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Erufosine, an alkylphosphocholine, with differential toxicity to human cancer cells and bone marrow cells

Abstract

Purpose

To investigate the activity and myeloprotective properties of erufosine, a novel alkylphosphocholine (APC), on human malignant cells and normal bone marrow cells.

Methods

Human or mouse bone marrow cells were exposed to erufosine, miltefosine, perifosine, or edelfosine in CFU-GM assays. Human MDA-MB-231 breast carcinoma, Panc-1 pancreatic carcinoma, and RPMI8226 multiple myeloma cells were exposed to erufosine in colony formation assays. Colony formation of Panc-1 tumor cells and mouse bone marrow cells ex vivo were quantified following intravenous administration of erufosine to tumor-bearing mice. Western blotting methods were applied to human U87 glioblastoma cells exposed to erufosine to investigate Akt inhibition.

Results

Erufosine was less toxic to human and mouse bone marrow cells than perifosine, miltefosine, and edelfosine and was equally toxic to human and mouse CFU-GM. The human cancer cells MDA-MB-231 breast, Panc-1 pancreatic, and RPMI8226 MM cells were more sensitive to erufosine in a colony formation assay than were human bone marrow cells generating an approximately tenfold differential in IC90 values. Erufosine injected intravenously significantly reduced Panc-1 tumor cell colony formation ex vivo but not mouse bone marrow CFU-GM. Erufosine inhibited Akt phosphorylation in human U87 glioblastoma cells.

Conclusions

Erufosine offers potential as a novel therapeutic for cancer with a reduced toxicity profile to bone marrow cells compared with other agents in this class. Human cancer cells were more sensitive to erufosine than human or mouse bone marrow cells indicating a favorable therapeutic window for erufosine.

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Abbreviations

APL:

Alkylphospholipid

APC:

Alkylphosphocholine

CFU-GM:

Colony-forming unit–granulocyte– macrophage

IC:

Inhibitory concentration

FBS:

Fetal bovine serum

rm:

Recombinant murine

rh:

Recombinant human

GBM:

Glioblastoma

IV:

Intravenous

CML:

Chronic myeloid leukemia

AML:

Acute myeloid leukemia

MM:

Multiple myeloma

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Correspondence to Rebecca G. Bagley.

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Bagley, R.G., Kurtzberg, L., Rouleau, C. et al. Erufosine, an alkylphosphocholine, with differential toxicity to human cancer cells and bone marrow cells. Cancer Chemother Pharmacol 68, 1537–1546 (2011). https://doi.org/10.1007/s00280-011-1658-0

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  • DOI: https://doi.org/10.1007/s00280-011-1658-0

Keywords

  • Erufosine
  • Alkylphosphocholine
  • Lipid
  • Bone marrow
  • Cancer
  • Toxicity