A phase I trial of recombinant human interleukin-1β(OCT-43) following high-dose chemotherapy and autologous bone marrow transplantation

Abstract

Summary:The use of lineage-specific hematopoietic growth factors such as GM-CSF and G-CSF shortens the duration of neuWe studied the effects of escalating doses of recombitropenia following high-dose chemotherapy and ABMT. 1-3 nant human IL-1␤ in patients receiving high-doseRecently with molecular cloning much interest has emerged chemotherapy and ABMT for metastatic breast cancer in the use of growth factors, which have multilineage proor malignant melanoma. Sixteen patients received ILliferative effects, to shorten the duration of neutropenia and 1␤, 4 to 32 ng/kg/day administered subcutaneously for platelet transfusion-dependence and to decrease the number 7 days beginning 3 h after bone marrow infusion. Three of red blood cell transfusions. 4 patients at the highest dose level also received G-CSF IL-1␤ is a polypeptide which exerts effects on hematofollowing completion of IL-1␤. All patients completed poiesis through several mechanisms, and produces a broad the 7 days of therapy. The majority of patients experispectrum of metabolic, immunologic and inflammatory enced chills and fever following one or more injections, effects. 5,6 In addition to having a direct stimulatory effect and seven had severe pain at the injection site. There on early myeloid precursors, 7 IL-1␤ stimulates the prowas one episode of hypotension and one episode of tranduction of other cytokines by accessory cells, including Gsient confusion at the highest dose level; other signifi-CSF, GM-CSF, M-CSF, IL-6, IL-1 receptor antagonist cant toxicity was not identified. Recovery of neutrophils molecule (IL-1ra) and soluble receptors for tumor necrosis to Ͼ0.5 ؋ 10 9 /l and platelet transfusion independence factor (sTNF-r) 8-11 all of which appear important in the occurred at a median of 23 and 22 days, respectively, growth of both early and late hematopoietic progenitor which was comparable to historical controls. The mean cells. IL-1 increases the proliferation and differentiation of number of bone marrow colony-forming unit granulobone marrow progenitor cells in the presence of G-CSF. 12 cyte-macrophage (CFU-GM) per 10 5 mononuclear cells IL-1␤ also enhances the resistance of normal and neutroon day ؉21 post-ABMT was more than twice that of penic mice to gram-negative infections and enhances hemacontrol patients or patients receiving G-CSF or GMtopoietic recovery after lethal irradiation or treatment with CSF. A linear correlation was found between the dose 5-fluorouracil. 13 Enhancement of natural killer (NK) cell of IL-1␤ and endogenous concentrations of several cytoactivity by IL-1 and direct cytotoxic activity against tumor kines. These patients also displayed significantly higher cells has also been reported. 5 Preclinical studies in nonconcentrations of endogenous G-CSF compared to hishuman primates have demonstrated enhanced neutrophil torical controls receiving GM-CSF. While IL-1␤ was recovery following chemotherapy in animals receiving ILmoderately toxic and had no effect on recovery of 1␤. 14 Phase I studies in humans with normal...

IL-1β Suppresses Prolonged Akt Activation and Expression of E2F-1 and Cyclin A in Breast Cancer Cells

“…G 1 CDK activity and G 1 cyclin availability define a final common pathway for growth factors (3) and cytostatic cytokines (4). IL-1␤ is a prototypical proinflammatory cytokine that exerts a plethora of biological activities, including tumor regression (5). The tumor-suppressing property of IL-1␤ has been attributed mostly to its ability to prime antitumor immunity (6), but the mechanism for its direct cytostatic actions in suppressing cell cycle progression is largely unknown.…”

Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin

“…IL-6 injection produces hyperalgesia, and in IL-6 Ϫ/Ϫ mutants, heat sensitivity of nociceptors has been shown to be reduced (Zhong et al, 1999). Second, some cytokines such as TNF-␣ or IL-1␤ have been used for adjuvant chemotherapy, but approximately one-half of the treated patients developed pain syndromes and complained about local tenderness at the injection site (Kemeny et al, 1990;Del Mastro et al, 1995;Elkordy et al, 1997). In experimental models, TNF-␣ and IL-1␤ induced excitation in nociceptors and hyperalgesia (Ferreira et al, 1988;Cunha et al, 1992;Sorkin et al, 1997;Kanaan et al, 1998;Sommer et al, 1998Sommer et al, , 1999, and both are suggested to activate receptor-associated kinases, e.g., IL-1 receptor-associated kinase (IRAK) (Cao et al, 1996).…”

Interleukin 1

“…beim Malignen Melanom (Protokoll: 4-32 ng IL-1β/kg/Tag, Beginn 3 h nach ABMT für 7 Tage) [13]. die ᭤ Expansion von Knochenmarkzellen ex vivo im Rahmen einer Chemotherapie oder s.c. Applikation nach Hochdosischemotherapie und autologer Knochenmarktransplantation z.B.…”