HEMATOPOIETIC RADIOPROTECTION BY CREMOPHOR EL - A POLYETHOXYLATED CASTOR-OIL

The polyethoxylated castor oil, Cremophor EL (Cremophor) is approved f or human use as a vehicle for oral and intravenous administration of w ater-insoluble compounds. Cremophor has also previously been shown to reverse the multidrug resistance phenotype at clinically acceptable do ses. This study demonstrates that doses of Cremophor in the range of 2 5-50 mu l/kg intravenously (i.v.) administered 1 day prior to near-let hal irradiation protected the regenerative capacity of the marrow, res ulting in haematopoietic radioprotection and long-term survival of nea r-lethally-irradiated mice. In normal mice, Cremophor administration ( 1) markedly reduced the level of serum haematopoietic inhibitory activ ity 4-8 h following injection; (2) resulted in a transient decrease in femoral bone marrow cellularity and upregulated B220 (B cells), and 7 /4 (neutrophils and activated macrophages), but not Thy-1 (T-cells) su rface antigen expression in bone marrow cells within 24 h of injection ; and (3) transiently elevated the incidence of both primitive and com mitted haematopoietic progenitor cells detected in clonal agar culture within 48 h of injection. Bone marrow progenitor cell content, and pe ripheral blood white cell, platelet and reticulocyte counts were unaff ected. This suggests that the haematopoietic radioprotection and recov ery observed in irradiated mice pretreated with Cremophor may be the r esult of accessory cell activation and/or modulation of accessory fact ors regulating haematopoietic progenitor cells. Our data suggest a pot ential clinical use of Cremophor as an adjunct to, or as a substitute for, cytokines to minimize myelosuppression following cytotoxic therap y.