kahalalide-f and Neoplasms

Many cyclic peptides and analogues derived from marine sources are known to possess biological properties, including anticancer, antitumor, antibacterial, antifungal, antiparasitic, anti-inflammation, anti-proliferative, anti-hypertensive, cytotoxic, and antibiotic properties. These compounds demonstrate different activities and modes of action according to their structure such as cyclic oligopeptide, cyclic lipopeptide, cyclic glycopeptide and cyclic depsipeptide. The recent advances in application of the above-mentioned cyclic peptides were reported in dolastatins, soblidotin, didemnin B, aplidine, salinosporamide A, kahalalide F and bryostatin 1 and they are currently in clinical trials. These cyclic peptides are possible novel drugs discovered and developed from marine origin. Literature data concerning the potential properties of marine cyclic peptides were reviewed here, and the structural diversity and biological activities of marine cyclic peptides are discussed in relation to the molecular mechanisms of these marine cyclic peptides.

Topics: Animals; Aquatic Organisms; Depsipeptides; Humans; Hypertension; Neoplasms; Oligopeptides; Peptides, Cyclic

In this study, we characterize the population pharmacokinetics of kahalalide F (KF), a novel marine anticancer drug, after intravenous (i.v.) administration in advanced cancer patients.. Data from 240 patients included in three Phase I and three Phase II trials receiving i.v. weekly and every 3 weeks infusions of KF, at doses ranging 266-6650 µg/m(2), were analyzed using NONMEM™ VII. The effect of demographics and/or pathophysiologically relevant factors on KF pharmacokinetic parameters was evaluated. Model evaluation was conducted using nonparametric bootstrap and visual predictive check (in both internal and external datasets).. An open two-compartment model with linear distribution and elimination from central compartment was suitable to describe the data. Volume of distribution at steady state and its between-subject variability (CV%) was estimated to be 6.56 L (28 %). Plasma clearance was estimated to be 6.25 L/h (43 %). Within the range of covariates evaluated, age, weight, body surface area, gender, ECOG performance status, presence of liver metastases, creatinine clearance, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, total protein and serum albumin did not contribute to explain KF pharmacokinetic variability to a significant extent. The developed model was deemed appropriate to describe the time course of KF plasma concentrations and its variability in advanced cancer patients.. The integration of pharmacokinetic data from six clinical studies demonstrated KF linear elimination from plasma, dose-proportional exposure and time-independent pharmacokinetics. Based on analyzed data, no clinically relevant covariates were identified as predictors of KF pharmacokinetics.

Topics: Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Depsipeptides; Humans; Neoplasm Metastasis; Neoplasms

Natural compounds derived from marine organisms have shown a wide variety of anti-tumor effects and a lot of attention has been drawn to further development of the isolated compounds. A vast quantity of individual chemical structures from different organisms has shown a variety of apoptosis inducing mechanisms in a variety of tumor cells. The bis-steroidal cephalostatin 1 for example, induces apoptosis via activation of caspases whereas the polyketide discodermolide inhibits cell growth by binding to and stabilizing microtubule and salisporamide A, the product of an actinobacterial strain, is an inhibitor of the proteasome. This great variety of mechanisms of action can help to overcome the multitude of resistances exhibited by different tumor specimens. Products from marine organisms and their synthetic derivates are therefore an important source for new therapeutics for single agent or combined therapy with other chemotherapeutics to support the struggle against cancer.

Topics: Alkaloids; Alkanes; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Apoptosis; Aquatic Organisms; Biological Products; Bryostatins; Carbamates; Cell Proliferation; Depsipeptides; Dioxoles; Drug Screening Assays, Antitumor; Humans; Lactones; Macrolides; Microtubules; Models, Chemical; Neoplasms; Phenanthrolines; Phenazines; Proteasome Endopeptidase Complex; Pyrones; Pyrroles; Quinolines; Spiro Compounds; Steroids; Tetrahydroisoquinolines; Thiazoles; Trabectedin

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

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

Kahalalide F (KF) is a dehydroaminobutyric acid-containing peptide from marine origin with activity against several human malignant cell lines. This dose-escalating phase I clinical trial evaluated the maximum tolerated dose (MTD), and the recommended dose for further phase II studies (RD) of weekly KF given as a prolonged (3- to 24-h) intravenous (i.v.) infusion.. Eligible patients with advanced solid tumors and adequate performance status, hematologic, renal, and hepatic function were recruited into this study.. A total of 106 patients were treated with KF at four different weekly schedules: 3-h (n = 40), 24-h (n = 59), and two transitional schedules [6-h (n = 4) and 12-h (n = 3)]. For the 3-h weekly schedule, the MTD was 1,200 μg/m² and the RD was 1,000 μg/m². For the 24-h weekly schedule, the MTD was reached (6,650 μg/m²), but the RD could not be confirmed. Asymptomatic and reversible grade 3/4 transaminase increase was the most common dose-limiting toxicity in both schedules. Fatigue, paresthesia, pruritus, nausea, vomiting, and rash were the most common KF-related adverse events. No major deviations from linearity were detected in the pharmacokinetic (PK) profiles of both schedules, which showed a narrow distribution and short body residence. Prolonged disease stabilization (≥3 months) occurred in eight patients: two with the 3-h schedule and six with the 24-h schedule.. Administration of KF as prolonged weekly infusion appears feasible, with 3-h and 24-h infusion times having an acceptable safety profile.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Cohort Studies; Colorectal Neoplasms; Depsipeptides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drugs, Investigational; Female; Humans; Incidence; Infusions, Intravenous; Lung Neoplasms; Male; Middle Aged; Neoplasms; Severity of Illness Index; Spain

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.

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

Bioassay-guided fractionation of a methanolic extract of the fungus Arthrinium sp., isolated from the Mediterranean sponge Geodia cydonium, afforded 10 natural products including five new diterpenoids, arthrinins A-D (1-4) and myrocin D (5). In addition, five known compounds were obtained, which included myrocin A (6), norlichexanthone (7), anomalin A (8), decarboxycitrinone (9) and 2,5-dimethyl-7-hydroxychromone (10). The structures of all isolated compounds were unambiguously elucidated based on extensive 1D and 2D NMR and HR-MS analyzes. The absolute configuration of arthrinins A-D (1-4) was established by the convenient Mosher method performed in NMR tubes and by interpretation of the ROESY spectra. Antiproliferative activity of the isolated compounds was assessed in vitro against four different tumor cell lines, including mouse lymphoma (L5178Y), human chronic myelogenous leukemia (K562), human ovarian cancer (A2780) and cisplatin-resistant ovarian cancer cells (A2780CisR), using the MTT assay. Norlichexanthone (7) and anomalin A (8) exhibited the strongest activities with IC₅₀ values ranging from 0.40 to 74.0 μM depending on the cell line investigated. This was paralleled by the inhibitory activity of both compounds against 16 cancer related protein kinases including aurora-B, PIM1, and VEGF-R2. In vitro IC₅₀ values of 7 and 8 against these three protein kinases ranged from 0.3 to 11.7 μM. Further investigation of the potential antitumoral activity of compounds 5-8 was performed in an in vitro angiogenesis assay against human umbilical vascular endothelial cells (HUVEC) sprouting induced by vascular endothelial growth factor A (VEGF-A). Anomalin A (8), myrocin D (5) and myrocin A (6) inhibited VEGF-A dependent endothelial cell sprouting with IC₅₀ values of 1.8, 2.6 and 3.7 μM, respectively, whereas norlichexanthone (7) was inactive.

Topics: Animals; Antineoplastic Agents; Ascomycota; Cell Line, Tumor; Diterpenes; Humans; Mice; Neoplasms; Neovascularization, Pathologic; Porifera; Protein Kinase Inhibitors; Protein Kinases; Vascular Endothelial Growth Factor A

The natural products kahalalide F, halichondrin B, and discodermolide are relatively large structures that were originally harvested from marine organisms. They are oxygen rich structures that, to varying degrees, should have the ability to bind iron (II or III) by Fe-O and/or Fe-N bonds. In this semi empirical study, the binding of these natural products to iron (II) is studied and the aqueous stability factor (ASF) is used to determine which bonding configuration is most stable. The energy, the complex charge (+1), the average Fe-O (or Fe-N) bond distances and the dipole moments are used to calculate the ASF. The ASF provides insight to which complex will be the most stable and water soluble, important for a medicinal application. The ability of a molecule with a more than six oxygen and/or nitrogen atoms to bind iron (hexavalent, octahedral) by shifting which six atoms (O/N) are bound to the iron qualifies it as a polarity adaptive molecule.

Topics: Alkanes; Animals; Antineoplastic Agents; Biological Products; Carbamates; Cell Line, Tumor; Chemical Phenomena; Computational Biology; Depsipeptides; Ethers, Cyclic; Humans; Inhibitory Concentration 50; Iron; Lactones; Macrolides; Models, Molecular; Molecular Conformation; Neoplasms; Oxygen; Pyrones; Siderophores; Structure-Activity Relationship