Modulation of acute myeloblastic leukemia (AML) cell proliferation and blast colony formation by antisense oligomer for IL-1 beta converting enzyme (ICE) and IL-1 receptor antagonist (IL-1ra).
In the present study we investigated the effects of IL-1 antagonism on the autonomous growth of cells in acute myeloblastic leukemia (AML). To examine the role of pro-IL-1 processing, antisense technology was employed with 16-mer phosphorothioate oligodeoxynucleotide directed against human IL-1 beta converting enzyme (ICR) in 7 randomly selected AML cases. The addition of 10-75 microM of antisense oligonucleotide (but not of control oligonucleotide) significantly inhibited spontaneous proliferation of bone marrow- (BM) and peripheral blood- (PB) derived low density leukemic cells in a dose-dependent way. Similarly, spontaneous as well as induced CFU-AML colony formation was inhibited by human ICE antisense oligonucleotide with sample-to-sample variability. In separate experiments, in order to examine the effects of blockade of endogenously produced IL-1 to IL-1 receptors, the functional activity of human recombinant IL-1 receptor antagonist (IL-1ra) was tested. Continuous exposure to high concentrations of IL-1ra (up to 100 micrograms/ml) produced dose-dependent inhibition of spontaneous proliferation of the BM-derived blast cells from 9 of the 14 patients and of the PB-derived cells from 10 of the 14 patients. However, in some of these patients, the lower IL-1ra doses (down to 100 ng/ml) induced potentiation of spontaneous proliferation, suggesting a novel regulatory pathway for IL-1 receptor engagement. Similar results were obtained on CFU-AML colony formation, showing inhibition at higher IL-1ra doses, but in a few AML cases stimulatory effect at lower IL-1ra doses.(ABSTRACT TRUNCATED AT 250 WORDS)
Stosić-Grujicić
S
S
Institute for Biological Research, Clinical Center of Serbia, Belgrade, Yugoslavia.
Basara
N
N
Milenković
P
P
Dinarello
C A
CA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D001752:Blast Crisis; D020170:Caspase 1; D002455:Cell Division / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007375:Interleukin-1; D016376:Oligonucleotides, Antisense; D011498:Protein Precursors; D017472:Receptors, Interleukin-1; D003546:Cysteine Endopeptidases; D020170:Caspase 1