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Jos H. Beijnen - One of the best experts on this subject based on the ideXlab platform.
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phase i clinical and pharmacokinetic study oF Kahalalide F in patients with advanced androgen reFractory prostate cancer
Clinical Cancer Research, 2005Co-Authors: Jeany M Rademakerlakhai, E. Stokvis, Jose Jimeno, Jos H. Beijnen, Luis Lopezlazaro, Simon Horenblas, Willem Meinhardt, Theo M. De Reijke, José Antonio Lopez Martin, Jan H.m. SchellensAbstract:Purpose: The purpose is to determine the maximum tolerated dose, proFile oF adverse events, and dose-limiting toxicity oF Kahalalide F (KF) in patients with androgen reFractory prostate cancer. Furthermore, the pharmacokinetics aFter KF administration and preliminary antitumor activity were evaluated. KF is a dehydroaminobutyric acid–containing peptide isolated From the marine herbivorous mollusk, Elysia ruFescens . Experimental Design: Adult patients with advanced or metastatic androgen reFractory prostate cancer received KF as an i.v. inFusion over 1 hour, during Five consecutive days every 3 weeks. The starting dose was 20 μg per m 2 per day. Clinical pharmacokinetics studies were done in all patients using noncompartmental analysis. Prostate-speciFic antigen levels were evaluated as a surrogate marker For activity against prostate cancer. Results: Thirty-two patients were treated at nine dose levels (20-930 μg per m 2 per day). The maximum tolerated dose on this schedule was 930 μg per m 2 per day. The dose-limiting toxicity was reversible and asymptomatic Common Toxicity Criteria grade 3 and 4 increases in transaminases. The recommended dose For phase II studies is 560 μg per m 2 per day. Pharmacokinetics analysis revealed dose linearity up to the recommended dose. ThereaFter, a more than proportional increase was observed. Elimination was rapid with a mean (SD) terminal halF-liFe ( t 1/2 ) oF 0.47 hour (0.11 hour). One patient at dose level 80 μg per m 2 per day had a partial response with a prostate-speciFic antigen decline by at least 50% For ≥4 weeks. Five patients showed stable disease. Conclusions: KF can be given saFely as a 1-hour i.v. inFusion during Five consecutive days at a dose oF 560 μg per m 2 per day once every 3 weeks.
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Phase I Clinical and Pharmacokinetic Study oF Kahalalide F in Patients with Advanced Androgen ReFractory Prostate Cancer
Clinical cancer research : an official journal of the American Association for Cancer Research, 2005Co-Authors: Jeany M. Rademaker-lakhai, E. Stokvis, Jose Jimeno, Luis Lopez-lazaro, Jos H. Beijnen, Simon Horenblas, Willem Meinhardt, Theo M. De Reijke, José Antonio Lopez Martin, Jan H.m. SchellensAbstract:The purpose is to determine the maximum tolerated dose, proFile oF adverse events, and dose-limiting toxicity oF Kahalalide F (KF) in patients with androgen reFractory prostate cancer. Furthermore, the pharmacokinetics aFter KF administration and preliminary antitumor activity were evaluated. KF is a dehydroaminobutyric acid-containing peptide isolated From the marine herbivorous mollusk, Elysia ruFescens. Adult patients with advanced or metastatic androgen reFractory prostate cancer received KF as an i.v. inFusion over 1 hour, during Five consecutive days every 3 weeks. The starting dose was 20 microg per m(2) per day. Clinical pharmacokinetics studies were done in all patients using noncompartmental analysis. Prostate-speciFic antigen levels were evaluated as a surrogate marker For activity against prostate cancer. Thirty-two patients were treated at nine dose levels (20-930 microg per m(2) per day). The maximum tolerated dose on this schedule was 930 microg per m(2) per day. The dose-limiting toxicity was reversible and asymptomatic Common Toxicity Criteria grade 3 and 4 increases in transaminases. The recommended dose For phase II studies is 560 microg per m(2) per day. Pharmacokinetics analysis revealed dose linearity up to the recommended dose. ThereaFter, a more than proportional increase was observed. Elimination was rapid with a mean (SD) terminal halF-liFe (t(1/2)) oF 0.47 hour (0.11 hour). One patient at dose level 80 microg per m(2) per day had a partial response with a prostate-speciFic antigen decline by at least 50% For > or =4 weeks. Five patients showed stable disease. KF can be given saFely as a 1-hour i.v. inFusion during Five consecutive days at a dose oF 560 microg per m(2) per day once every 3 weeks.
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Switching From an analogous to a stable isotopically labeled internal standard For the LC‐MS/MS quantitation oF the novel anticancer drug Kahalalide F significantly improves assay perFormance
Biomedical chromatography : BMC, 2004Co-Authors: E. Stokvis, Luis Lopez-lazaro, Hilde Rosing, J. H. M. Schellens, Jos H. BeijnenAbstract:The importance oF a stable isotopically labeled (SIL) internal standard For the quantitative LC-MS/MS assay For Kahalalide F in human plasma is highlighted. Similar results can be expected For other LC-MS/MS assays. ThereFore, we emphasize the need For an SIL internal standard For accurate and precise LC-MS/MS assays oF drugs in biological matrices.
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quantitative analysis oF the novel depsipeptide anticancer drug Kahalalide F in human plasma by high perFormance liquid chromatography under basic conditions coupled to electrospray ionization tandem mass spectrometry
Journal of Mass Spectrometry, 2002Co-Authors: E. Stokvis, Jos H. Beijnen, J Jimeno, Luis Lopezlazaro, Hilde Rosing, J. H. M. Schellens, I. Rodriguez, Jeffrey G. SupkoAbstract:Kahalalide F (KF) is a novel cyclic depsipeptide anticancer drug, which has shown anticancer activity both in vitro and in vivo especially against human prostate cancer cell lines. To characterize the pharmacokinetics oF KF during a phase I clinical trial in patients with androgen reFractory prostate cancer, a method was developed and validated For the quantitative analysis oF KF in human plasma using high-perFormance liquid chromatography (HPLC) coupled to positive electrospray ionization tandem mass spectrometry (ESI-MS/MS). Microbore reversed-phase liquid chromatography (LC) perFormed with mobile phases containing triFluoroacetic acid, an additive commonly used For separating peptides, resulted in substantial suppression oF the signal For KF on ESI-MS/MS. An alternative approach employing a basic mobile phase provided an excellent response For KF when detected in the positive ion mode. Plasma samples were prepared For LC MS/MS by solid-phase extraction on C18 cartridges. The LC separation was perFormed on a Zorbax Extend C18 column (150 × 2.1 mm i.d., particle size 5 µm) with acetonitrile –10 mM aqueous ammonia (85 : 15, v/v) as the mobile phase, at a Flow-rate oF 0.20 ml min−1. A butyric acid analogue oF KF was used as the internal standard. The lower limit oF quantitation (LLQ) using a 500 µl sample volume was 1 ng ml−1 and the linear dynamic range extended to 1000 ng ml−1. The inter-assay accuracy oF the assay was −15.1% at the LLQ and between −2.68 and −9.05% For quality control solutions ranging in concentration From 2.24 to 715 ng ml−1. The inter-assay precision was 9.91% or better at these concentrations. The analyte was stable in plasma under all relevant conditions evaluated and For a period oF 16 h aFter reconstituting plasma extracts For LC analysis at ambient temperature. Copyright © 2002 John Wiley & Sons, Ltd.
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Quantitative analysis oF the novel depsipeptide anticancer drug Kahalalide F in human plasma by high-perFormance liquid chromatography under basic conditions coupled to electrospray ionization tandem mass spectrometry.
Journal of mass spectrometry : JMS, 2002Co-Authors: E. Stokvis, Luis Lopez-lazaro, J Jimeno, Hilde Rosing, J. H. M. Schellens, I. Rodriguez, Jeffrey G. Supko, Jos H. BeijnenAbstract:Kahalalide F (KF) is a novel cyclic depsipeptide anticancer drug, which has shown anticancer activity both in vitro and in vivo especially against human prostate cancer cell lines. To characterize the pharmacokinetics oF KF during a phase I clinical trial in patients with androgen reFractory prostate cancer, a method was developed and validated For the quantitative analysis oF KF in human plasma using high-perFormance liquid chromatography (HPLC) coupled to positive electrospray ionization tandem mass spectrometry (ESI-MS/MS). Microbore reversed-phase liquid chromatography (LC) perFormed with mobile phases containing triFluoroacetic acid, an additive commonly used For separating peptides, resulted in substantial suppression oF the signal For KF on ESI-MS/MS. An alternative approach employing a basic mobile phase provided an excellent response For KF when detected in the positive ion mode. Plasma samples were prepared For LC MS/MS by solid-phase extraction on C(18) cartridges. The LC separation was perFormed on a Zorbax Extend C(18) column (150 x 2.1 mm i.d., particle size 5 micro m) with acetonitrile -10 mM aqueous ammonia (85 : 15, v/v) as the mobile phase, at a Flow-rate oF 0.20 ml min(-1). A butyric acid analogue oF KF was used as the internal standard. The lower limit oF quantitation (LLQ) using a 500 micro l sample volume was 1 ng ml(-1) and the linear dynamic range extended to 1000 ng ml(-1). The inter-assay accuracy oF the assay was -15.1% at the LLQ and between -2.68 and -9.05% For quality control solutions ranging in concentration From 2.24 to 715 ng ml(-1). The inter-assay precision was 9.91% or better at these concentrations. The analyte was stable in plasma under all relevant conditions evaluated and For a period oF 16 h aFter reconstituting plasma extracts For LC analysis at ambient temperature.
Fernando Albericio - One of the best experts on this subject based on the ideXlab platform.
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Electrostatic Binding and Hydrophobic Collapse oF Peptide-Nucleic Acid Aggregates QuantiFied Using Force Spectroscopy
ACS nano, 2013Co-Authors: Joan Camunas-soler, Roland Ramsch, Susana Vílchez, Conxita Solans, Fernando Moreno-herrero, Silvia Frutos, Cristiano Valim Bizarro, Sara De Loreno, Maria Eugenia Fuentes-perez, Fernando AlbericioAbstract:Knowledge oF the mechanisms oF interaction between selF-aggregating peptides and nucleic acids or other polyanions is key to the understanding oF many aggregation processes underlying several human diseases (e.g., Alzheimer’s and Parkinson’s diseases). Determining the aFFinity and kinetic steps oF such interactions is challenging due to the competition between hydrophobic selF-aggregating Forces and electrostatic binding Forces. Kahalalide F (KF) is an anticancer hydrophobic peptide that contains a single positive charge that conFers strong aggregative properties with polyanions. This makes KF an ideal model to elucidate the mechanisms by which selF-aggregation competes with binding to a strongly charged polyelectrolyte such as DNA. We use optical tweezers to apply mechanical Forces to single DNA molecules and show that KF and DNA interact in a two-step kinetic process promoted by the electrostatic binding oF DNA to the aggregate surFace Followed by the stabilization oF the complex due to hydrophobic inte...
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Electrostatic Binding and Hydrophobic Collapse oF PeptideNucleic Acid Aggregates QuantiFied Using Force
2013Co-Authors: Roland Ramsch, Fernando Albericio, Ernest Giralt, Susana Vílchez, Conxita Solans, Fernando Moreno-herrero, Sukhendu B. Dev, Felix RitortAbstract:Knowledge oF the mechanisms oF interaction between selF-aggregating peptides and nucleic acids or other polyanions is key to the understanding oF many aggregationprocessesunderlyingseveralhumandiseases(e.g.,Alzheimer'sandParkinson'sdiseases).DeterminingtheaFFinityandkineticstepsoFsuchinteractionsis challenging due to the competition between hydrophobic selF-aggregating Forces and electrostatic binding Forces. Kahalalide F (KF) is an anticancer hydrophobic peptidethatcontains asinglepositivechargethatconFers strongaggregativeproperties withpolyanions.This makesKFanidealmodeltoelucidatethemechanisms bywhichselF-aggregationcompeteswithbindingtoastronglychargedpolyelectrolytesuchasDNA.WeuseopticaltweezerstoapplymechanicalForcestosingleDNA molecules and show that KF and DNA interact in a two-step kinetic process promoted by the electrostatic binding oF DNA to the aggregate surFace Followedbythe stabilizationoFthecomplexduetohydrophobicinteractions.FromthemeasuredpullingcurveswedeterminethespectrumoFbindingaFFinities,kineticbarriers,and
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Electrostatic Binding and Hydrophobic Collapse oF Peptide–Nucleic Acid Aggregates QuantiFied Using Force Spectroscopy
2013Co-Authors: Joan Camunas-soler, Roland Ramsch, Susana Vílchez, Conxita Solans, Fernando Moreno-herrero, Silvia Frutos, Cristiano Valim Bizarro, Maria Eugenia Fuentes-perez, Sara De Lorenzo, Fernando AlbericioAbstract:Knowledge oF the mechanisms oF interaction between selF-aggregating peptides and nucleic acids or other polyanions is key to the understanding oF many aggregation processes underlying several human diseases (e.g., Alzheimer’s and Parkinson’s diseases). Determining the aFFinity and kinetic steps oF such interactions is challenging due to the competition between hydrophobic selF-aggregating Forces and electrostatic binding Forces. Kahalalide F (KF) is an anticancer hydrophobic peptide that contains a single positive charge that conFers strong aggregative properties with polyanions. This makes KF an ideal model to elucidate the mechanisms by which selF-aggregation competes with binding to a strongly charged polyelectrolyte such as DNA. We use optical tweezers to apply mechanical Forces to single DNA molecules and show that KF and DNA interact in a two-step kinetic process promoted by the electrostatic binding oF DNA to the aggregate surFace Followed by the stabilization oF the complex due to hydrophobic interactions. From the measured pulling curves we determine the spectrum oF binding aFFinities, kinetic barriers, and lengths oF DNA segments sequestered within the KF–DNA complex. We Find there is a capture distance beyond which the complex collapses into compact aggregates stabilized by strong hydrophobic Forces and discuss how the bending rigidity oF the nucleic acid aFFects this process. We hypothesize that within an in vivo context, the enhanced electrostatic interaction oF KF due to its aggregation might mediate the binding to other polyanions. The proposed methodology should be useFul to quantitatively characterize other compounds or proteins in which the Formation oF aggregates is relevant
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Solid-Phase Synthesis oF Aza-Kahalalide F Analogues: (2R,3R)-2-Amino-3-azidobutanoic Acid as Precursor oF the Aza-Threonine
European Journal of Organic Chemistry, 2010Co-Authors: Irene Izzo, Carmen Cuevas, Gerardo A. Acosta, Judit Tulla-puche, Tommaso Cupido, Maria Jesus Martin-lopez, Fernando AlbericioAbstract:The solid-phase synthesis oF six novel analogues oF Kahalalide\ud F (KF), a natural product currently undergoing Phase II\ud clinical trials, is reported. In all these compounds, amides\ud were used as isosteres For the depsi bond. For two oF these\ud compounds, we perFormed an eFFicient synthesis oF N-Fmoc-protected (2R,3R)-2-amino-3-azidobutanoic acid, precursor\ud oF the aza-threonine. This is the First example oF the solidphase\ud reduction oF an azide group in the preparation oF aza-\ud Thr-containing peptides in the solid phase
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Kahalalide F an antitumor depsipeptide in clinical trials and its analogues as eFFective antileishmanial agents
Molecular Pharmaceutics, 2009Co-Authors: Luis J. Cruz, Juan Roman Luqueortega, Luis Rivas, Fernando AlbericioAbstract:Leishmaniasis is a human parasitic disease caused by inFection by the protozoan Leishmania spp. Chemotherapy is currently the only treatment available, but its eFFicacy is increasingly challenged by the rising incidence oF resistance and the Frequent severe side eFFects associated with First-line drugs. Thus the development oF leads with distinct mechanisms oF action is urgently needed. A strategy oFten used For this purpose consists oF assaying For leishmanicidal activity drugs Formerly developed For other applications, such as amphotericin B (antiFungal) or milteFosine (antitumor), among others, to proFit From previous pharmacological and toxicological studies. Kahalalide F (KF) is a tumoricidal cyclic depsipeptide currently under phase II clinical trials For several types oF cancer and psoriasis. Its mechanism oF action has not been Fully elucidated. Here we report the leishmanicidal activity oF KF and its synthetic analogues at a micromolar range oF concentrations. Its lethality is strongly linked to ...
Mark T. Hamann - One of the best experts on this subject based on the ideXlab platform.
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SB-224289 Protects Against Theopapuamide, but Not Other Depsipeptides.
2016Co-Authors: Chelsi D. Cassilly, Mark T. Hamann, Marcus M. Maddox, Philip T. Cherian, John J. Bowling, Richard E. Lee, Todd B. ReynoldsAbstract:A. The structure oF several depsipeptides are shown. For each oF these compounds, 1x104 cells/ml were treated with serially diluted concentrations oF SB-224289 (SB) and were incubated For 3 hours at 37°C. Following this incubation, B. 3 μg/ml valinomycin (VA), C. 15 μg/ml Kahalalide F (KF), or D. 6 μg/ml theopapuamide (TA) was added and Further allowed to incubate overnight. Optical density (OD) was read at 600 nm the next day as a measure oF cell survival.
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an eFFicient and cost eFFective approach to Kahalalide F n terminal modiFications using a nuisance algal bloom oF bryopsis pennata
Biochimica et Biophysica Acta, 2015Co-Authors: Bin Wang, Amanda L. Waters, Frederick A. Valeriote, Mark T. HamannAbstract:Abstract Background Kahalalide F (KF) and its isomer iso-Kahalalide F (isoKF), both oF which can be isolated From the mollusk Elysia ruFescens and its diet alga Bryopsis pennata , are potent cytotoxic agents that have advanced through Five clinical trials. Due to a short halF-liFe, narrow spectrum oF activity, and a modest response in patients, Further eFForts to modiFy the molecule are required to address its limitations. In addition, due to the high cost in producing KF analogues using solid phase peptide synthesis (SPPS), a degradation and reconstruction approach was employed using natural KF From a seasonal algal bloom to generate KF analogues. Methods N -protected KF was careFully hydrolyzed at the amide linkage between l -Thr12 and d -Val13 using dilute HCl. The synthesis oF the C -terminal Fragment began with the Formation oF hexanoic succinimide ester, Followed by a reaction with dipeptides. The Final coupling reaction was perFormed between the semisynthesized Fmoc–KF hydrolysis product and the C -terminal Fragment, Followed by the deprotection oF the Fmoc group. Results Six KF analogues with an addition oF an amino acid residue on the N -terminal chain, d -Val14–isoKF (2) , Val13–Val14–isoKF (3) , d -Leu14–isoKF (4) , d -Pro14–isoKF (5) , d -Phe14–isoKF (6) , and 3,4-2F- d -Phe14-isoKF (7) were prepared using semisynthesis at the exposed N -terminal chain. Conclusions The overall yield oF the medication was 45%. This approach is economical, eFFicient and amendable to large-scale production while eliminated a nuisance algal bloom. General signiFicance B. pennata blooms are capable oF producing KF in good yields. The semisynthesis From the natural product produced N -terminal modiFications For the construction oF inexpensive semisynthetic KF libraries.
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An eFFicient and cost-eFFective approach to Kahalalide F N-terminal modiFications using a nuisance algal bloom oF Bryopsis pennata.
Biochimica et biophysica acta, 2015Co-Authors: Bin Wang, Amanda L. Waters, Frederick A. Valeriote, Mark T. HamannAbstract:Kahalalide F (KF) and its isomer iso-Kahalalide F (isoKF), both oF which can be isolated From the mollusk Elysia ruFescens and its diet alga Bryopsis pennata, are potent cytotoxic agents that have advanced through Five clinical trials. Due to a short halF-liFe, narrow spectrum oF activity, and a modest response in patients, Further eFForts to modiFy the molecule are required to address its limitations. In addition, due to the high cost in producing KF analogues using solid phase peptide synthesis (SPPS), a degradation and reconstruction approach was employed using natural KF From a seasonal algal bloom to generate KF analogues. N-protected KF was careFully hydrolyzed at the amide linkage between l-Thr12 and d-Val13 using dilute HCl. The synthesis oF the C-terminal Fragment began with the Formation oF hexanoic succinimide ester, Followed by a reaction with dipeptides. The Final coupling reaction was perFormed between the semisynthesized Fmoc-KF hydrolysis product and the C-terminal Fragment, Followed by the deprotection oF the Fmoc group. Six KF analogues with an addition oF an amino acid residue on the N-terminal chain, d-Val14-isoKF (2), Val13-Val14-isoKF (3), d-Leu14-isoKF (4), d-Pro14-isoKF (5), d-Phe14-isoKF (6), and 3,4-2F-d-Phe14-isoKF (7) were prepared using semisynthesis at the exposed N-terminal chain. The overall yield oF the medication was 45%. This approach is economical, eFFicient and amendable to large-scale production while eliminated a nuisance algal bloom. B. pennata blooms are capable oF producing KF in good yields. The semisynthesis From the natural product produced N-terminal modiFications For the construction oF inexpensive semisynthetic KF libraries. Copyright © 2015 Elsevier B.V. All rights reserved.
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Characterization oF the Bacterial Community oF the Chemically DeFended Hawaiian Sacoglossan Elysia ruFescens
Applied and environmental microbiology, 2013Co-Authors: Jeanette Davis, Mark T. Hamann, W. Florian Fricke, Eduardo Esquenazi, Pieter C. Dorrestein, Russell T. HillAbstract:Sacoglossans are characterized by the ability to sequester Functional chloroplasts From their algal diet through a process called kleptoplasty, enabling them to photosynthesize. The bacterial diversity associated with sacoglossans is not well understood. In this study, we coupled traditional cultivation-based methods with 454 pyrosequencing to examine the bacterial communities oF the chemically deFended Hawaiian sacoglossan Elysia ruFescens and its secreted mucus. E. ruFescens contains a deFense molecule, Kahalalide F, that is possibly oF bacterial origin and is oF interest because oF its antiFungal and anticancer properties. Our results showed that there is a diverse bacterial assemblage associated with E. ruFescens and its mucus, with secreted mucus harboring higher bacterial richness than entire-E. ruFescens samples. The most-abundant bacterial groups aFFiliated with E. ruFescens and its mucus are Mycoplasma spp. and Vibrio spp., respectively. Our analyses revealed that the Vibrio spp. that were highly represented in the cultivable assemblage were also abundant in the culture-independent community. EpiFluorescence microscopy and matrix-assisted laser desorption–ionization mass spectrometry (MALDI-MS) were utilized to detect the chemical deFense molecule Kahalalide F on a longitudinal section oF the sacoglossan.
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In vitro and In vivo Evaluation oF Select Kahalalide F Analogs with Antitumor and AntiFungal Activities
Bioorganic & medicinal chemistry, 2011Co-Authors: Abbas Gholipour Shilabin, Mark T. HamannAbstract:Kahalalide F (KF) and the regioisomer isoKF are novel anticancer drugs oF marine origin and currently under clinical investigation. Here we report the synthesis oF two new KF analogs with signiFicant in vitro and in vivo antiFungal and antitumor activities. The primary amine hydrogen oF ornithine in KF has been replaced with 4-Fluoro-3-methylbenzyl and morpholin-4-yl-benzyl via reductive N-alkylation. The TGI oF these analogs using the NCI-60 cell line screening revealed promising results when compared to paclitaxel. The result oF in vivo hollow Fiber and animal toxicity assays are presented.
Jose Jimeno - One of the best experts on this subject based on the ideXlab platform.
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Predictive Factors oF Sensitivity to Elisidepsin, a Novel Kahalalide F-Derived Marine Compound
Marine Drugs, 2013Co-Authors: Maria Serova, Jose Jimeno, Armand De Gramont, Ivan Bieche, Maria Riveiro, Carlos Galmarini, Miguel Aracil, Sandrine Faivre, Eric RaymondAbstract:Elisidepsin (PM02734, Irvalec®) is a synthetic marine-derived cyclic peptide oF the Kahalalide F Family currently in phase II clinical development. Elisidepsin was shown to induce rapid oncosis in ErbB3-expressing cells. Other predictive Factors oF elisidepsin sensitivity remained unknown. A panel oF 23 cancer cell lines oF diFFerent origin was assessed For elisidepsin cytotoxicity and correlated with mutational state, mRNA and protein expression oF selected genes. Elisidepsin showed potent and broad cytotoxic eFFects in our cancer cell line panel, being active at concentrations ranging From 0.4 to 2 μM that may be relevant For clinical settings. We have shown that elisidepsin is more active in cells harboring epithelial phenotype with high E-cadherin and low vimentin expression. In addition, high ErbB3 and Muc1 expression was correlated with sensitivity to elisidepsin, whereas the presence oF KRAS activating mutations was associated with resistance. In DU-PM cells with acquired resistance to elisidepsin, ErbB3 expression was decreased, while Bcl2 was increased. DU-PM cells displayed higher sensitivity to ErbB1-inhibitors suggesting possible cross-talk oF ErbB1 and ErbB3 signaling pathways. Combinations oF elisidepsin with lapatinib and several chemotherapies including 5-FU and oxaliplatin resulted in synergistic eFFects that oFFer the potential oF clinical use oF elisidepsin in combination settings
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2013Co-Authors: Maria Serova, Jose Jimeno, Ivan Bieche, Maria Riveiro, Carlos Galmarini, Miguel Aracil, Sandrine Faivre, Eric RaymondAbstract:) is a synthetic marine-derived cyclic peptide oF the Kahalalide F Family currently in phase II clinical development. Elisidepsin was shown to induce rapid oncosis in ErbB3-expressing cells. Other predictive Factors oF elisidepsin sensitivity remained unknown. A panel oF 23 cancer cell lines oF diFFerent origin was assessed For elisidepsin cytotoxicity and correlated with mutational state, mRNA and protein expression oF selected genes. Elisidepsin showed potent and broad cytotoxic eFFects in our cancer cell line panel, being active at concentrations ranging From 0.4 to 2 μM that may be relevant For clinical settings. We have shown that elisidepsin is more active in cells harboring epithelial phenotype with high E-cadherin and low vimentin expression. In addition, high ErbB3 and Muc1 expression was correlated with sensitivity to elisidepsin, whereas the presence oF KRAS activating mutations was associated with resistance. I
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Phase I clinical and pharmacokinetic study oF Kahalalide F administered weekly as a 1-hour inFusion to patients with advanced solid tumors
Clinical cancer research : an official journal of the American Association for Cancer Research, 2008Co-Authors: Beatriz Pardo, Luis Paz-ares, Josep Tabernero, Eva Ciruelos, Margarita García, Ramon Salazar, Ana M. López, María Nicolás Blanco, Antonio Nieto, Jose JimenoAbstract:A dose-escalation, phase I study evaluated the saFety, pharmacokinetics, and eFFicacy oF a weekly 1-h regimen oF Kahalalide F, a cyclic depsipeptide isolated From the marine mollusk Elysia ruFescens, in adult patients with advanced solid tumors and no standard treatment available. Patients received an i.v. 1-h inFusion oF Kahalalide F once weekly until disease progression or unacceptable toxicity. The starting Kahalalide F dose was 266 microg/m(2), and dose escalation proceeded based on the worst toxicity Found in the previous cohort. Thirty-eight patients were enrolled at three Spanish institutions and received once-weekly Kahalalide F 1-h inFusions at doses between 266 and 1,200 microg/m(2). Dose-limiting toxicities consisted oF transient grade 3/4 increases in transaminase blood levels. The maximum tolerated dose For this Kahalalide F schedule was 800 microg/m(2), and the recommended dose For phase II studies was 650 microg/m(2). No accumulated toxicity was Found. One patient with malignant melanoma had unconFirmed partial response, one patient with metastatic lung adenocarcinoma had minor response, and six patients with diFFerent types oF metastatic solid tumors had stable disease For 2.8 to 12.7 months. The noncompartmental pharmacokinetics oF this Kahalalide F schedule was linear and showed a narrow distribution and short body residence. The transaminitis associated with Kahalalide F was dose dependent. The maximum tolerated dose was 800 microg/m(2). Dose-limiting toxicities with weekly Kahalalide F 1-h i.v. inFusions were transient grade 3/4 increases in blood transaminase levels, and 650 microg/m(2) was declared the recommended dose For phase II studies. This schedule showed a Favorable saFety proFile and hints oF antitumor activity.
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phase i clinical and pharmacokinetic study oF Kahalalide F administered weekly as a 1 hour inFusion to patients with advanced solid tumors
Clinical Cancer Research, 2008Co-Authors: Beatriz Pardo, Josep Tabernero, Eva Ciruelos, Margarita García, Ramon Salazar, Ana M. López, María Nicolás Blanco, Antonio Nieto, Luis Pazares, Jose JimenoAbstract:Purpose: A dose-escalation, phase I study evaluated the saFety, pharmacokinetics, and eFFicacy oF a weekly 1-h regimen oF Kahalalide F, a cyclic depsipeptide isolated From the marine mollusk Elysia ruFescens , in adult patients with advanced solid tumors and no standard treatment available. Experimental Design: Patients received an i.v. 1-h inFusion oF Kahalalide F once weekly until disease progression or unacceptable toxicity. The starting Kahalalide F dose was 266 μg/m 2 , and dose escalation proceeded based on the worst toxicity Found in the previous cohort. Results: Thirty-eight patients were enrolled at three Spanish institutions and received once-weekly Kahalalide F 1-h inFusions at doses between 266 and 1,200 μg/m 2 . Dose-limiting toxicities consisted oF transient grade 3/4 increases in transaminase blood levels. The maximum tolerated dose For this Kahalalide F schedule was 800 μg/m 2 , and the recommended dose For phase II studies was 650 μg/m 2 . No accumulated toxicity was Found. One patient with malignant melanoma had unconFirmed partial response, one patient with metastatic lung adenocarcinoma had minor response, and six patients with diFFerent types oF metastatic solid tumors had stable disease For 2.8 to 12.7 months. The noncompartmental pharmacokinetics oF this Kahalalide F schedule was linear and showed a narrow distribution and short body residence. The transaminitis associated with Kahalalide F was dose dependent. Conclusions: The maximum tolerated dose was 800 μg/m 2 . Dose-limiting toxicities with weekly Kahalalide F 1-h i.v. inFusions were transient grade 3/4 increases in blood transaminase levels, and 650 μg/m 2 was declared the recommended dose For phase II studies. This schedule showed a Favorable saFety proFile and hints oF antitumor activity.
Peter Proksch - One of the best experts on this subject based on the ideXlab platform.
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Cytotoxic glucosphingolipid From Celtis AFricana.
Pharmacognosy Magazine, 2015Co-Authors: Shagufta Perveen, Areej Mohammad Al-taweel, Ghada Ahmed Fawzy, Azza M. El-shafae, Afsar Khan, Peter ProkschAbstract:Background: Literature survey proved the use oF the powdered sun-dried bark and roots oF Celtis aFricana For the treatment oF cancer in South AFrica. Objective: The aim oF this study was to do Further isolation work on the ethyl acetate Fraction and to investigate the cytotoxic activities oF the various Fractions and isolated compound. Materials and Methods: Cytotoxicity oF petroleum ether, chloroForm, ethyl acetate, n -butanol Fractions and compound 1 were tested on mouse lymphoma cell line L5178Y using the microculture tetrazolium assay. Results: One new glucosphingolipid 1 was isolated From the aerial parts oF C. aFricana . The structure oF the new compound was determined by extensive analysis by one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy and mass spectrometry. The ethyl acetate Fraction and compound 1 showed strong cytotoxic activity with an EC 50 value oF 8.3 μg/mL and 7.8 μg/mL, respectively, compared with Kahalalide F positive control (6.3 μg/mL). Conclusion: This is the First report oF the occurrence oF a cytotoxic glucosphingolipid in Family Ulmaceae .
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Cytotoxic glucosphingolipid From Celtis AFricana.
Pharmacognosy magazine, 2015Co-Authors: Shagufta Perveen, Areej Mohammad Al-taweel, Ghada Ahmed Fawzy, Azza M. El-shafae, Afsar Khan, Peter ProkschAbstract:Literature survey proved the use oF the powdered sun-dried bark and roots oF Celtis aFricana For the treatment oF cancer in South AFrica. The aim oF this study was to do Further isolation work on the ethyl acetate Fraction and to investigate the cytotoxic activities oF the various Fractions and isolated compound. Cytotoxicity oF petroleum ether, chloroForm, ethyl acetate, n-butanol Fractions and compound 1 were tested on mouse lymphoma cell line L5178Y using the microculture tetrazolium assay. One new glucosphingolipid 1 was isolated From the aerial parts oF C. aFricana. The structure oF the new compound was determined by extensive analysis by one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy and mass spectrometry. The ethyl acetate Fraction and compound 1 showed strong cytotoxic activity with an EC50 value oF 8.3 μg/mL and 7.8 μg/mL, respectively, compared with Kahalalide F positive control (6.3 μg/mL). This is the First report oF the occurrence oF a cytotoxic glucosphingolipid in Family Ulmaceae.
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Bioactive sesterterpenes and triterpenes From marine sponges: occurrence and pharmacological signiFicance
2013Co-Authors: Sherif S. Ebada, Wenhan Lin, Peter ProkschAbstract:Abstract: Marine ecosystems (>70 % oF the planet's surFace) comprise a continuous resource oF immeasurable biological activities and immense chemical entities. This diversity has provided a unique source oF chemical compounds with potential bioactivities that could lead to potential new drug candidates. Many marine-living organisms are soFt bodied and/or sessile. Consequently, they have developed toxic secondary metabolites or obtained them From microorganisms to deFend themselves against predators [1]. For the last 30–40 years, marine invertebrates have been an attractive research topic For scientists all over the world. A relatively small number oF marine plants, animals and microbes have yielded more than 15,000 natural products including numerous compounds with potential pharmaceutical potential. Some oF these have already been launched on the pharmaceutical market such as Prialt ® (ziconotide; potent analgesic) and Yondelis ® (trabectedin or ET-743; antitumor) while others have entered clinical trials, e.g., alpidin and Kahalalide F. Amongst the vast array oF marine natural products, the terpenoids are one oF the more commonly reported and discovered to date. Sesterterpenoids (C25) and triterpenoids (C30) are oF Frequent occurrence, particularly in marine sponges, and they show prominen
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Bioactive sesterterpenes and triterpenes From marine sponges: occurrence and pharmacological signiFicance.
Marine drugs, 2010Co-Authors: Sherif S. Ebada, Wenhan Lin, Peter ProkschAbstract:Marine ecosystems (>70% oF the planet’s surFace) comprise a continuous resource oF immeasurable biological activities and immense chemical entities. This diversity has provided a unique source oF chemical compounds with potential bioactivities that could lead to potential new drug candidates. Many marine-living organisms are soFt bodied and/or sessile. Consequently, they have developed toxic secondary metabolites or obtained them From microorganisms to deFend themselves against predators [1]. For the last 30–40 years, marine invertebrates have been an attractive research topic For scientists all over the world. A relatively small number oF marine plants, animals and microbes have yielded more than 15,000 natural products including numerous compounds with potential pharmaceutical potential. Some oF these have already been launched on the pharmaceutical market such as Prialt® (ziconotide; potent analgesic) and Yondelis® (trabectedin or ET-743; antitumor) while others have entered clinical trials, e.g., alpidin and Kahalalide F. Amongst the vast array oF marine natural products, the terpenoids are one oF the more commonly reported and discovered to date. Sesterterpenoids (C25) and triterpenoids (C30) are oF Frequent occurrence, particularly in marine sponges, and they show prominent bioactivities. In this review, we survey sesterterpenoids and triterpenoids obtained From marine sponges and highlight their bioactivities.
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Anthraquinones and naphthopyrones From the marine echinoderm Comanthus sp.
Planta Medica, 2009Co-Authors: Sherif S. Ebada, Ruangelie Edrada-ebel, Victor Wray, Peter ProkschAbstract:A detailed analysis oF a Philippine specimen oF the marine echinoderm Comanthus sp. yielded FiFteen compounds including Four anthraquinones identiFied as 1'-deoxyrhodoptilometrin (1) along with its 6-O-sulFate derivative (3), and rhodoptilometrin (2) with its 6-O-sulFate derivative (4). In addition Five naphthpyrones including comaparvin (5), 6-methoxycomaparvin (6), 6-methoxycomaparvin-5-methylether (7), 6-methoxycomaparvin-5-methylether-8-O-sulFate (8), and 6-hydroxycomaparvin-8-O-sulFate (9) were likewise isolated and identiFied. Further compounds include steroids and a nucleoside derivative. The structures oF the isolated compounds were unambiguously elucidated based on HRESIMS analysis, 1D and 2D NMR, and by comparison with the literature. For compounds 2 and 4 the absolute conFigurations were identiFied For the First time using the Mosher reaction. Both compounds are (S)-(-) enantiomers. All isolated compounds were evaluated For their cytotoxic activities against cancer cells using the (MTT) assay and compared to the well known marine cancer drug candidate Kahalalide F (EC50=6.3 µg/mL). 1'-Deoxyrhodoptilometrine (1) and an unseparable mixture oF comaparvin (5) and 6-methoxycomaparvin (6) exhibited pronounced cytotoxicity against mouse lymphoma L5178Y cells with EC50 values oF 2.3 and 5.2 µg/mL, respectively
