Induction of interleukin 1 receptor antagonist after interleukin 1 therapy in patients with cancer.
The interleukin 1 receptor antagonist (IL-1ra) is a naturally occurring molecule that shares homology with IL-1alpha and IL-1beta and binds competitively to IL-1 receptors. Serum concentrations of IL-1ra were measured by ELISA in patients enrolled in Phase I clinical trials of IL-1alpha and IL-1beta given by 15-min infusion. Pretreatment levels of IL-1ra were <1500 (mean, 453 +/- 57) pg/ml. IL-1ra levels were increased in some patients within 1 h of completing the IL-1 infusion. By 2 h after infusion, serum levels of IL-1ra had increased dramatically, and they remained stable 4 h after infusion. There was evidence that peak IL-1ra levels were IL-1 dose dependent. Seven patients treated with IL-1alpha had IL-1ra levels that exceeded 1 microgram/ml. In contrast, serum levels of IL-1 declined rapidly and were undetectable 1 h after completing IL-1 infusion in most patients receiving <1.0 microgram/kg. IL-1ra levels remained slightly elevated over pretreatment values in serum obtained 18-24 h after IL-1 infusion, but there was no evidence for progressive accumulation over repeated days of therapy. A similar pattern of IL-1ra elevation was observed after the last IL-1 infusion on day 6. This study shows that cancer patients produce 2 to >6 log incremental increases in IL-1ra rapidly following treatment with IL-1, a response that has implications for the design of future clinical trials with IL-1 and with agents thought to induce IL-1 production.
Kopp
W C
WC
Clinical Services Program, Science Applications International Corp. Services, Inc., National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA.
Urba
W J
WJ
Rager
H C
HC
Alvord
W G
WG
Oppenheim
J J
JJ
Smith
J W
JW
Longo
D L
DL
D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009369:Neoplasms / Q000628:therapy*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D012795:Sialoglycoproteins / Q000096:biosynthesis*
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins