The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies.
The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies.
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DOI：
10.1200/jco.1992.10.7.1141
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发表时间：
1992-07
期刊：
影响因子：
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通讯作者：
J. Smith;W. Urba;B D Curti;L J Elwood;R. Steis;J. E. Janik;W. Sharfman;L L Miller-L;R G Fenton;K C Conlon
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文献类型：
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作者：
J. Smith;W. Urba;B D Curti;L J Elwood;R. Steis;J. E. Janik;W. Sharfman;L L Miller-L;R G Fenton;K C Conlon
目的：由于白介素1α(IL-1α)具有抗增殖、免疫刺激、抗感染、骨髓保护和骨髓修复等特性，可用于癌症治疗，因此进行了I期试验。患者和方法在这项I期试验中，IL-1α静脉注射(IV)，每天15分钟，连续7天治疗晚期实体恶性肿瘤患者。结果IL-1α单独给药的最大耐受量为0.3微克/公斤。第二组患者在临床前研究的基础上加用吲哚美辛和IL-1α，结果表明消炎痛可以消除IL-1α引起的低血压，但IL-1α加消炎痛的MTD比单独使用IL-1α低0.1微克/公斤。发热、寒战、头痛、恶心、呕吐和肌痛是常见的，但不受剂量限制。低血压是由于全身血管阻力显著降低所致，所需升压水平分别为0.3和1.0微克/公斤IL-1α。剂量限制毒性包括低血压、心肌梗死、神志不清、剧烈腹痛和肾功能不全。IL-1α治疗导致WBC总数(主要是分段的中性粒细胞和中性粒细胞带)显著增加，且与剂量相关。骨髓细胞密度增加是因为相对成熟的髓系细胞和巨核细胞数量增加。血小板计数在治疗期间下降，但在治疗后1到2周显著高于基线水平；这可能是IL-6的影响，这被证明是由IL-1α治疗所诱导的。治疗后观察到甘油三酯、皮质醇、C反应蛋白、促甲状腺激素显著升高，而胆固醇、睾酮和蛋白C显著降低。结论我们得出结论，在癌症患者可以安全地给予IL-1α的剂量下，出现了显著的、潜在有益的造血效应。
PURPOSE A phase I trial was undertaken because interleukin-1 alpha (IL-1 alpha) possesses antiproliferative, immunostimulatory, antiinfection, myeloprotective, and myelorestorative properties that could be beneficial in cancer treatment. PATIENTS AND METHODS In this phase I trial, IL-1 alpha was administered intravenously (IV) during a 15-minute period daily for 7 days to patients with advanced solid malignancies. RESULTS The maximum-tolerated dose (MTD) of IL-1 alpha alone was 0.3 microgram/kg. A second group of patients received indomethacin plus IL-1 alpha based on preclinical studies, which indicated that indomethacin could abrogate IL-1 alpha-induced hypotension; however, the MTD of IL-1 alpha plus indomethacin was 0.1 microgram/kg lower than IL-1 alpha alone. Fever, chills, headache, nausea, vomiting, and myalgia were common but were not dose-limiting. Hypotension resulted from a marked decrease in systemic vascular resistance and required pressors at 0.3 and 1.0 micrograms/kg IL-1 alpha. Dose-limiting toxicities included hypotension, myocardial infarction, confusion, severe abdominal pain, and renal insufficiency. IL-1 alpha treatment caused a significant, dose-related increase in the total WBC count (mainly segmented neutrophils and neutrophilic bands). Bone marrow cellularity increased because of enhanced numbers of relatively mature myeloid cells and megakaryocytes. Platelet counts decreased during therapy but were significantly elevated above baseline values 1 to 2 weeks posttreatment; this may have been an effect of IL-6 that was shown to be induced by IL-1 alpha treatment. Significant increases in triglycerides, cortisol, C-reactive protein, thyroid-stimulating hormone and decreases in cholesterol, testosterone, and protein-C were observed with treatment. CONCLUSION We conclude that at doses of IL-1 alpha that can be given safely to cancer patients, significant, potentially beneficial hematopoietic effects occur.