PHASE I EVALUATION OF INTERLEUKIN-1 ALPHA

白介素1(IL-1)在免疫反应中发挥核心作用，并可能是 有益于癌症患者的治疗有几个原因。我们 进行了IL-1α的I期临床试验，以确定：(1) 白介素1对癌症患者的毒性作用，(2)白介素1对免疫的影响 系统；(3)IL-1对造血系统的影响；(4)药代动力学 IL-1的影响；(5)加入消炎痛对上述指标的影响。 所有患者都有寒战、发烧、头痛，还有一些患者出现恶心、呕吐、 肌肉痛、关节痛和腹痛。低血压，肾功能不全， 精神错乱和腹痛是剂量限制的毒性。这个 住院患者单独使用IL-1α的最大耐受量(MTD) 血压支持值为0.3mog/kg。与 加入吲哚美辛，每8小时25毫克，最大耐受量 被确定为0.1mog/kg。IL-1α不会导致血管紧张素转换酶活性增加 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治疗确实引起了血清中可溶性的增加 IL-2受体水平和IL-6水平。药代动力学研究表明 在两个最高剂量水平下可测量的IL-1α水平与 阿尔法半衰期很短，为10-15分钟。IL-1引起的剂量相关2-7 白血球计数成倍增加(主要是中性粒细胞和 中性粒细胞条带)。治疗期间，血小板计数略有下降。 但在一周后比基线增加了1.5到2倍 当时有五名患者接受了研究。骨髓抽吸一天后 治疗结束时，细胞数增加，M/E比值增加 与治疗前相比。

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.