kahalalide-f and elisidepsin

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

Because of the poor results observed after platinum-based first-line chemotherapy, research on new strategies for second-line treatment of advanced non-small-cell lung cancer (NSCLC) is warranted. Current research focuses on the development of new agents and the assessment of a combination of therapies, especially those with different mechanisms of action. PM02734 (elisidepsin, Irvalec) is a compound related to Kahalalide F (KF), a moderately soluble marine product that belongs to a family of dehydro aminobutyric acid-containing peptides isolated from the herbivorous marine mollusk Elysia rufescens. Preclinical and clinical studies showed that KF induces strong cytotoxic activity against different solid tumors, including NSCLC, particularly in patients with squamous histology; in fact, almost 40% of patients treated in the second line were still alive at 1 year after beginning treatment with KF. Analysis of data collected during clinical development has revealed that KF has a predictable and manageable toxicity profile. The toxicities most commonly associated with KF are generally transient and mild or moderate. The absence of hematologic toxicity and cumulative toxic effects suggests that KF may be suitable for combination trials with other anticancer agents. The development of KF could stopped because of the unavailability of a natural source of the compound. PM02734 is a closely related derivative of KF with similar activity and characteristics. Herein, we summarize the studies of PM02734 and future clinical perspectives.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Depsipeptides; Humans; Injections, Intravenous; Lung Neoplasms; Mollusk Venoms; Randomized Controlled Trials as Topic