Radioprotection of hematopoietic progenitors by low dose amifostine prophylaxis

Abstract

Purpose: Amifostine is a highly efficacious cytoprotectant when administered in vivo at high doses. However, at elevated doses, drug toxicity manifests for general, non-clinical radioprotective purposes. Various strategies have been developed to avoid toxic side-effects: The simplest is reducing the dose. In terms of protecting hematopoietic tissues, where does this effective, non-toxic minimum dose lie?

Material and methods: C3H/HEN mice were administered varying doses of amifostine (25–100 mg/kg) 30 min prior to cobalt-60 irradiation and euthanized between 4–14 days for blood and bone marrow collection and analyses.

Results: Under steady-state, amifostine had little effect on bipotential and multi-potential marrow progenitors but marginally suppressed a more primitive, lineage negative progenitor subpopulation. In irradiated animals, prophylactic drug doses greater than 50 mg/kg resulted in significant regeneration of bipotential progenitors, moderate regeneration of multipotential progenitors, but no significant and consistent regeneration of more primitive progenitors. The low amifostine dose (25 mg/kg) failed to elicit consistent and positive, radioprotective actions on any of the progenitor subtypes.

Conclusions: Radioprotective doses for amifostine appear to lie between 25 and 50 mg/kg. Mature, lineage-restricted progenitors appear to be more responsive to the protective effects of low doses of amifostine than the more primitive, multipotential progenitors.

Keywords::

• Amifostine
• bone marrow
• hematopoietic progenitors
• radiation
• radioprotectants
• WR2721

Acknowledgements

The opinions or assertions contained herein are the private views of the authors and are not necessarily those of the Armed Forces Radiobiology Research Institute, the Uniformed Services University of the Health Sciences, or the Department of Defense. The authors acknowledge the general service support of various departments within the Armed Forces Radiobiology Research Institute including the departments of Veterinary Science, Radiation Science, and the general administration. The authors would also like to express an appreciation for the review and comments by our colleagues, namely Drs. K. Sree Kumar, Venkataraman Srinivasan, Michael Landauer and Mark Whitnall, and for the excellent technical assistance of Mr Jason F. Deen. The authors are thankful to Miss Victoria L. Newman and Miss Patricia L. Romaine for graphics.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. The authors gratefully acknowledge the research support of US Department of Defense.