Investigational New Drugs

, Volume 30, Issue 4, pp 1396–1403

In vitro effects of perifosine, bortezomib and lenalidomide against hematopoietic progenitor cells from healthy donors

  • Martin Schmidt-Hieber
  • Robert Dabrowski
  • Babette Aicher
  • Philipp Lohneis
  • Antonia Busse
  • Carola Tietze-Buerger
  • Birgit Reufi
  • Eckhard Thiel
  • Igor Wolfgang Blau
PRECLINICAL STUDIES

DOI: 10.1007/s10637-011-9705-6

Cite this article as:
Schmidt-Hieber, M., Dabrowski, R., Aicher, B. et al. Invest New Drugs (2012) 30: 1396. doi:10.1007/s10637-011-9705-6

Summary

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.

Keywords

Bortezomib D 21266 (perifosine) Inhibitory concentration 50 Lenalidomide Myeloid progenitor cells 

Supplementary material

10637_2011_9705_MOESM1_ESM.doc (683 kb)
Supplemental Figure 1Depiction of exemplary Ki-67 and caspase-3 staining of CD34+ selected PB HPC after 24 h incubation with lenalidomide (1 µM). Percentages refer to positive cells. Tonsilar tissue with follicular hyperplasia was used as a positive control with a high Ki-67 proliferative index and numerous cleaved caspase-3+ apoptotic cells within the germinal centers. (DOC 683 kb)

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Martin Schmidt-Hieber
    • 1
  • Robert Dabrowski
    • 1
  • Babette Aicher
    • 2
  • Philipp Lohneis
    • 3
  • Antonia Busse
    • 1
  • Carola Tietze-Buerger
    • 1
  • Birgit Reufi
    • 1
  • Eckhard Thiel
    • 1
  • Igor Wolfgang Blau
    • 1
  1. 1.Department of Medicine III (Hematology, Oncology and Transfusion Medicine), Charité Campus Benjamin FranklinBerlinGermany
  2. 2.Æterna Zentaris GmbHFrankfurt/MainGermany
  3. 3.Institute for Pathology, Charité Campus MitteBerlinGermany

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