PARENT SESSION

Experimental and Clinical Therapeutics

(PP174) Radioprotective effects of low dose amifostine prophylaxis on hematopoietic tissues.

Seed, T^*,1, Inal , C², Deen , J², Aguilar, K¹, ¹ Vitreous State Laboratory, Washington, DC, USA² Radiation Casualty Management, Bethesda, MD, USA

ABSTRACT- Amifostine (WR2721) is a highly efficacious cytoprotectant when administered in vivo at high doses. However, at elevated doses drug toxicity manifests and is problematic when considering this agent for nonclinical purposes. Various strategies have been developed in attempting to avoid the drug's toxic side-effects: the simplest option is to reduce drug dose to the effective minimum. In terms of protecting hematopoietic tissues, where does this minimum lie? Experimental design. C3H/HEN mice were sorted into groups and given sc injections of either 25, 50, 75, or 100 mg/kg of amifostine in buffered saline (PBS) solution, or PBS alone. Thirty minutes following drug/vehicle treatments, half of the treated animals were gamma irradiated (7 Gy/0.6 Gy/min) and the remaining half sham-irradiated. At 4,10, and 14 days postexposures, animals were randomly selected from the treatment groups and euthanized. Blood/marrow specimens were collected and processed for CBCs/diffs, and for progenitorial content. The latter included both (a)matrix cloning assays for bipotential, myeloid committed progenitors (GM-CFU) and multipotential, myeloid committed progenitors (GEMM-CFU); and (b) flow cytometry assays for primitive progenitors bearing a cKit+ lin- phenotype. Results. Under steady-state, amifostine treatments had little effect on numbers of marrow GM-CFU and GEMM-CFU but marginally suppressed marrow levels of the +cKit lin- subpopulation. Under the marked disequilibrium caused by gamma irradiation, escalating prophylactic doses of amifostine resulted in (a) significant, time-dependent regeneration of the lineage-restricted bipotential marrow progenitors (GM-CFU), (b) moderate regeneration of multipotential progenitors (GEMM-CFU), and (c) a lack of significant and consistent regeneration of primitive, multipotential +cKit lin- progenitors. In contrast to the protective effects of higher amifostine doses, the low amifostine dose of 25 mg/kg consistently failed to radioprotect any/all of progenitorial subtypes assayed. Conclusions. (1) Radioprotective threshold doses for amifostine appear to lie between 25 and 50 mg/kg; and (2) more mature, lineage-restricted progenitors appear to be more responsive to low doses of amifostine than the more primitive, multipotential marrow progenitors.

Key words: radioprotector, amifostine, hematopoiesis, progenitors