Role of suramin as an IL-1 inhibitor in suppression of acute myelogenous leukemia progenitor proliferation.
Interleukin-1 (IL-1) modulates both autocrine and paracrine growth-stimulatory mechanisms of acute myelogenous leukemia (AML) cell proliferation. Recent studies show that blocking the interaction between IL-1 and its receptor may suppress this proliferation. Because suramin, a polysulfonated naphthylurea originally described as an antitrypanosomal agent, was found to inhibit the binding of several growth factors to their receptor, we tested its effect on AML progenitor proliferation. We first examined the effect of suramin on murine EL-4.6.1 cells that express type I IL-1 receptors and found that suramin inhibited the binding of IL-1 to its receptor. We then tested the effect of suramin on AML progenitors using bone marrow samples from 17 patients with AML. In all experiments, suramin inhibited AML blast proliferation in a dose-dependent fashion at concentrations ranging from 30 to 240 microM. IL-1 beta (100 U/mL) partially reversed this inhibitory effect. Suramin also inhibited normal early and mature hematopoietic progenitors, as assessed by both the delta assay and the mixed colony culture assay; however, at the same concentration, suramin suppressed the colony growth of colony-forming units granulocyte-macrophage (CFU-GM) by only 45% compared with an 89% suppression of AML progenitors. IL-1 beta did not negate this inhibitory effect, which suggests that another growth inhibitory mechanism might be operative. Our data suggest that suramin may inhibit AML progenitor proliferation by blocking the interaction of IL-1 and its receptor; therefore, further studies are warranted to evaluate suramin's therapeutic potential in patients with AML.
Estrov
Z
Z
Department of Clinical Investigation, University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA.
Talpaz
M
M
Estey
E H
EH
Strassmann
G
G
D000328:Adult; D000368:Aged; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D013498:Suramin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D016179:Granulocyte Colony-Stimulating Factor; D013498:Suramin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor