The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies.

Smith, John W.; Urba, Walter J.; Curti, Brendan D.; Elwood, L J; Steis, Ronald G.; Janik, John E.; Sharfman, William H.; Miller, Langdon L.; Fenton, R. G.; Conlon, Kevin C.

doi:10.1200/jco.1992.10.7.1141

Cited by 158 publications

(70 citation statements)

References 24 publications

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“…Clinical trials of cancer patients with IL-1 have been performed before, but only resulted in an antitumor response of o5% to daily bolus IL-1 therapy, mainly due to tachyphylaxis (Smith et al, 1992;Janik et al, 1996). Our observations suggest that combined treatment of IL-1b and IFNg might be more efficient.…”

Section: Discussionmentioning

confidence: 81%

Prolonged exposure to IL-1β and IFNγ induces necrosis of L929 tumor cells via a p38MAPK/NF-κB/NO-dependent mechanism

et al. 2008

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Interleukin-1b (IL-1b) is a cytokine that shares with tumor necrosis factor (TNF) the ability to initiate largely similar signaling pathways, leading to proinflammatory gene expression. In contrast to TNF, however, IL-1b is not believed to induce tumor cell death. Here we demonstrate that prolonged treatment with IL-1b, in combination with interferon-c (IFNc), is cytotoxic for L929 tumor cells. IL-1b/IFNc-induced cytotoxicity requires only minimal amounts of IL-1b and shows morphological features of necrosis. Although TNF induces a similar response, we could exclude a contribution of endogenous TNF production in the effect of IL-1b/IFNc. Cell death in response to IL-1b/IFNc is independent of caspases, but requires the IL-1b/IFNc-induced production of inducible nitric oxide synthase (iNOS) and NO. Moreover, necrosis and iNOS/NO production could be prevented by treatment of the cells with a p38 mitogen activated protein kinase (p38MAPK) or IjB kinase b inhibitor. Altogether, these findings demonstrate that prolonged exposure to IL-1b plus IFNc induces L929 tumor cell necrosis, via a p38MAPK and nuclear factorjB (NF-jB)-dependent signaling pathway, leading to the expression of iNOS and the production of toxic NO levels.

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Section: Discussionmentioning

confidence: 81%

Prolonged exposure to IL-1β and IFNγ induces necrosis of L929 tumor cells via a p38MAPK/NF-κB/NO-dependent mechanism

et al. 2008

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“…In the Memorial Sloan-Kettering and BRMP studies, significant increases in the platelet counts were observed one to two weeks after treatment, and increased megakaryocytes were also observed in bone marrow biopsies performed after seven days of IL-1 treatment in the IL-1 study at the BRMP. Dose-related increases in serum IL-6 levels also were noted after IL-1 treatment in both studies [16,17].…”

Section: Phase I Trialsmentioning

confidence: 99%

“…Patients experienced a number of flu-like symptoms including chills, rigors, fever, nausea, vomiting, fatigue, headache, myalgia and mild somnolence [16]. Fever, chills and rigors occurred in almost every patient but were not dose-limiting.…”

Section: Phase I Trialsmentioning

confidence: 99%

“…Cardiovascular effects were the most worrisome side effects that interfered with dose escalation in all the clinical trials of IL-1 and were well-described in the IL-1α trial [16]. Systolic blood pressure (BP) rose during the first 30 min after treatment but decreased consistently thereafter reaching 90 mm Hg or lower between 3 h and 5 h after treatment with the higher doses.…”

Section: Phase I Trialsmentioning

confidence: 99%

“…infusion over 15 min for seven days in patients with advanced malignancies [16]. An inpatient MTD with maximal supportive measures including blood pressure support with pressors was determined to be 0.3 µg/kg.…”

Section: Phase I Trialsmentioning

confidence: 99%

See 2 more Smart Citations

Interleukin 1 Trials in Cancer Patients: A Review of the Toxicity, Antitumor and Hematopoietic Effects

Veltri

Smith

1996

STEM CELLS

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Abstract. Clinical trials of interleukin 1α (IL-1α)and IL-1β have been completed that assess the toxicities of these cytokines as well as their hematopoietic and antitumor effects. Both forms of IL-1 recognize the same cell surface receptors and have similar toxicities and similar biological activities. Toxicities including fever, flu-like symptoms and dose-limiting hypotension can be severe yet manageable, and IL-1 can be given safely to human cancer patients. Most toxicities and biological effects appear to be dose-related. IL-1 alone has little antitumor activity against melanoma, renal cell carcinomas or other malignancies. The hematopoietic effects, including megakaryocytopoietic effects, are modest and are probably not worth the toxicity necessary to achieve them. However, IL-1 seems to endow certain progenitor cells with responsiveness to other hematopoietic cytokines including colony-stimulating factors and IL-3. One potential application of IL-1 is to help expand bone marrow ex vivo following stem cell harvest, which could allow further chemotherapy dose escalations in chemotherapy-sensitive tumors.

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Antitumor Activity of Interleukin-1 and Cisplatin in a Murine Model System

Grandis

Chang²,

Yu³

et al. 1995

Archives of Otolaryngology - Head and Neck Surgery

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The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies.

Abstract: We conclude that at doses of IL-1 alpha that can be given safely to cancer patients, significant, potentially beneficial hematopoietic effects occur.

Cited by 158 publications

References 24 publications

Prolonged exposure to IL-1β and IFNγ induces necrosis of L929 tumor cells via a p38MAPK/NF-κB/NO-dependent mechanism

Prolonged exposure to IL-1β and IFNγ induces necrosis of L929 tumor cells via a p38MAPK/NF-κB/NO-dependent mechanism

Interleukin 1 Trials in Cancer Patients: A Review of the Toxicity, Antitumor and Hematopoietic Effects

Antitumor Activity of Interleukin-1 and Cisplatin in a Murine Model System

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