PHASE-I STUDY OF BRYOSTATIN-1 - ASSESSMENT OF INTERLEUKIN-6 AND TUMOR-NECROSIS-FACTOR-ALPHA INDUCTION IN-VIVO
PHASE-I STUDY OF BRYOSTATIN-1 - ASSESSMENT OF INTERLEUKIN-6 AND TUMOR-NECROSIS-FACTOR-ALPHA INDUCTION IN-VIVO
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DOI：
10.1093/jnci/85.22.1812
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发表时间：
1993-11-17
期刊：
影响因子：
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通讯作者：
HARRIS, AL
中科院分区：
文献类型：
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作者：
PHILIP, PA;REA, D;HARRIS, AL
背景资料：许多癌基因已被证明编码生长因子受体，其参与细胞生长和增殖的调节，并可通过蛋白激酶C激活转录。苔藓抑素1是一种蛋白激酶C的部分激动剂，在体外和体内人类肿瘤异种移植物中已显示出有效的抗肿瘤活性。目的：该I期研究的目的是确定苔藓抑素1的最佳剂量和毒性特征及其对体内细胞因子释放的影响。研究方法：由35名患有各种恶性肿瘤的患者组成的三个连续的队列通过静脉内输注苔藓抑素1 1超过1小时进行治疗，如下：队列A-35 μ g/m2（3名患者）或50 mug/m2（8名患者）每2周一次;队列B-25 mug/m2每周一次（8名患者）;和C组-每周一次25 μ g/m2，持续3周，在第4周期间不进行治疗（16名患者）。分别用免疫放射分析法和放射免疫分析法测定血浆肿瘤坏死因子α（TNF-α）和白细胞介素6（IL-6）水平。结果如下：剂量限制性毒性为3级或4级肌痛，队列A的11例患者中有4例，队列B的8例患者中有2例，队列C的16例患者中无1例。肌痛的发生与剂量相关。除了血小板计数的小而短暂的下降外，没有显著的骨髓抑制。6例患者发生急性但短暂的皮肤潮红、呼吸困难、低血压和心动过缓，可能与苔藓抑素1溶媒相关。分别在治疗后2小时和24小时在血浆中检测到TNF-α和IL-6，并且水平与剂量相关（P = .02）。2例转移性恶性黑色素瘤患者在治疗3或4个周期后部分缓解;缓解分别持续6周和10+个月。结论：苔藓抑素1的剂量限制性毒性为肌痛。血浆IL-6和TNF-α浓度在治疗后24小时内升高。在治疗过程的早期观察到对恶性黑色素瘤的抗肿瘤活性。含义：苔藓抑素1在II期研究中的推荐剂量为25 μ g/m2，每周一次静脉输注1小时，持续3周，第4周不进行治疗。IL-6和TNF-α血浆浓度可用于监测苔藓抑素1的生物活性。未来的研究应探索使用这种药物与其他传统的免疫调节剂和传统的细胞毒性药物。
Background: Many oncogenes have been shown to code for growth factor receptors that are involved in regulation of cell growth and proliferation and can activate transcription via protein kinase C. Bryostatin 1, a partial agonist of protein kinase C, has demonstrated potent antitumor activity in vitro and in vivo in human tumor xenografts. Purpose: The aim of this phase I study was to determine the optimal dosage and toxicity profile of bryostatin 1 and its influence on cytokine release in vivo. Methods: Three successive cohorts consisting of 35 patients with various malignant tumors were treated with bryostatin 1 by intravenous infusion over 1 hour as follows: cohort A-35 mug/m2 (three patients) or 50 mug/m2 (eight patients) once every 2 weeks; cohort B-25 mug/m2 once a week (eight patients); and cohort C-25 mug/m2 once a week for 3 weeks, with no treatment during the 4th week (16 patients). Plasma levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) were measured by immunoradiometric assay and by radioimmunoassay, respectively. Results: The dose-limiting toxicity was grade 3 or 4 myalgia in four of 11 patients in cohort A, in two of eight in cohort B, and in none of 16 in cohort C. Occurrence of myalgia was dose related. There was no significant myelosuppression, apart from a small and transient fall in platelet count. Six patients experienced acute but transient skin flushing, dyspnea, hypotension, and bradycardia, probably related to the bryostatin 1 vehicle. TNF-alpha and IL-6 were detected in plasma at 2 and 24 hours after treatment, respectively, and the levels were dose related (P = .02). Two patients with metastatic malignant melanoma had partial remission after three or four cycles of therapy; remission lasted 6 weeks and 10+ months, respectively. Conclusions: The dose-limiting toxicity of bryostatin 1 was myalgia. Plasma IL-6 and TNF-alpha concentrations were increased within 24 hours of therapy. Antitumor activity against malignant melanoma was observed early in the course of treatment. Implications: The recommended dosage of bryostatin 1 for phase II studies is 25 mug/m2 by intravenous infusion for 1 hour once a week for 3 weeks, with no treatment in the 4th week. IL-6 and TNF-alpha plasma concentrations may be useful in monitoring biological activity of bryostatin 1. Future studies should explore use of this drug with other conventional immune modulators and conventional cytotoxic drugs.