A diphtheria toxin-interleukin 3 fusion protein is cytotoxic to primitive acute myeloid leukemia progenitors but spares normal progenitors

Michaela Feuring-Buske, Arthur E. Frankel, Richard L. Alexander, Brigitte Gerhard, Donna E. Hogge

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

The relative cytotoxicity of a diphtheria toxin (DT) human interleukin 3 (IL3) fusion protein (DT388IL3) was tested against primitive normal (n = 3) and acute myeloid leukemia (AML) progenitors (n = 7). After 24-h culture with 50 ng/ml DT388IL3, the mean percentages of kill of AML colony-forming cells (CFCs), long-term culture-initiating cells (LTC-ICs), and suspension culture-ICs (SC-ICs) were 82% (range, 47-100), 56% (range, 28-91), and 74% (range, 43-87), respectively, with most surviving progenitors being cytogenetically normal. Engraftment of DT388IL-3-treated AML cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice followed for 16 weeks was eradicated for two of these samples. In contrast, with normal bone marrow, mean percentages of CFC kill of 49 and 64% were seen with 50 or 250 ng/ml DT388IL3, respectively, whereas no significant kills were observed in the LTC-IC and SC-IC assays. The NOD/SCID mouse repopulating cell (RC) frequency in normal BM cells was also not reduced by DT388IL3 treatment. In subsequent experiments, NOD/SCID mice that received AML blasts i.v. followed in 24 h by 0.045 μg/g DT388IL3 daily i.p. × 5 showed mean percentages of reduction in AML engraftment of 83% (range, 14-100) and 57% (range, 0-98) after 4 and 12 weeks, respectively (n = 6). No evidence of leukemia was detected with two of six AML samples 12 weeks after one 5-day course of DT388IL3. Repeating the DT388IL3 treatment every 4 weeks enhanced its effectiveness against two additional samples. Thus, DT388IL3 kills primitive leukemic progenitors from a proportion of AML patients but shows no significant toxicity against equivalent normal cells.

Original languageEnglish (US)
Pages (from-to)1730-1736
Number of pages7
JournalCancer research
Volume62
Issue number6
StatePublished - Mar 15 2002

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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