Thrombopoietic effects and toxicity of interleukin-6 in patients with ovarian cancer before and after chemotherapy: a multicentric placebo- controlled, randomized phase Ib study

Recombinant human interleukin-6 (IL-6) has previously been shown to increase platelet counts in normal and sublethally irradiated mice, dogs, and primates. To assess its tolerance and efficacy in clinical use, we performed a randomized phase Ib study in patients with ovarian carcinoma. IL-6 was administered during an initial 7-day cycle before any chemotherapy. Beginning 7 days later, six cycles of chemotherapy containing carboplatin were administered every 3 weeks. During chemotherapy cycles 2 to 6, IL-6 was administered from day 4 through day 17 at escalating dose levels from 0.5 to 10 micrograms/kg/d. At each level, three patients received IL-6 and one patient received a placebo. During the prechemotherapy cycle of IL-6, a dose-dependent increase in platelet count was observed from day 12 to 15 and was maximal on day 15 (r = .77; P < .01). The median ploidy of bone marrow megakaryocytes shifted from 16 N to 32 N after 7 days of the initial prechemotherapy IL-6 administration. Dose-dependent increases in C-reactive protein (CRP) and fibrinogen levels were observed on day 8 (P < .0001 for both). A significant decrease in hemoglobin level occured rapidly after initiation of IL-6 therapy and was maximal on day 8 (P < .001). When given after chemotherapy, IL-6 accelerated platelet recovery after chemotherapy cycles 2 to 6. Postponements of scheduled chemotherapy due to thrombocytopenia were less frequent in patients treated with IL-6. No difference in either neutrophils or peripheral blood progenitor assays was observed during or after IL-6 treatment. Toxicity of IL-6 appeared mild and was not dose-limiting up to 10 micrograms/kg/d. Systemic symptoms such as fever, headache, and myalgia were the main side effects and were easily relieved by acetaminophen administration. No biologic toxicity was observed. The data indicate that IL-6 is a well-tolerated cytokine and capable of accelerating platelet recovery in patients receiving chemotherapy.

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Concentrations of the acute phase reactants high-sensitive C-reactive protein and YKL-40 and of interleukin-6 before and after treatment in patients with acromegaly and growth hormone deficiency

Clinical Endocrinology ◽

10.1111/j.1365-2265.2007.02986.x ◽

2007 ◽

Vol 67 (6) ◽

pp. 909-916 ◽

Cited By ~ 13

Author(s):

Mikkel Andreassen ◽

Henrik Vestergaard ◽

Lars Østergaard Kristensen

Keyword(s):

Growth Hormone ◽

Growth Hormone Deficiency ◽

Acute Phase ◽

Interleukin 6 ◽

Hormone Deficiency ◽

C Reactive Protein ◽

Acute Phase Reactants ◽

Reactive Protein ◽

Before And After

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S100A8/A9 (Calprotectin), Interleukin-6, and C-Reactive Protein in Obesity and Diabetes before and after Roux-en-Y Gastric Bypass Surgery

Obesity Facts ◽

10.1159/000478097 ◽

2017 ◽

Vol 10 (4) ◽

pp. 386-395 ◽

Cited By ~ 4

Author(s):

Louise Lylloff ◽

Lise Bathum ◽

Sten Madsbad ◽

Josefine Liv Gilling Grundtvig ◽

Inge Nordgaard-Lassen ◽

...

Keyword(s):

Gastric Bypass ◽

Interleukin 6 ◽

Bypass Surgery ◽

Gastric Bypass Surgery ◽

C Reactive Protein ◽

Reactive Protein ◽

Obesity And Diabetes ◽

Before And After

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In vivo effects of recombinant human interleukin-6 in primates: stimulated production of platelets

Blood ◽

10.1182/blood.v75.8.1602.bloodjournal7581602 ◽

1990 ◽

Vol 75 (8) ◽

pp. 1602-1605 ◽

Cited By ~ 1

Author(s):

S Asano ◽

A Okano ◽

K Ozawa ◽

T Nakahata ◽

T Ishibashi ◽

...

Keyword(s):

Interleukin 6 ◽

C Reactive Protein ◽

Subcutaneous Injections ◽

Acid Glycoprotein ◽

Reactive Protein ◽

Morphologic Analysis ◽

In Vivo Effects ◽

Dose Dependent ◽

Second Peak

In cynomolgus monkeys, twice daily subcutaneous injections of recombinant human interleukin-6 (rhIL-6) at doses of 5 to 80 micrograms/kg/d for 14 consecutive days caused dose-dependent increases in platelet count, usually continuing for more than 1 week after cessation of the injections. The count reached a level approximately twofold or more above the preinjection level even at 5 micrograms/kg/d, and at doses of more than 20 micrograms/kg/d, the increase became biphasic with a higher second peak 3 days after cessation of the injections. Morphologic analysis of the bone marrow after the 7 day- injections with 80 micrograms/kg/d revealed a marked increment in size of megakaryocytes compared with control, indicating the promotion of megakaryocyte maturation. Other changes attributable to the rhIL-6 treatment include dose-dependent loss of body weight, anemia, neutrophilia and monocytosis, elevation of serum C-reactive protein and alpha-1 acid glycoprotein levels, and decrease of serum albumin; all of which returned to normal within 1 week after cessation of the injections and were tolerable at doses of less than 10 micrograms/kg/d. These findings suggest that rhIL-6 may be an effective strategy for the treatment of thrombocytopenia.

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C-reactive protein and vein graft disease: evidence for a direct effect on smooth muscle cell phenotype via modulation of PDGF receptor-β

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00079.2008 ◽

2008 ◽

Vol 295 (3) ◽

pp. H1132-H1140 ◽

Cited By ~ 12

Author(s):

Karen J. Ho ◽

Christopher D. Owens ◽

Thomas Longo ◽

Xin X. Sui ◽

Cristos Ifantides ◽

...

Keyword(s):

Smooth Muscle ◽

Vein Graft ◽

Cell Phenotype ◽

C Reactive Protein ◽

Vein Grafts ◽

Reactive Protein ◽

Vein Graft Disease ◽

Graft Disease ◽

Dose Dependent Increase ◽

Dose Dependent

Plasma C-reactive protein (CRP) concentration is a biomarker of systemic atherosclerosis and may also be associated with vein graft disease. It remains unclear whether CRP is also an important modulator of biological events in the vessel wall. We hypothesized that CRP influences vein graft healing by stimulating smooth muscle cells (SMCs) to undergo a phenotypic switch. Distribution of CRP was examined by immunohistochemistry in prebypass human saphenous veins (HSVs, n = 21) and failing vein grafts ( n = 18, 25–4,400 days postoperatively). Quiescent HSV SMCs were stimulated with human CRP (5–50 μg/ml). SMC migration was assessed in modified Boyden chambers with platelet-derived growth factor (PDGF)-BB (5–10 ng/ml) as the chemoattractant. SMC viability and proliferation were assessed by trypan blue exclusion and reduction of Alamar Blue substrate, respectively. Expression of PDGF ligand and receptor (PDGFR) genes was examined at RNA and protein levels after 24–72 h of CRP exposure. CRP staining was present in 13 of 18 diseased vein grafts, where it localized to the deep media and adventitia, but it was minimally detectable in most prebypass veins. SMCs pretreated with CRP demonstrated a dose-dependent increase in migration to PDGF-BB ( P = 0.02), which was inhibited by a PDGF-neutralizing antibody. SMCs treated with CRP showed a dose-dependent increase in PDGFRβ expression and phosphorylation after 24–48 h. Exogenous CRP had no effect on SMC viability or proliferation. These data suggest that CRP is detectable within the wall of most diseased vein grafts, where it may exert local effects. Clinically relevant levels of CRP can stimulate SMC migration by a mechanism that may involve upregulation and activation of PDGFRβ.

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In vivo effects of recombinant human interleukin-6 in primates: stimulated production of platelets

Blood ◽

10.1182/blood.v75.8.1602.1602 ◽

1990 ◽

Vol 75 (8) ◽

pp. 1602-1605 ◽

Cited By ~ 169

Author(s):

S Asano ◽

A Okano ◽

K Ozawa ◽

T Nakahata ◽

T Ishibashi ◽

...

Keyword(s):

Interleukin 6 ◽

C Reactive Protein ◽

Subcutaneous Injections ◽

Acid Glycoprotein ◽

Reactive Protein ◽

Morphologic Analysis ◽

In Vivo Effects ◽

Dose Dependent ◽

Second Peak

Abstract In cynomolgus monkeys, twice daily subcutaneous injections of recombinant human interleukin-6 (rhIL-6) at doses of 5 to 80 micrograms/kg/d for 14 consecutive days caused dose-dependent increases in platelet count, usually continuing for more than 1 week after cessation of the injections. The count reached a level approximately twofold or more above the preinjection level even at 5 micrograms/kg/d, and at doses of more than 20 micrograms/kg/d, the increase became biphasic with a higher second peak 3 days after cessation of the injections. Morphologic analysis of the bone marrow after the 7 day- injections with 80 micrograms/kg/d revealed a marked increment in size of megakaryocytes compared with control, indicating the promotion of megakaryocyte maturation. Other changes attributable to the rhIL-6 treatment include dose-dependent loss of body weight, anemia, neutrophilia and monocytosis, elevation of serum C-reactive protein and alpha-1 acid glycoprotein levels, and decrease of serum albumin; all of which returned to normal within 1 week after cessation of the injections and were tolerable at doses of less than 10 micrograms/kg/d. These findings suggest that rhIL-6 may be an effective strategy for the treatment of thrombocytopenia.

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