kahalalide-f and plitidepsin

Cyclic depsipeptides are polypeptides in which one or more amino acid is replaced by a hydroxy acid, resulting in the formation of at least one ester bond in the core ring structure. Many natural cyclic depsipeptides possessing intriguing structural and biological properties, including antitumor, antifungal, antiviral, antibacterial, anthelmintic, and anti-inflammatory activities, have been identified from fungi, plants, and marine organisms. In particular, the potent effects of cyclic depsipeptides on tumor cells have led to a number of clinical trials evaluating their potential as chemotherapeutic agents. Although many of the trials have not achieved the desired results, romidepsin (FK228), a bicyclic depsipeptide that inhibits histone deacetylase, has been shown to have clinical efficacy in patients with refractory cutaneous T-cell lymphoma and has received Food and Drug Administration approval for use in treatment. In this review, we discuss antitumor cyclic depsipeptides that have undergone clinical trials and focus on their structural features, mechanisms, potential applications in chemotherapy, and pharmacokinetic and toxicity data. The results of this study indicate that cyclic depsipeptides could be a rich source of new cancer therapeutics.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Depsipeptides; Histone Deacetylase Inhibitors; Humans; Lactams; Lactones; Lymphoma, T-Cell, Cutaneous; Peptides, Cyclic

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Aquatic Organisms; Aza Compounds; Carbazoles; Chemistry, Pharmaceutical; Depsipeptides; Furans; Humans; Indoles; Naphthyridines; Peptides, Cyclic; Phosphoinositide-3 Kinase Inhibitors; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Pyrimidines; Staurosporine; Terpenes

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

The sea, covering 70% of the Earth's surface, offers a considerably broader spectrum of biological diversity than terra firma. Containing approximately 75% of all living organisms, 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, PharmaMar, which currently has a large number of oncology products in late preclinical and clinical development. These include: ecteinascidin-743 (ET-743), a marine-derived antitumor agent isolated from the Caribbean tunicate, Ecteinascidia turbinata; aplidine (Aplidin), a cyclopeptide cytotoxic agent derived from the Mediterranean tunicate, Aplidium albicans; kahalalide F, a depsipeptide isolated from the Hawaiian mollusc, Elysia rufescens; and ES-285, a molecule isolated from the mollusc, Spisula polynyma. Many of these innovative compounds have novel mechanisms of anti-tumor action that have yet to be fully elucidated.

Topics: Animals; Antineoplastic Agents; Depsipeptides; Dioxoles; Drug Screening Assays, Antitumor; Humans; Isoquinolines; Marine Biology; Mollusca; Peptides; Peptides, Cyclic; Tetrahydroisoquinolines; Trabectedin

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.. 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.. 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.. 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