Atkins M B, Gould J A, Allegretta M, Li J J, Dempsey R A, Rudders R A, Parkinson D R, Reichlin S, Mier J W
J Clin Oncol. 1986 Sep;4(9):1380-91. doi: 10.1200/JCO.1986.4.9.1380.
Seventeen patients with refractory malignant tumors were treated with recombinant human interleukin-2 (IL-2) administered by weekly bolus intravenous (IV) injection in a phase I dose escalation trial. Patients received 10,000 to 1,000,000 U/m2 per injection over a course of 3 to 33 weeks. Toxicity was dose related and consisted primarily of fever, chills, nausea, and vomiting. Hypotension was observed at doses of 500,000 U/m2 or higher and in one instance was sufficiently severe to require pressors. No tumor regression was seen and all patients eventually developed progressive disease. Blood levels of cortisol, ACTH, prolactin, and growth hormone as well as the acute phase reactant C-reactive protein (CRP) increased after the administration of IL-2 in most patients. Serum IL-2 levels in excess of 250 U/mL were detected five minutes after an IV injection of 1,000,000 U/m2, after which the levels declined with a half-life of approximately 25 minutes. No alteration in lymphocyte surface phenotype or enhancement in natural cell-mediated cytotoxicity against natural killer (NK)-sensitive and resistant tumor cell lines was observed when these parameters were measured weekly just before the IL-2 injections. However, a dramatic but transient decline in circulating lymphocytes and NK activity was noted within hours of receiving IL-2. This effect was independent of fever and was not abrogated by pretreatment with ibuprofen or metyrapone. The majority of patients developed serum IgG antibodies of IL-2 detectable with a sensitive enzyme-linked immunosorbent assay (ELISA) and a nitrocellulose dot blot assay. The development of anti-IL-2 antibodies was not associated with symptoms suggestive of serum sickness, reductions in serum complement levels, or deterioration in lymphocyte tumoricidal activity. This investigation provides insight into the in vivo actions of this potent biological response modifier and will assist in the design of future studies with IL-2 administered alone or in conjunction with other treatment modalities.
在一项I期剂量递增试验中，对17例难治性恶性肿瘤患者采用重组人白细胞介素-2（IL-2）进行每周一次大剂量静脉注射治疗。患者在3至33周的疗程中每次注射剂量为10,000至1,000,000 U/m²。毒性与剂量相关，主要包括发热、寒战、恶心和呕吐。在剂量为500,000 U/m²或更高时观察到低血压，有1例严重到需要使用升压药。未观察到肿瘤缩小，所有患者最终均出现疾病进展。大多数患者在给予IL-2后，皮质醇、促肾上腺皮质激素、催乳素和生长激素的血药浓度以及急性期反应物C反应蛋白（CRP）均升高。静脉注射1,000,000 U/m²后5分钟检测到血清IL-2水平超过250 U/mL，此后水平下降，半衰期约为25分钟。在每周IL-2注射前测量这些参数时，未观察到淋巴细胞表面表型改变或针对自然杀伤（NK）敏感和耐药肿瘤细胞系的自然细胞介导细胞毒性增强。然而在接受IL-2后数小时内，循环淋巴细胞和NK活性显著但短暂下降。这种效应与发热无关，布洛芬或美替拉酮预处理不能消除这种效应。大多数患者通过灵敏的酶联免疫吸附测定（ELISA）和硝酸纤维素斑点印迹法检测到可检测到的IL-2血清IgG抗体。抗IL-2抗体的产生与血清病相关症状、血清补体水平降低或淋巴细胞杀瘤活性恶化无关。本研究深入了解了这种强效生物反应调节剂的体内作用，并将有助于设计未来单独使用IL-2或与其他治疗方式联合使用的研究。
