Haematopoietic radioprotection by Cremophor EL: a polyethoxylated castor oil.
The polyethoxylated castor oil, Cremophor EL (Cremophor) is approved for human use as a vehicle for oral and intravenous administration of water-insoluble compounds. Cremophor has also previously been shown to reverse the multidrug resistance phenotype at clinically acceptable doses. This study demonstrates that doses of Cremophor in the range of 25-50 microliters/kg intravenously (i.v.) administered 1 day prior to near-lethal irradiation protected the regenerative capacity of the marrow, resulting in haematopoietic radioprotection and long-term survival of near-lethally-irradiated mice. In normal mice, Cremophor administration (1) markedly reduced the level of serum haematopoietic inhibitory activity 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) surface antigen expression in bone marrow cells within 24 h of injection; and (3) transiently elevated the incidence of both primitive and committed haematopoietic progenitor cells detected in clonal agar culture within 48 h of injection. Bone marrow progenitor cell content, and peripheral blood white cell, platelet and reticulocyte counts were unaffected. This suggests that the haematopoietic radioprotection and recovery observed in irradiated mice pretreated with Cremophor may be the result of accessory cell activation and/or modulation of accessory factors regulating haematopoietic progenitor cells. Our data suggest a potential clinical use of Cremophor as an adjunct to, or as a substitute for, cytokines to minimize myelosuppression following cytotoxic therapy.
Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
I
I
Bertoncello
A B
AB
Kriegler
D M
DM
Woodcock
B
B
Williams
L
L
Barber
S K
SK
Nilsson
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000528:radiation effects; D001854:Bone Marrow Cells; D002368:Castor Oil; D002999:Clone Cells; D003114:Colony-Forming Units Assay; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005990:Glycerol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010976:Platelet Count / Q000187:drug effects / Q000528:radiation effects*; D011247:Pregnancy; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D017701:Reticulocyte Count / Q000187:drug effects / Q000528:radiation effects*; D012485:Salmonella typhi; D013997:Time Factors
D006133:Growth Substances; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011837:Radiation-Protective Agents; D011994:Recombinant Proteins; C000515:cremophor EL; D002368:Castor Oil; D005990:Glycerol