the most prevalent toxicity. Aplidin has shown a positive therapeutic index in phase I trials and phase II studies are ongoing. In contrast to the lack of bone marrow toxicity, a set of translational results anticipates a potential in leukemia. Kahalalide F has also successfully completed the phase I program in solid tumors with evidence of activity in resistant tumors and phase II studies are under way. Finally, the mechanistic data generated in parallel with the clinical program confirms the potential of the marine ecosystem in the discovery of new agents acting against new cellular targets of relevance in cancer cell biology.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Chemistry, Pharmaceutical; Clinical Trials as Topic; Depsipeptides; Dioxoles; Humans; Isoquinolines; Marine Biology; Neoplasms; Peptides; Peptides, Cyclic; Tetrahydroisoquinolines; Trabectedin

Aplidin is a cell cycle inhibitor being developed by PharmaMar SA for the potential treatment of a variety of cancers, including non-Hodgkin's lymphoma (NHL), non-small-cell lung cancer (NSCLC), acute lymphoblastic leukemia (ALL), neuroendocrine, prostate, gastric and colorectal cancers [390131], [464778].

Topics: Animals; Cell Cycle; Clinical Trials as Topic; Depsipeptides; Growth Inhibitors; Humans; Neoplasms; Peptides, Cyclic; Technology, Pharmaceutical

The marine environment offers a rich source of natural products with potential therapeutic application. Marine organisms have evolved the enzymatic capability to produce potent chemical entities that make them promising sources of innovative cytotoxic compounds. Prominent in the identification and development of novel anti-cancer agents from marine sources is the Spanish biotechnology company, Pharma Mar, which currently has a large number of oncology products in late preclinical and clinical development. These include: Ecteinascidin-743 (ET-743), Aplidin, Kahalalide F and ES-285. Many of these innovative compounds have novel mechanisms of anti-tumor action that have yet to be fully elucidated.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Depsipeptides; Dioxoles; Female; Humans; Isoquinolines; Male; Marine Biology; Mollusca; Neoplasms; Peptides; Peptides, Cyclic; Porifera; Survival Analysis; Tetrahydroisoquinolines; Trabectedin; Urochordata

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 gemcitabin

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Depsipeptides; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Lymphoma; Male; Middle Aged; Neoplasms; Niacinamide; Peptides, Cyclic; Phenylurea Compounds; Prospective Studies; Sorafenib; Young Adult

Plitidepsin (Aplidin®) is a marine-derived anticancer compound currently investigated in phase III clinical trials. This article describes the distribution, metabolism and excretion of this novel agent and it mainly aims to identify the major routes of elimination. Six subjects were enrolled in a mass balance study during which radiolabelled plitidepsin was administered as a 3-h intravenous infusion. Blood samples were taken and urine and faeces were collected. Total radioactivity (TRA) analysis using Liquid Scintillation Counting (LSC) was done to determine the amount of radioactivity excreted from the body and plitidepsin concentrations in whole blood, plasma and urine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. In total, a mean of 77.4% of the administered radioactivity was excreted over a time period of 20 days, of which 71.3% was recovered in faeces and 6.1% was found in urine. The majority excreted in urine was accounted for by unchanged plitidepsin, with only 1.5% of the total administered dose explained by metabolites in urine. Faeces, on the other hand contained low levels of parent compound, which means that most of the TRA excreted in faeces was accounted for by metabolites. TRA levels were 3.7 times higher in whole blood compared to plasma. Plitidepsin was widely distributed and plasma clearance was low. This study shows that red blood cells are a major distribution compartment and that the biliary route is the main route of total radioactivity excretion.

Topics: Administration, Oral; Aged; Carbon Radioisotopes; Depsipeptides; Feces; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Peptides, Cyclic; Tissue Distribution

This phase I trial evaluated the toxicity profile and maximum tolerated dose of the combination between the marine derived cyclodepsipeptide plitidepsin and bevacizumab in advanced cancer patients. Thirteen patients were enrolled and treated with plitidepsin at three dose levels (2.8 mg/m, n=3; 3.8 mg/m, n=4; and 4.8 mg/m, n=6) with a fixed dose of bevacizumab (10 mg/kg). Both agents were administered intravenously at D1 and D15 of a 28-day cycle. All 13 patients were evaluable for safety and toxicity. Dose-limiting toxicities occurred in two out of six patients treated at the maximum dose tested (plitidepsin 4.8 mg/m and bevacizumab 10 mg/kg) and consisted of grade 3 fatigue, grade 3 myalgia, and two grade 2/3 alanine aminotransferase increases lasting for more than 7 days or leading to subsequent cycle delay greater than 2 weeks (n=1 each). The recommended dose for the combination of plitidepsin with bevacizumab was 3.8 mg/m for plitidepsin and 10 mg/kg for bevacizumab every 2 weeks. Most frequent treatment-related adverse events were nausea, vomiting, fatigue, epistaxis, and headache. Relevant hematological toxicity was minimal. Objective disease responses were not observed; however, stable disease (>3 months) was observed in four patients with colorectal cancer, renal cancer, and cervical cancer. Combining plitidepsin with bevacizumab combination is feasible. Stable disease was the best response obtained.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Colorectal Neoplasms; Depsipeptides; Dose-Response Relationship, Drug; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasms; Peptides, Cyclic; Prospective Studies; Uterine Cervical Neoplasms

To determine the maximum tolerated dose, the recommended dose (RD) for phase II studies, dose-limiting toxicities and pharmacokinetics (PK) for plitidepsin administered as a 3-h intravenous infusion every 2weeks (one cycle) to children with refractory or relapsed solid tumours.. Consecutive cohorts of patients were treated according to a standard '3+3' design with escalating doses of plitidepsin at 4, 5 and 6mg/m(2). Additional 15 patients were recruited at the RD to further evaluate safety and pharmacokinetic associations with respect to age, dose level and toxicity.. Thirty-eight of 41 patients registered received plitidepsin. Dose-limiting toxicities during the first three treatment cycles related to myalgia, elevated creatine phosphokinase, transaminase increase and nausea/vomiting. The RD for plitidepsin is 5mg/m(2). PK analyses revealed high inter-patient variability in plasma, but a similar clearance of plitidepsin in children and adolescents. One partial response confirmed at 4weeks in a patient with neuroblastoma and one unconfirmed partial response in a pancreatoblastoma were observed; four other patients with neuroblastoma, medulloblastoma, glioblastoma and rhabdoid tumour had disease stabilisations lasting ⩾3months.. Plitidepsin administered to children as a 3-h infusion every 2weeks is received with manageable toxicity for children with cancer, and the RD is 5mg/m(2). Pharmacokinetic parameters in children and adolescents are comparable to adults. Future phase II studies of plitidepsin are warranted, and our results suggest that plitidepsin could be appropriately developed in combination with other antitumour where myelosuppression is dose-limiting.

Topics: Adolescent; Antineoplastic Agents; Child; Child, Preschool; Cohort Studies; Depsipeptides; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infant; Infusions, Intravenous; Male; Maximum Tolerated Dose; Neoplasms; Peptides, Cyclic

This dose-escalating phase I clinical trial was designed to determine the recommended dose (RD) and to assess the safety and feasibility of weekly plitidepsin (1-hour i.v. infusion, Days 1, 8 and 15) combined with carboplatin (1-hour i.v. infusion, Day 1, after plitidepsin) in 4-week (q4wk) cycles given to patients with advanced solid tumors or lymphomas. Twenty patients were enrolled and evaluable for both safety and efficacy. The starting dose was plitidepsin 1.8 mg/m(2) and carboplatin area under the curve (AUC) = 5 min*mg/ml; dose escalation proceeded based on worst toxicity in the previous cohort. The maximum tolerated dose (MTD) was plitidepsin 3.0 mg/m(2) and carboplatin AUC = 5 min*mg/ml, with grade 3 transaminase increases as the most common dose-limiting toxicities (DLTs). The RD for phase II studies was plitidepsin 2.4 mg/m(2) and carboplatin AUC = 5 min*mg/ml, with fatigue, myalgia and nausea as the most common drug-related adverse events (AEs). No unexpected toxicity was seen. Twelve patients (60%), ten of whom were heavily pretreated (≥2 previous chemotherapy lines) showed stable disease (SD), with a median time to progression (TTP) of 4.4 months. In conclusion, plitidepsin 2.4 mg/m(2) and carboplatin AUC = 5 min*mg/ml is a safe dose for future phase II studies evaluating the use of this combination in cancer patients potentially sensitive to platinum-based therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; Depsipeptides; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Lymphoma; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Peptides, Cyclic; Treatment Outcome

Plitidepsin, given as a 1-hour weekly i.v. infusion for 3 consecutive weeks during a 4-week treatment cycle, was investigated in patients with solid tumors to determine the maximum tolerated dose and the recommended dose (RD) using this administration schedule.. Consecutive cohorts of patients with metastatic solid tumors or non-Hodgkin's lymphomas were to be treated at escalating doses of plitidepsin in a conventional phase I study including pharmacokinetic analyses of plitidepsin in plasma, whole blood, and blood cell pellets.. Forty-nine patients with solid tumors were enrolled, and 48 were treated with plitidepsin (doses from 0.133 to 3.6 mg/m2/week). Dose-limiting toxicities (defining 3.6 mg/m2/week as the maximum tolerated dose) included myalgia, increased creatine phosphokinase levels, and sustained grade 3/4 increases of hepatic enzyme levels. The RD was established at 3.2 mg/m2/week. The most common toxicities were fatigue, vomiting/nausea, anorexia, injection site reaction, and pain, mostly of mild or moderate severity. Muscular toxicity manifested by mild-moderate myalgia, weakness, and/or creatine phosphokinase elevations occurred in approximately 25% of patients and seemed to be dose related. Transient transaminase elevations were frequent but achieved grade 3 or 4 in only approximately 10% of patients. Plitidepsin lacked significant hematologic toxicity. No complete or partial tumor responses were observed; however, five patients had disease stabilization (including one patient with medullary thyroid carcinoma with an unconfirmed partial response and one patient with renal carcinoma with major tumor shrinkage in lung metastases). Pharmacokinetic results for the RD indicated a long plasma half-life give value (16.8 +/- 7.7 hour) and a high volume of distribution value (525.2 +/- 219.3 L).. The recommended dose for plitidepsin given as a weekly 1-hour schedule was 3.2 mg/m2/week. Muscular and liver toxicity were dose limiting at 3.6 mg/m2/week. Additional evaluation of this dose dense schedule is warranted.

Topics: Adult; Aged; Antineoplastic Agents; Depsipeptides; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Peptides, Cyclic

Aplidine is a cyclic depsipeptide isolated from the marine tunicate Aplidium albicans.. This phase I study of Aplidine given as a 1-hour i.v. infusion daily for 5 days every 3 weeks was conducted in patients with refractory solid tumors. Objectives were to define the dose limiting toxicities, the maximal tolerated dose, and the recommended phase II dose.. Thirty-seven patients were accrued on study. Doses ranged from 80 microg/m(2) to 1500 microg/m(2)/day. Eleven patients received more than three cycles of Aplidine. Dose-limiting toxicities occurred at 1500 microg/m(2) and 1350 microg/m(2)/day and consisted of nausea, vomiting, myalgia, fatigue, skin rash and diarrhea. Mild to moderate muscular pain and weakness was noted in patients treated with multiple cycles with no significant drug related neurotoxicity. Bone marrow toxicity was not observed. The recommended dose for phase II studies was 1200 microg/m(2) daily for 5 days, every 3 weeks. Pharmacokinetic studies performed during the first cycle demonstrated that therapeutic plasma levels of Aplidine are reachable well below the recommended dose. Nine patients with progressive disease at study entry had stable disease and two had minor responses, one in non-small cell lung cancer and one in colorectal cancer.. Aplidine given at a dose of 1200 microg/m(2) daily for 5 days, every 3 weeks is well tolerated with few severe adverse events. This schedule of Aplidine is under evaluation in phase II studies in hematological malignancies and solid tumors.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Canada; Depsipeptides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Infusion Pumps; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Peptides, Cyclic

To establish the safety, pharmacokinetic parameters, maximum-tolerated dose, and recommended dose of aplidine, a novel marine cyclodepsipeptide, in patients with advanced cancer.. Using a modified Fibonacci method, we performed a phase I and pharmacokinetic study of aplidine administered as a 24-hour intravenous infusion every 2 weeks.. Sixty-seven patients received aplidine at a dose ranging from 0.2 to 8 mg/m(2). Dose-limiting myotoxicity corresponding to grade 2 to 3 creatine phosphokinase elevation and grade 1 to 2 myalgia and muscle weakness occurred in two of six patients at 6 mg/m(2). No cardiac toxicity was observed. Electron microscopy analysis showed the disappearance of thick filaments of myosin. Grade 3 muscle toxicity occurred in three of 14 patients at the recommended dose of 5 mg/m(2) and seemed to be more readily reversible with oral carnitine (1 g/10 kg). Therefore, dose escalation was resumed using carnitine prophylactically, allowing an increase in the recommended dose to 7 mg/m(2). Other toxicities were nausea and vomiting, diarrhea, asthenia, and transaminase elevation with mild hematologic toxicity. Aplidine displayed a long half-life (21 to 44 hours), low clearance (45 to 49 L/h), and a high volume of distribution (1,036 to 1,124 L) with high interpatient variability in plasma, whereas in whole blood, clearance ranged from 3.0 to 6.2 L/h. Minor responses and prolonged tumor stabilizations were observed in patients with medullary thyroid carcinoma.. Muscle toxicity was dose limiting in this study. Recommended doses of aplidine were 5 and 7 mg/m(2) without and with carnitine, respectively. The role of carnitine will be further explored in phase II studies.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Carnitine; Depsipeptides; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Metabolic Clearance Rate; Middle Aged; Neoplasm Metastasis; Neoplasms; Peptides, Cyclic; Vitamin B Complex

To evaluate the compassionate use of plitidepsin as an antiviral treatment in hospitalized immunocompromised adult patients with moderate-to-severe COVID-19.. Retrospective observational study of data -collected from January 01, 2021 to April 30, 2022- from 35 immunocompromised adult patients with COVID-19 non-eligible for other available antiviral treatments. Main outcome measures were time to respiratory recovery (SpFi ≥ 315); COVID-19-related 30-day-cumulative mortality after first plitidepsin infusion; and time to undetectable levels of viral RNA.. Thirty-three patients receiving a full course of plitidepsin (2.5 mg [n = 29] or 1.5 mg [n = 4]) were included. Most (69.7%) had a malignant hematologic disease and 27.3% had solid tumors. A total of 111 infusions were administered with lack of relevant safety events. Median time from plitidepsin initiation to SpFi ≥315 was 8 days (95% confidence interval [CI], 7-19). Median time to first negative reverse transcription-polymerase chain reaction for SARS-CoV-2 (cycle threshold >36) was 17 days (95% CI 13-25). Mortality rate was 16.3% (95% CI 3-37.3).. These data support plitidepsin as a well-tolerated treatment that might have potential clinical and antiviral efficacy in COVID-19 immunocompromised patients.

Topics: Adult; Antiviral Agents; Compassionate Use Trials; COVID-19; Humans; Neoplasms; SARS-CoV-2

Topics: Antineoplastic Agents; COVID-19 Drug Treatment; Depsipeptides; Humans; Neoplasms; Peptides, Cyclic

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. 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).. 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.. 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

Aplidin (plitidespin) is a novel cyclic depsipeptide, currently in Phase II clinical trials for solid and hematologic malignancies. We examined the effects of oxygen on the cytotoxicity of Aplidin and the interactions between Aplidin and radiation. These factors will be important if Aplidin is used clinically in combination with radiotherapy.. Exponentially-growing EMT6 mouse mammary tumour cells in monolayer cultures were treated with Aplidin and 250 kV X-rays.. The cytotoxicity of Aplidin was not altered either by incubation in moderate hypoxia before and during a 24 h drug treatment or by incubation in severe hypoxia before and during a 2 h drug treatment. Treatment with Aplidin plus radiation produced cytotoxicities compatible with additive or supraadditive cytotoxicities. Cells treated with 1 microM Aplidin for 24 h then killed by 100 Gy of radiation were toxic to untreated cells co-cultured with them.. The cytotoxicity of Aplidin is independent of the oxygenation during treatment. Aplidin, or an active metabolite of Aplidin, is retained in the cells and later released as the radiation-sterilised cells die, producing a Bystander effect that kills neighbouring cells. This Bystander effect could affect the outcome of therapeutic regimens combining Aplidin and radiation.

Topics: Animals; Bystander Effect; Cell Hypoxia; Cell Line, Tumor; Depsipeptides; Mice; Neoplasms; Peptides, Cyclic; Radiation Tolerance

Aplidin (plitidepsin) is an antitumoral agent that induces apoptosis via Rac1-JNK activation. A proteomic approach using 2D-DIGE technology found 52 cytosolic and 39 membrane proteins differentially expressed in wild-type and Aplidin-resistant HeLa cells, of which 39 and 27 were identified by MALDI-TOF mass spectrometry and database interrogation. A number of proteins involved in apoptosis pathways were found to be deregulated. Alterations in Rab geranylgeranyltransferase, protein disulfide isomerase (PDI), cystathionine gamma-lyase, ezrin, and cyclophilin A (CypA) were confirmed by immunoblotting. Moreover, the role of PDI and CypA in Aplidin resistance was functionally confirmed by using the inhibitor bacitracin and overexpression, respectively. These deregulated proteins are candidates to mediate, at least partially, Aplidin action and might provide a route to the cells to escape the induction of apoptosis by this drug.

Topics: Antineoplastic Agents; Apoptosis Regulatory Proteins; Blotting, Western; Cell Membrane; Cytosol; Depsipeptides; Drug Resistance, Neoplasm; Echocardiography, Doppler; HeLa Cells; Humans; Neoplasm Proteins; Neoplasms; Peptides, Cyclic; Proteomics

Topics: Antineoplastic Agents; Clinical Trials as Topic; Depsipeptides; Dose-Response Relationship, Drug; Drug Design; Humans; Maximum Tolerated Dose; Neoplasms; Neuromuscular Diseases; Peptides, Cyclic

Topics: Depsipeptides; Drugs, Investigational; Humans; Neoplasms; Peptides, Cyclic

Ecteinascidine-743 (ET-743) and aplidine are two marine-derived antineoplastics currently in phase II development. With the aim of evaluating whether in vitro haematopoietic studies can predict the toxicity of these two drugs in patients, human bone marrow (BM) samples were incubated with these drugs under conditions which mimicked the administration exposures used in the clinics. As it was observed in different cancer cell lines, ET-743 was more toxic on an equimolar basis in human hematopoietic progenitors (inhibitory concentration reducing the viability to 50% after 24 h exposures; IC50(24h): 10-50 nM) compared with doxorubicin (IC50(24h) values: 280-460 nM), used as a control anticancer drug. In contrast to the high haematotoxic effects observed for ET-743, similar IC values were obtained for aplidine (IC50(24h): 150-530 nM) compared with doxorubicin. For both ET-743 and aplidine, the megakaryocytic progenitor was the most sensitive, compared with the other haematopoietic progenitors (IC50 values were 3- to 5-fold lower in the CFU-Megs compared with the CFU-GMs). The observation that the Cmax observed in patients treated with the aplidine maximum tolerated dose (MTD) (7.1 nM) was 21-75 fold lower than the IC50(24h) value observed for the different haematopoietic progenitors is highly consistent with the lack of haematotoxicity observed in patients treated with this drug. In the case of ET-743, differences between the Cmax value corresponding to the MTD (2.6 nM) and the in vitro IC50 values corresponding to the different progenitors were much lower (4-19-fold), also consistent with the haematotoxicity that was observed in patients treated at recommended doses (RDs) and MTDs. Although CFU-Megs were more sensitive than CFU-GM progenitors to ET-743 in vitro, clinical data showed that neutropenic events were more frequent than thrombocytopenic episodes. Aiming to further improve the predictive value of in vitro IC values corresponding to the different haematopoietic progenitors, additional refinement parameters derived from pharmacokinetic and animal studies are proposed.

Topics: Antineoplastic Agents; Bone Marrow Diseases; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Depsipeptides; Dioxoles; Doxorubicin; Drug Screening Assays, Antitumor; Hematopoietic Stem Cells; Humans; Inhibitory Concentration 50; Isoquinolines; Neoplasms; Peptides, Cyclic; Tetrahydroisoquinolines; Trabectedin; Tumor Cells, Cultured