PHASE I EVALUATION OF INTERLEUKIN-1 ALPHA

白介素1α(IL-1α)具有抗增殖、 免疫刺激、抗感染、骨髓保护和骨髓保存 可能有益于癌症治疗的特性。在这个阶段 I试验，IL-1α静脉注射，每天超过15分钟，连续7天 给晚期实体恶性肿瘤患者。可容忍的最大值 单用IL-1α剂量(MTD)为0.3微克/公斤。第二组 患者在临床前基础上接受吲哚美辛联合IL-1α治疗 研究表明吲哚美辛可消除IL-1α诱导的 低血压；然而，IL-1α加的最大耐受量 吲哚美辛0.1微克/公斤低于单独使用IL-1α。发烧， 通常会出现寒战、头痛、恶心、呕吐和肌痛。 但不是剂量限制的。低血压是由于血压显著下降引起的 在0.3和1.0的体循环血管阻力和所需升压 微量g/kg IL-1α。剂量限制毒性包括低血压， 心肌梗死、神志不清和肾功能不全。IL-1α 治疗引起与剂量相关的总白质显著增加。 血细胞计数(主要是分段的中性粒细胞和中性粒细胞条带)。骨 由于相对数量的增加，骨髓细胞密度增加 成熟的髓系细胞和巨核细胞。血小板计数下降 在治疗期间，但显著高于基线1-2周 治疗结束后，这可能是由于IL-6 显示是由IL-1α处理诱导的。显著增加了 甘油三酯、皮质醇、C反应蛋白、促甲状腺激素 并观察到胆固醇、睾酮和蛋白-C的下降 接受治疗。药代动力学研究表明IL-1α具有 半衰期短，为10-15分钟。我们得出的结论是，在剂量为 可以安全地给予癌症患者的IL-1α，意义重大， 具有潜在的有益的造血作用。

Interleukin-1 alpha (IL-1Alpha) possesses antiproliferative, immunostimulatory, anti-infection, myeloprotective, and myelorestorative properties that could be beneficial in cancer treatment. In this phase I trial, IL-1Alpha was administered IV over 15 minutes daily for 7 days to patients with advanced solid malignancies. The maximum tolerated dose (MTD) of IL-1Alpha alone was 0.3 Micro g/kg. A second group of patients received indomethacin plus IL-1Alpha based on preclinical studies indicating that indomethacin could abrogate IL-1Alpha-induced hypotension; however, the maximum tolerated dose of IL-1Alpha plus indomethacin, 0.1 Micro g/kg, was lower than IL-1Alpha alone. Fever, chills, headache, nausea, vomiting, and myalgia were commonly observed but were not dose-limiting. Hypotension resulted from a marked decrease in systemic vascular resistance and required pressors at 0.3 and 1.0 Micro g/kg IL-1Alpha. Dose-limiting toxicities included hypotension, myocardial infarction, confusion, and renal insufficiency. IL-1Alpha treatment caused a significant, dose-related increase in total white blood count (mainly segmented neutrophils and neutrophilic bands). Bone marrow cellularity increased due to enhanced numbers of relatively mature myeloid cells and megakaryocytes. Platelet counts declined during therapy but were significantly elevated above baseline 1-2 weeks after the end of treatment; this may have been due to IL-6 that was shown to be induced by IL-1Alpha treatment. Significant increases in triglycerides, cortisol, C-reactive protein, thyroid stimulating hormone and decreases in cholesterol, testosterone and protein-C were observed with treatment. Pharmacokinetic studies indicated IL-1Alpha to have a short half-life of 10-15 minutes. We conclude that at doses of IL-1Alpha that can be safely given to cancer patients, significant, potentially beneficial hematopoietic effects occur.