Treatment of acute myelocytic leukemia with interleukin-6 Pseudomonas exotoxin fusion protein in a rat leukemia model.
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.
Institute of Hematology, Erasmus University, Rotterdam, The Netherlands.
H
H
Rozemuller
W J
WJ
Rombouts
I P
IP
Touw
D J
DJ
FitzGerald
R J
RJ
Kreitman
I
I
Pastan
A
A
Hagenbeek
A C
AC
Martens
D036002:ADP Ribose Transferases; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D005098:Exotoxins / Q000008:administration & dosage*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007260:Infusion Pumps; D015850:Interleukin-6 / Q000008:administration & dosage*; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011914:Rats, Inbred BN; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D005098:Exotoxins; C064195:IL-6-PE40 protein, chimeric; D015850:Interleukin-6; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D036002:ADP Ribose Transferases