Haematopoietic Radioprotection by Cremophor EL: A Polyethoxylated Castor Oil

Abstract

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.

Differential modulation of cisplatin accumulation in leukocytes and tumor cell lines by the paclitaxel vehicle Cremophor EL

“…Recent studies in mice showed that such low i.v. doses of Cremophor EL did not result in localized toxicity or marrow destruction [25], which is consistent with flow cytometric studies demonstrating that even very high concentrations of Cremophor EL (> 10%) did not lyse bone marrow cell membranes [26]. Moreover, the i.v.…”

“…Moreover, the i.v. administration of Cremophor EL was associated with an increase in the incidence of both primitive and committed progenitors, and protected mice from irradiation-induced death [25]. These findings provide a rationale for attempts to circumvent cw-Pt-associated myelotoxicity by concomitant administration of Cremophor EL.…”

A Phase I and Pharmacokinetic Study of Weekly Paclitaxel and Carboplatin in Patients with Metastatic Esophageal Cancer

“…Experimental studies have shown an antagonistic interaction between the two drugs in the megakaryoblast cell line MEG-01 as a model of a platelet precursor (36), which may involve induced production of hematopoietic cytokines, including thrombopoietin, possibly combined with gluthatione S-transferase-mediated detoxification of carboplatin (37). Alternatively, we have recently shown that Cremophor EL, at concentrations achieved in the patients in the current study, acts as a protector for cisplatin-associated hematological side effects in both mice and cancer patients (38), presumably by modulation of accessory factors regulating hematopoietic progenitor cells through the operation of cytokine cascades (39). Further studied beyond the scope of this trial will be required to fully elucidate the mechanisms underlying the platelet-sparing effect of the paclitaxel-carboplatin combination.…”

Genistein treatment protects mice from ionizing radiation injury

“…Mice administered the PEG-400 vehicle also exhibited a significant enhancement in 30-day survival, with a DRF of 1.04. PEG-400 had previously been shown to be radioprotective (Shaeffer et al, 1986), as were other excipients such as Emulphor (Landauer et al, 2001a), Cremophor (Bertoncello et al, 1995), and dimethyl sulfoxide (Moos et al, 1967).…”