In vitro interleukin-3 binding to leukemia cells predicts cytotoxicity of a diphtheria toxin/IL-3 fusion protein

R. L. Alexander, G. L. Kucera, B. Klein, A. E. Frankel

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Patients with acute myeloid leukemia frequently develop chemotherapy resistant blasts. To overcome multidrug resistance, a diphtheria toxin fusion protein (DTIL3) was engineered by fusing the catalytic and translocation domains of diphtheria toxin (DT) to human interleukin-3 (IL-3). However, when blasts were isolated from patients and tested for colony growth inhibition by DTIL3, only a third of the samples showed sensitivity to the fusion protein. Prior to clinical development, we need to be able to identify which patients are likely to respond to therapy with DTIL3. In this report, we compared the inhibition of thymidine incorporation in human leukemia cell lines by DTIL3 to the IL-3 receptor number and affinity. We found DTIL3 was cytotoxic to four of the eight cell lines tested with half-maximal inhibition of thymidine incorporation (IC50) from 1 to 50 pM. The IL-3 receptor density for these cell lines ranged from 0 to 2635 receptors per cell. The dissociation constant for an IL-3 high-affinity receptor agonist was 0.5 nM for cell lines with receptors. We found a correlation for the cell lines between the presence of high-affinity IL-3 receptors and sensitivity to DTIL3 (p = 0.03). These results suggest the variability in sensitivity of patient leukemic progenitors to DTIL3 may be due in part to the presence or absence of high-affinity IL-3 receptors.

Original languageEnglish (US)
Pages (from-to)564-568
Number of pages5
JournalBioconjugate Chemistry
Volume11
Issue number4
DOIs
StatePublished - Jul 2000

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Diphtheria Toxin
Interleukin-3 Receptors
Interleukin-3
Cytotoxicity
Leukemia
Fusion reactions
Cells
Proteins
Cell Line
Thymidine
Chemotherapy
Multiple Drug Resistance
Acute Myeloid Leukemia
Inhibitory Concentration 50
Catalytic Domain
In Vitro Techniques
Drug Therapy
Growth

ASJC Scopus subject areas

  • Chemistry(all)
  • Organic Chemistry
  • Clinical Biochemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

Cite this

In vitro interleukin-3 binding to leukemia cells predicts cytotoxicity of a diphtheria toxin/IL-3 fusion protein. / Alexander, R. L.; Kucera, G. L.; Klein, B.; Frankel, A. E.

In: Bioconjugate Chemistry, Vol. 11, No. 4, 07.2000, p. 564-568.

Research output: Contribution to journalArticle

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