Plitidepsin: design, development, and potential place in therapy

• Published in: Drug design, development and therapy Vol. 11; pp. 253 - 264
• Main Authors: Alonso-Álvarez, Sara, Pardal, Emilia, Sánchez-Nieto, Diego, Navarro, Miguel, Caballero, Maria Dolores, Mateos, Maria Victoria, Martín, Alejandro
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01-01-2017; Taylor & Francis Ltd; Dove Medical Press
• Subjects: Angiogenesis; Animals; Anticancer properties; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - therapeutic use; Antitumor activity; Antitumor agents; Aplidin; Apoptosis; Biomarkers; Cancer therapies; Clinical trials; Commercialization; Cytotoxicity; Depsipeptides - chemical synthesis; Depsipeptides - chemistry; Depsipeptides - therapeutic use; Dexamethasone; Dosage and administration; Drug Design; Growth factors; Hematology; Humans; In vivo methods and tests; Kinases; Leukemia; Lung cancer; Lymphocytes T; Lymphoma; Medical research; Melanoma; Metastasis; Multiple myeloma; myeloma; Neoplasms - drug therapy; Patients; Peptides, Cyclic; plitidepsin; Product development; Review; Skin cancer; Solid tumors; T-cell lymphoma; Testing; Tumors; Spain; plitidepsin; melanoma; aplidin; myeloma; lymphoma
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S94165

Plitidepsin is a cyclic depsipeptide that was first isolated from a Mediterranean marine tunicate (
) and, at present, is manufactured by total synthesis and commercialized as Aplidin
. Its antitumor activity, observed in preclinical in vitro and in vivo studies has prompted numerous clinical trials to be conducted over the last 17 years, alone or in combination with other anticancer agents. Single-agent plitidepsin has shown limited antitumor activity and a tolerable safety profile in several malignancies, such as noncutaneous peripheral T-cell lymphoma, melanoma, and multiple myeloma. In patients with relapsed or refractory multiple myeloma, plitidepsin activity seems to be enhanced after addition of dexamethasone while remaining well tolerated, and a Phase III trial comparing plitidepsin plus dexamethasone vs dexamethasone alone is underway. Additional studies are required to better define the role of plitidepsin in combination with other active agents in these indications. Results of plitidepsin activity in other hematological malignancies or solid tumors have been disappointing so far. Further studies analyzing its mechanisms of action and potential biomarkers will help select patients who may benefit most from this drug. In this review, we critically analyze the published studies on plitidepsin in hematological malignancies and solid tumors and discuss its current role and future perspectives in treating these malignancies. We also review its design, pharmaceutical data, and mechanism of action.