title: In vitro effects of perifosine, bortezomib and lenalidomide against hematopoietic progenitor cells from healthy donors.
abstract: The novel AKT inhibitor perifosine possesses myelopoiesis-stimulating effects in rodents. We studied the in vitro effects of the novel agents perifosine, bortezomib and lenalidomide in addition to adriamycin against normal human hematopoietic progenitor cells (HPC) using different clonogenic and non-clonogenic assays. All agents inhibited colony-forming unit (CFU) formation, perifosine inhibiting mainly CFU-granulocyte/macrophage formation and the other agents burst-forming unit-erythroid formation. Perifosine combined with lenalidomide or adriamycin tended to act antagonistically in suppressing CFU formation. Despite their inhibition of CFU formation, perifosine, bortezomib and lenalidomide induced only slight or moderate cytotoxicity in CD34(+) selected HPC, as assessed using different assays such as flow cytometry-based detection of activated caspases and immunohistochemistry studies (e.g., Ki-67 staining). In contrast to its myelopoiesis-stimulating effects in rodents, perifosine--like bortezomib and lenalidomide--suppresses the clonogenic potential of HPC from healthy donors in vitro and thus probably plays no role in preventing neutropenia or in shorting its duration after intensive chemotherapy. However, all these novel agents typically induce only slight or moderate suppression of the clonogenic potential or loss of viability of normal HPC at clinically achievable plasma concentrations, assuming that hematoxicity is manageable and functional HPC can be collected after treatment with these compounds.
authors.affiliation: Department of Medicine III, Hematology, Oncology and Transfusion Medicine, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. martin.schmidt-hieber@charite.de
authors.forename: Martin
authors.initials: M
authors.lastname: Schmidt-Hieber
authors.forename: Robert
authors.initials: R
authors.lastname: Dabrowski
authors.forename: Babette
authors.initials: B
authors.lastname: Aicher
authors.forename: Philipp
authors.initials: P
authors.lastname: Lohneis
authors.forename: Antonia
authors.initials: A
authors.lastname: Busse
authors.forename: Carola
authors.initials: C
authors.lastname: Tietze-Buerger
authors.forename: Birgit
authors.initials: B
authors.lastname: Reufi
authors.forename: Eckhard
authors.initials: E
authors.lastname: Thiel
authors.forename: Igor Wolfgang
authors.initials: IW
authors.lastname: Blau
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D003114:Colony-Forming Units Assay; D004317:Doxorubicin / Q000494:pharmacology; D005434:Flow Cytometry; D006262:Health; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D000077269:Lenalidomide; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D013194:Staining and Labeling; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014019:Tissue Donors; D014343:Trypan Blue / Q000378:metabolism
chemical_list: D017304:Annexin A5; D018952:Antigens, CD34; D001897:Boronic Acids; D011719:Pyrazines; D010767:Phosphorylcholine; C105905:perifosine; D013792:Thalidomide; D000069286:Bortezomib; D004317:Doxorubicin; D020169:Caspases; D000077269:Lenalidomide; D014343:Trypan Blue