Bukowski R M, Olencki T, Gunn H, McLain D, Budd G T, Sandstrom K, Tuason L, Redovan C, Rayman P, Tubbs R, Resta D, Elson P, Finke J
Departments of Hematology and Medical Oncology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Clin Cancer Res. 1996 Feb;2(2):347-57.
We conducted a Phase I trial of s.c. recombinant human interleukin 3 (rhIL-3) to evaluate the toxicity, maximal tolerated dose, pharmacokinetics, and in vivo biological effects of this cytokine. Thirty-one patients with refractory cancer were entered into the study between November 1991 and June 1993. Therapy consisted of s.c. rhIL-3 daily for 15 days administered to cohorts of three to nine patients at dose levels of 60-4000 microgram/m2/day. Cycles were repeated at intervals of 28 days. Seventy-five cycles of rhIL-3 were administered (median, two per patient) and the maximal tolerated dose was 2000 microgram/m2/day. Toxicity was moderate, with most patients developing chills, fever, and myalgia. Dose-limiting toxicity consisted of diarrhea (two patients) and headache (one patient). Hematological effects of rhIL-3 included significant dose-related increases of WBC (P < 0.001), neutrophils (P < 0.001), and eosinophils (P < 0.001). Platelet counts and absolute lymphocyte numbers also increased. Various CD3(+) lymphocyte subsets increased; however, lytic activity (natural killer and lymphokine-activated killer) of peripheral blood lymphocytes was not enhanced. Serum levels of the soluble IL-2 receptor increased in a dose-related fashion, and IL-2-induced lymphocyte proliferation also was increased variably. Pharmacokinetic studies were performed in 13 patients, and area under the curve and maximal concentration values increased with increasing rhIL-3 dose levels (P < 0.001) and correlated with maximal changes from baseline in WBC, neutrophils, and eosinophils. rhIL-3 antibodies were detected in 8% of patients by day 29 of cycle 1 but were not neutralizing. rhIL-3 is well tolerated when administered s.c. and has reproducible hematological and immunological effects. The pleiotropic effects of this cytokine on various in vivo biological parameters were demonstrated clearly. Further studies of its immunoregulatory effects are warranted.
我们进行了一项皮下注射重组人白细胞介素3（rhIL-3）的I期试验，以评估这种细胞因子的毒性、最大耐受剂量、药代动力学及体内生物学效应。1991年11月至1993年6月期间，31例难治性癌症患者进入该研究。治疗方案为皮下注射rhIL-3，每日1次，共15天，以60 - 4000微克/平方米/天的剂量水平给予3至9名患者为一组。每28天重复一个周期。共给予75个rhIL-3周期（中位数为每名患者2个周期），最大耐受剂量为2000微克/平方米/天。毒性为中度，大多数患者出现寒战、发热和肌痛。剂量限制性毒性包括腹泻（2例患者）和头痛（1例患者）。rhIL-3的血液学效应包括白细胞（P < 0.001）、中性粒细胞（P < 0.001）和嗜酸性粒细胞（P < 0.001）显著的剂量相关增加。血小板计数和绝对淋巴细胞数也增加。各种CD3(+)淋巴细胞亚群增加；然而，外周血淋巴细胞的溶解活性（自然杀伤细胞和淋巴因子激活的杀伤细胞）未增强。可溶性IL-2受体的血清水平呈剂量相关升高，IL-2诱导的淋巴细胞增殖也有不同程度增加。对13例患者进行了药代动力学研究，曲线下面积和最大浓度值随rhIL-3剂量水平增加而升高（P < 0.001），并与白细胞、中性粒细胞和嗜酸性粒细胞相对于基线的最大变化相关。在第1周期第29天时，8%的患者检测到rhIL-3抗体，但这些抗体无中和作用。皮下注射rhIL-3耐受性良好，具有可重复的血液学和免疫学效应。该细胞因子对各种体内生物学参数的多效性效应得到了明确证实。有必要对其免疫调节作用进行进一步研究。
