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Pediatric Blood & Cancer Sep 2009Aplidin was tested in vitro at concentrations ranging from from 0.1 nM to 1.0 microM and in vivo at a dose of 0.6 mg/kg administered intraperitoneally on an every 4 days...
Aplidin was tested in vitro at concentrations ranging from from 0.1 nM to 1.0 microM and in vivo at a dose of 0.6 mg/kg administered intraperitoneally on an every 4 days x 3-schedule that was repeated at day 21. In vitro, Aplidin was most active against acute lymphoblastic leukemia (ALL) cell lines. In vivo, Aplidin induced significant differences in EFS distribution in 12 of 28 (43%) solid tumor models and 2 of 6 evaluable ALL models. Aplidin showed potent in vitro activity and induced significant in vivo tumor growth inhibition in some xenografts, but did not induce tumor regressions.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Depsipeptides; Female; Humans; Mice; Mice, Inbred BALB C; Mice, SCID; Peptides, Cyclic; Xenograft Model Antitumor Assays
PubMed: 19418543
DOI: 10.1002/pbc.21976 -
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 -
British Journal of Cancer Jun 2008Aplidin is an antitumour drug, currently undergoing phase II evaluation in different haematological and solid tumours. In this study, we analysed the antimyeloma effects...
Aplidin is an antitumour drug, currently undergoing phase II evaluation in different haematological and solid tumours. In this study, we analysed the antimyeloma effects of Aplidin in the syngeneic 5T33MM model, which is representable for the human disease. In vitro, Aplidin inhibited 5T33MMvv DNA synthesis with an IC(50) of 3.87 nM. On cell-cycle progression, the drug induced an arrest in transition from G0/G1 to S phase, while Western blot showed a decreased cyclin D1 and CDK4 expression. Furthermore, Aplidin induced apoptosis by lowering the mitochondrial membrane potential, by inducing cytochrome c release and by activating caspase-9 and caspase-3. For the in vivo experiment, 5T33MM-injected C57Bl/KaLwRij mice were intraperitoneally treated with vehicle or Aplidin (90 microg kg(-1) daily). Chronic treatment with Aplidin was well tolerated and reduced serum paraprotein concentration by 42% (P<0.001), while BM invasion with myeloma cells was decreased by 35% (P<0.001). Aplidin also reduced the myeloma-associated angiogenesis to basal values. This antiangiogenic effect was confirmed in vitro and explained by inhibition of endothelial cell proliferation and vessel formation. These data indicate that Aplidin is well tolerated in vivo and its antitumour and antiangiogenic effects support the use of the drug in multiple myeloma.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Blotting, Western; Cell Cycle; DNA Replication; Depsipeptides; Disease Models, Animal; Mice; Mice, Inbred C57BL; Multiple Myeloma; Peptides, Cyclic; Rats
PubMed: 18521088
DOI: 10.1038/sj.bjc.6604388 -
Annals of Oncology : Official Journal... Sep 2006Aplidine is a cyclic depsipeptide isolated from the marine tunicate Aplidium albicans.
Phase I study of Aplidine in a dailyx5 one-hour infusion every 3 weeks in patients with solid tumors refractory to standard therapy. A National Cancer Institute of Canada Clinical Trials Group study: NCIC CTG IND 115.
BACKGROUND
Aplidine is a cyclic depsipeptide isolated from the marine tunicate Aplidium albicans.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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
PubMed: 16966366
DOI: 10.1093/annonc/mdl165 -
Annals of Oncology : Official Journal... Sep 2006
Topics: Antineoplastic Agents; Clinical Trials as Topic; Depsipeptides; Dose-Response Relationship, Drug; Drug Design; Humans; Maximum Tolerated Dose; Neoplasms; Neuromuscular Diseases; Peptides, Cyclic
PubMed: 16966365
DOI: 10.1093/annonc/mdl325 -
Annals of Oncology : Official Journal... Oct 2005Aplidine (APL) is a marine depsipeptide isolated from the Mediterranean tunicate Aplidium albicans that is under clinical phase II development. In contrast to the lack...
BACKGROUND
Aplidine (APL) is a marine depsipeptide isolated from the Mediterranean tunicate Aplidium albicans that is under clinical phase II development. In contrast to the lack of bone marrow toxicity reported in phase I/II studies, it has been shown to induce cytotoxicity at very low concentration against lymphoblastic leukemia blast, as well as having an impact in the vascular endothelial growth factor (VEGF)/VEGF receptor 1 loop.
PATIENTS AND METHODS
To confirm these findings we investigated APL-related VEGF inhibition and its cytotoxic effect on myeloid leukemic cells lines (K-562, HEL and HL60) and fresh leukemia blasts derived from 30 patients with acute myeloid leukemia (AML). The conventional active 4-demetoxi-daunorubicin (idarubicin; IDA) was included as a positive control.
RESULTS
APL was found to be significantly (P<0.001) more active than IDA in obtaining 50% growth-inhibition in K-562, HEL and HL60 cell lines. Results obtained with AML blast cells were super imposible. ID(50) ranged from 0.024 to 0.610 microM for IDA (0.200+/-0.176) and from 0.001 to 0.108 microM for APL (0.020+/-0.031). Annexin V tests and cell cycle analysis performed on cell lines confirmed the stronger citotoxic capability of APL as apoptotic inducer and as a G(1) blocker. The inhibitory effects of APL on VEGF release and secretion have been confirmed by ELISA tests performed on HEL: the VEGF concentration in cell surnatant was reduced from 169 to 36 pg/ml after 24 h of exposure to a pharmacological concentration of APL.
CONCLUSIONS
APL harbors a strong in vitro antileukemic activity at a concentration achievable in patients at non-myelotoxic doses. Our data also support the notion of an impact on VEGF secretion. Clinical studies with this new marine-derived compound in relapsed/resistant leukemia are underway.
Topics: Acute Disease; Apoptosis; Cell Cycle; Depsipeptides; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme-Linked Immunosorbent Assay; HL-60 Cells; Humans; Leukemia, Myeloid; Peptides, Cyclic; Vascular Endothelial Growth Factor A
PubMed: 16014640
DOI: 10.1093/annonc/mdi311 -
The Journal of Biological Chemistry Mar 2005While investigating the mechanism of action of the novel antitumor drug Aplidin, we have discovered a potent and novel cell-killing mechanism that involves the formation...
While investigating the mechanism of action of the novel antitumor drug Aplidin, we have discovered a potent and novel cell-killing mechanism that involves the formation of Fas/CD95-driven scaffolds in membrane raft clusters housing death receptors and apoptosis-related molecules. Fas, tumor necrosis factor-receptor 1, and tumor necrosis factor-related apoptosis-inducing ligand receptor 2/death receptor 5 were clustered into lipid rafts in leukemic Jurkat cells following Aplidin treatment, the presence of Fas being essential for apoptosis. Preformed membrane-bound Fas ligand (FasL) as well as downstream signaling molecules, including Fas-associated death domain-containing protein, procaspase-8, procaspase-10, c-Jun amino-terminal kinase, and Bid, were also translocated into lipid rafts, connecting death receptor extrinsic and mitochondrial intrinsic apoptotic pathways. Blocking Fas/FasL interaction partially inhibited Aplidin-induced apoptosis. Aplidin was rapidly incorporated into membrane rafts, and drug uptake was inhibited by lipid raft disruption. Actin-linking proteins ezrin, moesin, RhoA, and RhoGDI were conveyed into Fas-enriched rafts in drug-treated leukemic cells. Disruption of lipid rafts and interference with actin cytoskeleton prevented Fas clustering and apoptosis. Thus, Aplidin-induced apoptosis involves Fas activation in both a FasL-independent way and, following Fas/FasL interaction, an autocrine way through the concentration of Fas, membrane-bound FasL, and signaling molecules in membrane rafts. These data indicate a major role of actin cytoskeleton in the formation of Fas caps and highlight the crucial role of the clusters of apoptotic signaling molecule-enriched rafts in apoptosis, acting as concentrators of death receptors and downstream signaling molecules and as the linchpin from which a potent death signal is launched.
Topics: Actins; Antineoplastic Agents; Apoptosis; Cytoskeleton; Depsipeptides; Fas Ligand Protein; Humans; Jurkat Cells; Membrane Glycoproteins; Membrane Microdomains; Peptides, Cyclic; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; fas Receptor
PubMed: 15659383
DOI: 10.1074/jbc.M411781200 -
British Journal of Cancer Oct 2004Aplidin (APL) is a new antitumoral drug from marine origin currently in phase II clinical trials against a wide multiplicity of cancers. As resistance may be, as with...
Aplidin (APL) is a new antitumoral drug from marine origin currently in phase II clinical trials against a wide multiplicity of cancers. As resistance may be, as with other drugs, an important obstacle to the APL therapeutic efficacy, we have established an acquired resistance cellular model by continuous exposure of HeLa cells to the drug. The stably resistant subline generated (HeLa-APL), possessing more than 1000-fold relative resistance to APL than parental cells, did not show crossresistance to a subset of clinically relevant antitumoral agents. In addition, resistance was not related to overexpression of P-glycoprotein or differences in overall drug accumulation. Comparing to parental cells, HeLa-APL cells did not present either significant differences in the growth rate or apparent alterations in the cell cycle distribution. Aplidin induced rapid and persistent phosphorylation of both JNK and p38 MAPKs, resulting in activation of the mitochondrial apoptotic pathway in parental cells, but, notably, in HeLa-APL-resistant cells MAPKs activation only occurred in a slight and transiently manner, failing to activate the above-mentioned apoptotic machinery. These results suggest that sustained activation of JNK and p38 is essential for triggering the apoptotic programme induced by APL and that HeLa-APL cells bypass this apoptotic response by preventing the specific mechanisms that prime and sustain the long-term activation of these signalling cascades. Although far from human tumour physiology in vivo, HeLa-APL cells represent a potentially useful tool in gaining insights into the mode of action of APL, in selecting non-crossresistant APL structural analogues, as well as in investigating and developing methods to prevent resistance to this drug.
Topics: Apoptosis; Blotting, Western; Carcinoma; Cell Survival; Depsipeptides; Drug Resistance, Neoplasm; Flow Cytometry; HeLa Cells; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Peptides, Cyclic; Phosphorylation; p38 Mitogen-Activated Protein Kinases
PubMed: 15365569
DOI: 10.1038/sj.bjc.6602166 -
British Journal of Cancer Jun 2004The antineoplastic compound aplidine, a new marine-derived depsipeptide, has shown preclinical activity in vitro on haematological and solid tumour cell lines. It is...
The antineoplastic compound aplidine, a new marine-derived depsipeptide, has shown preclinical activity in vitro on haematological and solid tumour cell lines. It is currently in early phase clinical trials. The exact mechanism of action of this anticancer agent still needs to be clarified. We have previously reported that aplidine blocks the secretion of the angiogenic factor vascular endothelial growth factor (VEGF) by the human leukaemia cells MOLT-4, suggesting a possible effect on tumour angiogenesis. This study was designed to investigate the antiangiogenic effect of aplidine. In vivo, in the chick embryo allantoic membrane (CAM) assay, aplidine inhibited spontaneous angiogenesis, angiogenesis elicited by exogenous VEGF and FGF-2, and induced by VEGF overexpressing 1A9 ovarian carcinoma cells. In vitro, at concentrations achievable in the plasma of patients, aplidine inhibited endothelial cell functions related to angiogenesis. It affected VEGF- and FGF-2-induced endothelial cell proliferation, inhibited cell migration and invasiveness assessed in the Boyden chamber and blocked the production of matrix metalloproteinases (MMP-2 and MMP-9) by endothelial cells. Finally, aplidine prevented the formation of capillary-like structures by endothelial cells on Matrigel. These findings indicate that aplidine has antiangiogenic activity in vivo and inhibits endothelial cell functional responses to angiogenic stimuli in vitro. This effect might contribute to the antineoplastic activity of aplidine.
Topics: Angiogenesis Inhibitors; Animals; Biological Assay; Capillaries; Cell Culture Techniques; Chick Embryo; Depsipeptides; Endothelial Cells; Humans; Matrix Metalloproteinases; Neovascularization, Pathologic; Peptides, Cyclic; Umbilical Veins
PubMed: 15173857
DOI: 10.1038/sj.bjc.6601864 -
Experimental Hematology Nov 2003In addition to neutropenias and/or thrombocytopenias as a short-term effect, antineoplastics also can produce long-term effects as a consequence of damage to the...
OBJECTIVE
In addition to neutropenias and/or thrombocytopenias as a short-term effect, antineoplastics also can produce long-term effects as a consequence of damage to the hematopoietic stem cells. The aim of the present study was to evaluate the toxicity of three marine-derived antineoplastics on murine hematopoietic stem cells. These antitumoral compounds currently are being evaluated in patients in phase II (aplidin and kahalalide F) and phase II/III (trabectedin) clinical trials.
MATERIALS AND METHODS
Long-term competitive repopulating assays were performed in mice to analyze toxic effects on the hematopoietic stem cells responsible for the multipotential long-term repopulation of hematopoiesis. Furthermore, granulocytic and T- and B-lymphoid lineages were studied, as well as myeloid (CFU-GM) and megakaryocytic (CFU-Meg) progenitors.
RESULTS
When cells were treated in vitro for 24 hours with CFU-GM IC(50) dose of trabectedin (9.59+/-4.96 nM), no significant effects were observed in the stem cells. The dose of trabectedin that produced 90% of inhibition in CFU-GM (IC(90): 23.71+/-1.27 nM) only inhibited 45% survival of stem cells. Doses of aplidin that produced reductions of 50% (56.9+/-13.32 nM) or 90% (195.88+/-21.39 nM) in myeloid progenitors did not show any effect on hematopoietic stem cells. Kahalalide F did not show any toxic effect in either short-term or long-term repopulating cells up to 10 microM.
CONCLUSIONS
Our data show that the hematopoietic stem cells effects of antitumoral drugs can be properly characterized by the murine competitive repopulating assays. Our results suggest that long-term myelosuppression as a consequence of trabectedin, aplidin, or kahalalide F treatment would not be expected.
Topics: Animals; Antineoplastic Agents; Cell Survival; Depsipeptides; Dioxoles; Hematopoietic Stem Cells; Isoquinolines; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Peptides; Peptides, Cyclic; Tetrahydroisoquinolines; Trabectedin
PubMed: 14585376
DOI: No ID Found