PHASE I EVALUATION OF INTERLEUKIN-1 ALPHA

INTERLEUKIN-1 ALPHA 的 I 期评估

• 批准号: 3874542
• 负责人: J W SMITH
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3874542
• 关键词: biological response modifiers; clinical trials; cytokine receptors; dosage; drug administration rate /duration; drug adverse effect; human subject; human therapy evaluation; human tissue; immunomodulators; immunotoxicity; indomethacin; interleukin 1; interleukin 6; leukocyte activation /transformation; neoplasm /cancer immunology; neoplasm /cancer immunotherapy

Interleukin-1 (IL-1) plays a central role in immune responses and might be useful in the treatment of cancer patients for several reasons. We conducted a phase I clinical trial of IL-1 alpha to determine the: (1) toxicity of IL-1 in cancer patients, (2) effects of IL-1 in the immune system, (3) effects of IL-1 on the hemopoietic system, (4) pharmacokinetics of IL-1 and (5) the effect of adding indomethacin on all of the above. All patients had chills, fever, headache, and some had nausea, vomiting, myalgia, arthralgia, and abdominal pain. Hypotension, renal insufficiency, confusion, and abdominal pain were the dose-limiting toxicities. The inpatient-maximum tolerated dose (MTD) of IL-1 alpha administered alone with blood pressure support was determined to be 0.3 mog/kg. With the addition of indomethacin at 25 mg every 8 hours, the maximum tolerated dose was determined to be 0.1 mog/kg. IL-1 alpha did not cause an increase in peripheral blood natural killer cell and lymphokine activated killer cell activity. However, IL-1 treatment did induce increases in serum soluble IL-2 receptor levels and in IL-6 levels. Pharmacokinetic studies indicated measurable IL-1 alpha levels at the two highest dose levels consistent with a short alpha half-life of 10-15 minutes. IL-1 caused a dose related 2-7 fold increase in the white blood count (mainly increased neutrophils and neutrophil bands). The platelet count declined slightly during treatment but increased one and a half to two times above baseline one week later in five patients studied at that time. Bone marrow aspirates one day after the end of treatment showed increased cellularity and increased M/E ratio compared to ones obtained before treatment.

白细胞介素-1（IL-1）在免疫应答中起着重要作用， 用于治疗癌症患者有几个原因。 我们 进行了IL-1 α的I期临床试验，以确定：（1） IL-1在癌症患者中的毒性，（2）IL-1在免疫中的作用 系统，（3）IL-1对造血系统的影响，（4）药代动力学 （5）吲哚美辛对上述指标的影响。 所有患者均有寒战、发热、头痛，部分患者有恶心、呕吐， 肌痛、关节痛和腹痛。 低血压，肾功能不全， 意识模糊和腹痛是剂量限制性毒性。 的 单独给予IL-1 α的住院患者最大耐受剂量（MTD） 在血压支持的情况下，确定为0.3 mog/kg。 与 每8小时增加吲哚美辛25 mg，最大耐受剂量 测定为0.1 mog/kg。 IL-1 α并没有引起 外周血自然杀伤细胞和淋巴因子激活的杀伤细胞 活动 然而，IL-1治疗确实诱导血清可溶性 IL-2受体水平和IL-6水平。 药代动力学研究表明 两个最高剂量水平下的可测量IL-1 α水平与 α半衰期较短，为10-15分钟。 IL-1引起剂量相关的2-7 白色血细胞计数成倍增加（主要是中性粒细胞增加， 中性粒细胞带）。 治疗期间血小板计数略有下降 但一周后， 当时有五名患者接受了研究。 一天后抽取骨髓 治疗结束时显示细胞结构增加和M/E比值增加 与治疗前相比。