Toxicology and pharmacokinetics of DT388-GM-CSF, a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human granulocyte-macrophage colony-stimulating factor (GM-CSF)in C57BL/6 mice

Philip D. Hall, Robert J. Kreitman, Mark C. Willingham, Arthur E. Frankel

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Because the majority of acute myeloid leukemia (AML) blasts express the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor, we are developing a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human GM-CSF for multi-drug resistant AML. Our goal was to determine the toxicity and pharmacokinetics of DT388-GM-CSF in C57BL/6 mice. Because human GM-CSF does not cross-react with the mouse GM-CSF receptor, the toxicity observed should be nonspecific toxicity of DT388. We injected C57BL/6 mice ip with 0.1, 0.5, 1.0, 1.5, 1.75, 2.0, 3.5, 5.0, or 10 μg/day of DT388-GM-CSF for 5 consecutive days. For pharmacokinetics, blood samples were drawn at 20, 40, 60, 120, and 180 min after ip administration of 81 μg/kg of DT388-GM-CSF. In mice, the LD10 of DT388-GM-CSF is between 84.4 (1.5) and 104.4 (1.75) μg/kg (μg) when administered for 5 consecutive days. All mice receiving ≤201 μg/kg (3.5 μg) for 5 consecutive days died. Histopathologic examination of morbid animals showed only renal toxicity with acute proximal tubular necrosis. DT388-GM-CSF is stable in vivo based on nonreducing SDS-PAGE gel of plasma samples of 125I-labeled DT388-GM-CSF injected ip. The peak concentration of DT388-GM-CSF was 3.3 x 10-8M at 40 min and exhibited a t 1/4 of 24 min. Based on its haft-life, DT388-GM-CSF concentrations in the plasma are above the concentration inhibiting 50% protein synthesis and inducing apoptosis in 50% of HL-60 cells (AML cell line) for 5.2 h. Only four of 17 mice developed a weak immune response (0.9-160 ng/mL) 3 weeks after treatment. DT388-GM-CSF exhibits a short t 1/4 , but concentrations exceed those required in vitro to inhibit AML cell lines.

Original languageEnglish (US)
Pages (from-to)91-97
Number of pages7
JournalToxicology and Applied Pharmacology
Volume150
Issue number1
DOIs
StatePublished - May 1998

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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