title: In vitro hematotoxicity of Aplidine on human bone marrow and cord blood progenitor cells.
abstract: Aplidine is a cyclic depsipeptide that was isolated from a Mediterranean marine tunicate, Aplidium albicans. In experimental animals, Aplidine mediated an in vivo inhibitory effect in a number of tumor cell types. In humans, Aplidine is currently used in phase I clinical trials. Aiming to predict the hematotoxicity of Aplidine in humans, samples from human bone marrow (BM) and cord blood (CB) were exposed in vitro to increasing concentrations of the drug and then assayed for the clonogenic ability of myeloid (CFU-GM), erythroid (BFU-E), megakaryocitic (CFU-Meg) and pluripotent (CFU-Mix) hematopoietic progenitors. We investigated whether predictions of the hematotoxicity of Aplidine based on bone marrow (BM) cultures were reproduced when a more readily available source of human hematopoietic cells, cord blood cells, was used in experiments involving 24-h exposures. Although hematopoietic progenitors derived from bone marrow were generally more sensitive than those derived from cord blood, differences on the IC50, IC70 and IC90 varied within a relatively small range of 1.6-6.2-fold. Moreover, data obtained from cord blood cultures confirmed the observation made in bone marrow assays indicating that the myeloid (CFU-GM) and the erythroid (BFU-E) progenitors were the least sensitive to Aplidine. Regardless of the origin of the hematopoietic progenitors (bone marrow or cord blood) the toxicity of Aplidine in human hematopoietic progenitors (IC50: 150-2250 nM) was lower than that observed in previous studies with tumoral cell lines.
authors.affiliation: Department of Molecular and Cellular Biology, CIEMAT, Avda Complutense 22, 28040 Madrid, Spain.
authors.forename: S G
authors.initials: SG
authors.lastname: Gómez
authors.forename: G
authors.initials: G
authors.lastname: Faircloth
authors.forename: L
authors.initials: L
authors.lastname: López-Lázaro
authors.forename: J
authors.initials: J
authors.lastname: Jimeno
authors.forename: J A
authors.initials: JA
authors.lastname: Bueren
authors.forename: B
authors.initials: B
authors.lastname: Albella
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects*; D002478:Cells, Cultured; D002999:Clone Cells; D003114:Colony-Forming Units Assay; D047630:Depsipeptides; D004317:Doxorubicin / Q000633:toxicity; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects*; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007231:Infant, Newborn; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000187:drug effects*; D009842:Oligopeptides / Q000633:toxicity*; D010456:Peptides, Cyclic / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D009842:Oligopeptides; D010456:Peptides, Cyclic; D004317:Doxorubicin; C098980:plitidepsin