High affinity interleukin-3 receptor expression on blasts from patients with acute myelogenous leukemia correlates with cytotoxicity of a diphtheria toxin/IL-3 fusion protein.
Diphtheria fusion proteins are a novel class of agents for the treatment of chemotherapy resistant AML. We prepared DT(388)IL3 composed of human interleukin-3 (IL3) fused to the catalytic and translocation domain of diphtheria toxin (DT(388)) and assessed its activity on patient AML blasts. The number and affinity of IL3 receptors in circulating blasts was measured using a radiolabeled IL3 agonist (SC-65461). Ninety-two percent of patients' blasts had both high and low affinity IL3 receptors. DT(388)IL3 cytotoxicity (>1 log cell kill) was seen in nine of 25 samples (36%). There was a significant correlation between DT(388)IL3 log cell kill and blast high affinity IL3 receptor density (P=0.0044). These results show that specific high affinity IL3 binding is one factor important in the sensitivity of patients' leukemic blasts to DT(388)IL3.
Alexander
R L
RL
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Ramage
J
J
Kucera
G L
GL
Caligiuri
M A
MA
Frankel
A E
AE
D000208:Acute Disease; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D004167:Diphtheria Toxin / Q000494:pharmacology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D016185:Receptors, Interleukin-3 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013234:Stem Cells / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; D007377:Interleukin-3; D016185:Receptors, Interleukin-3; D011993:Recombinant Fusion Proteins; C407154:diphtheria toxin-interleukin-3 fusion protein, recombinant