Treatment of acute myelocytic leukemia with interleukin-6 Pseudomonas exotoxin fusion protein in a rat leukemia model

Leukemia. 1996 Nov;10(11):1796-803.


We studied the applicability of interleukin-6 Pseudomonas exotoxin fusion protein (IL-6PE4E) for treatment of acute myelocytic leukemia (AML). Leukemic cells from five out of 10 AML patients studied expressed IL-6 receptor (IL-6R) and proliferation in vitro was inhibited in four of these cases. The potential of this approach in vivo was tested in a pre-clinical model for AML; the Brown Norway acute myelocytic leukemia (BNML). To obtain IL-6R expression levels on BNML cells comparable to the numbers expressed on human AML, human IL-6R gene transfectants of the BNML sub-line LT12 (LT12/IL-6R) were generated. IL-6PE4E is cytotoxic in vitro to LT12/IL-6R expressing 1400 high affinity IL-6R per cell with 50% inhibition of DNA synthesis at 1 ng/ml. In vivo treatment of leukemic rats carrying LT12/IL-6R leukemia indicated that the maximal tolerated dose of IL-6PE4E was 275 +/- 25 microg/kg/day, when continuously administered for 7 days and resulted in a 90% reduction in leukemic cell load. At this dose level of IL-6PE4E no reduction of normal hemopoietic progenitors was seen in non-leukemic rats. At higher dose levels (350-1050 microg/kg/day) severe systemic toxicity was encountered. On the basis of these pre-clinical studies the feasibility of growth factor-toxins for selective in vivo targeting to AML cells is evaluated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases
  • Animals
  • Antigens, CD / biosynthesis
  • Antigens, CD / genetics
  • Cell Death / drug effects
  • Exotoxins / administration & dosage*
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Infusion Pumps
  • Interleukin-6 / administration & dosage*
  • Leukemia, Experimental / drug therapy*
  • Leukemia, Experimental / metabolism
  • Leukemia, Experimental / pathology
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Rats
  • Rats, Inbred BN
  • Receptors, Interleukin / biosynthesis
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin-6
  • Recombinant Fusion Proteins*
  • Transfection
  • Tumor Cells, Cultured


  • Antigens, CD
  • Exotoxins
  • IL-6-PE40 protein, chimeric
  • Interleukin-6
  • Receptors, Interleukin
  • Receptors, Interleukin-6
  • Recombinant Fusion Proteins
  • ADP Ribose Transferases