Bracho F, Krailo M D, Shen V, Bergeron S, Davenport V, Liu-Mares W, Blazar B R, Panoskaltsis-Mortari A, van de Ven C, Secola R, Ames M M, Reid J M, Reaman G H, Cairo M S
Lombardi Cancer Center, Georgetown University Hospital, Washington, DC 20007, USA.
Clin Cancer Res. 2001 Jan;7(1):58-67.
A Phase I trial was conducted to determine the safety, biological activity, and hematopoietic recovery by the combination of interleukin 6 (IL-6) and granulocyte-colony stimulating factor (G-CSF) after myelosuppressive chemotherapy in children. Patients <22 years of age at diagnosis with either recurrent or refractory solid tumors received ifosfamide 1,800 mg/m2/day x 5 days, carboplatin 400 mg/m2/ day x 2 days, and etoposide 100 mg/m2/day x 5 days, followed by daily s.c. G-CSF (5 microg/kg/day) and IL-6 (2.5, 3.75, or 5.0 microg/kg/day). Pharmacokinetic, proinflammatory mediator levels, hematopoietic colony assays, and cytokine receptor expression studies were performed during course one. Nineteen patients were evaluable for toxicity and received IL-6 at doses of 2.5 (n = 8), 3.75 (n = 5), or 5.0 (n = 6) microg/kg/day. Dose-limiting constitutional toxicity occurred in two of six patients at 5.0 microg/kg/day, two of five patients at 3.75 microg/kg/day, and two of eight patients at 2.5 microg/kg/day. The maximum tolerated dose (MTD) exceeded the lowest dose tested. Because of lack of drug availability, an MTD was not established. The maximum concentration of IL-6 (2.5 microg/kg/day) was 0.799 +/- 1.055 ng/ml (mean +/- SD). During the first course, the median time to absolute neutrophil count > or = 1,000/mm3 and platelets > or = 100,000 mm3 was estimated at 19 and 23 days, respectively. Peripheral blood progenitor cells expressing receptors to IL-3, IL-6, and G-CSF increased significantly over baseline (P < 0.05). After the first dose of IL-6, IFN-gamma levels were abnormal in 13 patients, and IL-1beta levels were abnormal in 10 patients. IL-6 has a high incidence of constitutional toxicity and a lower MTD in children compared with adults. In vivo use of IL-6 in children after chemotherapy remains limited. However, IL-6 may be more optimally investigated in children under ex vivo conditions.
开展了一项I期试验，以确定儿童骨髓抑制性化疗后白细胞介素6（IL-6）与粒细胞集落刺激因子（G-CSF）联合应用的安全性、生物学活性和造血恢复情况。诊断时年龄<22岁的复发性或难治性实体瘤患者接受异环磷酰胺1800mg/m²/天×5天、卡铂400mg/m²/天×2天、依托泊苷100mg/m²/天×5天，随后每日皮下注射G-CSF（5μg/kg/天）和IL-6（2.5、3.75或5.0μg/kg/天）。在第一个疗程期间进行了药代动力学、促炎介质水平、造血集落测定和细胞因子受体表达研究。19例患者可评估毒性，并接受了2.5（n=8）、3.75（n=5）或5.0（n=6）μg/kg/天剂量的IL-6。在5.0μg/kg/天剂量组的6例患者中有2例、3.75μg/kg/天剂量组的5例患者中有2例、2.5μg/kg/天剂量组的8例患者中有2例发生了剂量限制性全身毒性。最大耐受剂量（MTD）超过了所测试的最低剂量。由于缺乏药物供应，未确定MTD。IL-6（2.5μg/kg/天）的最大浓度为0.799±1.055ng/ml（平均值±标准差）。在第一个疗程期间，绝对中性粒细胞计数≥1000/mm³和血小板≥100000/mm³的中位时间分别估计为19天和23天。表达IL-3、IL-6和G-CSF受体的外周血祖细胞较基线水平显著增加（P<0.05）。首次给予IL-6后，13例患者的IFN-γ水平异常，10例患者的IL-1β水平异常。与成人相比，IL-6在儿童中全身毒性发生率高且MTD较低。化疗后在儿童体内使用IL-6仍然受限。然而，在体外条件下对儿童进行IL-6的研究可能更具优势。
