Grant S, Roberts J, Poplin E, Tombes M B, Kyle B, Welch D, Carr M, Bear H D
Department of Medicine, Virginia Commonwealth University, Richmond 23298-0230, USA.
Clin Cancer Res. 1998 Mar;4(3):611-8.
A Phase Ib trial of bryostatin 1, a macrocyclic lactone and protein kinase C (PKC) activator, was conducted in patients with refractory nonhematological malignancies with the primary goal of determining whether down-regulation of peripheral blood mononuclear cell (PBMNC) PKC activity could be achieved in vivo in humans. Patients (four patients/cohort) received bryostatin 1 (25 microg/m2) as a 1-h infusion weekly three times every 4 weeks, but to study the schedule dependence of pharmacokinetics and pharmacodynamics, the first dose was administered according to one of three schedules: (a) a 1-h infusion; (b) a 24-h infusion; or (c) a split course (12.5 microg/m2 as a 30-min infusion) on days 1 and 4. Conventional toxicities (grades I-III) included myalgias, fever, anemia, fatigue, phlebitis, and headache; in addition, two patients in cohort 3 experienced transient elevations in liver function tests, although these patients had preexisting liver metastases. No objective clinical responses were encountered. Effects on PBMNC PKC activity were heterogeneous. Several patients in cohorts 1 and 2 experienced significant declines in activity (approximately 50%) that were sustained in some cases for periods of > or = 72 h. Comparison of 72-h with baseline values for all three patient cohorts combined revealed a trend toward PKC down-regulation (P = 0.06; signed rank test). For each schedule, plasma bryostatin 1 levels were below the level of detection of a platelet aggregation-based bioassay (3-4 nm). Bryostatin 1 administration failed to produce consistent alterations in lymphocyte immunophenotypic profiles, interleukin 2-induced proliferation, or cytotoxicity, although two of three samples from patients in cohort 3 did show significant posttreatment increases in proliferation. Moreover, in some patients, bryostatin 1 treatment increased lymphokine-activated killer cell activity. These findings indicate that bryostatin 1 doses of 25 microg/m2 can induce in vivo PBMNC PKC down-regulation in at least a subset of patients and raise the possibility that higher bryostatin 1 doses may be more effective in achieving this effect.
进行了一项1b期试验，研究对象为患有难治性非血液系统恶性肿瘤的患者，试验药物为大环内酯类蛋白激酶C（PKC）激活剂苔藓抑素1，主要目的是确定在人体内能否实现外周血单个核细胞（PBMNC）PKC活性的下调。患者（每组4名患者）每4周接受3次苔藓抑素1（25μg/m²）静脉输注，每次输注1小时，但为研究药代动力学和药效学对给药方案的依赖性，首次给药按照以下三种方案之一进行：（a）1小时输注；（b）24小时输注；或（c）分疗程给药（第1天和第4天各输注30分钟，剂量为12.5μg/m²）。常见毒性（I - III级）包括肌痛、发热、贫血、疲劳、静脉炎和头痛；此外，第3组有2名患者肝功能检查出现短暂升高，尽管这两名患者之前已有肝转移。未观察到客观的临床反应。对PBMNC PKC活性的影响存在异质性。第1组和第2组的几名患者PKC活性显著下降（约50%），在某些情况下这种下降持续超过或等于72小时。将所有三组患者的72小时PKC活性值与基线值进行比较，显示出PKC下调的趋势（P = 0.06；符号秩检验）。对于每种给药方案，血浆苔藓抑素1水平均低于基于血小板聚集的生物测定法的检测水平（3 - 4nm）。尽管第3组患者的三个样本中有两个在治疗后增殖显著增加，但苔藓抑素1给药未能使淋巴细胞免疫表型、白细胞介素2诱导的增殖或细胞毒性产生一致的改变。此外，在一些患者中，苔藓抑素1治疗可增强淋巴因子激活的杀伤细胞活性。这些发现表明，25μg/m²的苔藓抑素1剂量至少可在部分患者体内诱导PBMNC PKC下调，并增加了更高剂量的苔藓抑素1可能更有效地实现这一效果的可能性。
