Mikulski S, Grossman A, Carter P, Shogen K, Costanzi J
THOMPSON CANC SURVIVAL CTR,KNOXVILLE,TN 37916.
Int J Oncol. 1993 Jul;3(1):57-64. doi: 10.3892/ijo.3.1.57.
ONCONASE(R) (ONC), previously known as P-30 Protein, is a novel amphibian protein isolated from Rana pipiens eggs/early embryos (1) which demonstrates cytostatic and cytotoxic activity against several human tumor cell lines in vitro, as well as anti-tumor activity in vivo. Animal toxicology studies in rats and dogs revealed dose-dependent weight loss, some skeletal muscle and myocardial degenerative changes, a decrease in albumin and bilirubin levels in rats, and a dose-related elevation of serum transaminases and alkaline phosphatase in both species. A human weekly schedule Phase I study of intravenous bolus ONC was initiated, with dose levels ranging from 60 mug/m2 (anticipated human dose) to 960 mug/m2. Five patients were treated per dose level, without dose escalations within the same patients. Dose levels were doubled in new groups of patients with a variety of relapsing and resistant tumors. A correlation was noted between the dose level and the number of doses (cumulative effect), and the toxicities observed. The dose limiting toxicity was renal as manifested by proteinuria with edema, +/- azotemia and fatigue. Other side effects included flushing, myalgias, transient dizziness, and decreased appetite. Two patients, one at 480 mug/m2 and another at 960 mug/m2 levels, developed reversible hypotensive reactions preceded by flushing. The maximum tolerated dose (MTD) appears to be 960 mug/m2. Incidental findings included some objective responses in non-small cell lung, esophageal, and colorectal carcinomas. It has been concluded that ONCONASE was well tolerated by the majority of patients, demonstrated a consistent and reversible clinical toxicity patterns, did not induce most of the toxicities (such as, e.g., myelosuppression and alopecia) associated with most of the chemotherapeutic agents and, in view of its demonstrated objective clinical activity observed in patients harboring resistant solid tumors, the Phase II clinical trials have been initiated and are currently ongoing.
昂科纳酶（ONCONASE，ONC），以前称为P - 30蛋白，是一种从豹蛙卵/早期胚胎中分离出的新型两栖类蛋白（1），它在体外对多种人类肿瘤细胞系表现出细胞生长抑制和细胞毒性活性，在体内也具有抗肿瘤活性。对大鼠和狗进行的动物毒理学研究显示，会出现剂量依赖性体重减轻、一些骨骼肌和心肌退行性变化、大鼠白蛋白和胆红素水平降低，以及两种动物血清转氨酶和碱性磷酸酶与剂量相关的升高。启动了一项人类每周一次静脉推注ONC的I期研究，剂量水平范围为60μg/m²（预期人类剂量）至960μg/m²。每个剂量水平治疗5名患者，同一患者内不进行剂量递增。对于患有各种复发性和耐药性肿瘤的新患者组，剂量水平加倍。观察到剂量水平与剂量数量（累积效应）以及所观察到的毒性之间存在相关性。剂量限制性毒性为肾脏毒性，表现为蛋白尿伴水肿，±氮质血症和疲劳。其他副作用包括脸红、肌痛、短暂性头晕和食欲下降。两名患者，一名接受480μg/m²剂量，另一名接受960μg/m²剂量，在脸红之前出现了可逆性低血压反应。最大耐受剂量（MTD）似乎为960μg/m²。偶然发现包括在非小细胞肺癌、食管癌和结直肠癌中出现一些客观反应。得出的结论是，大多数患者对昂科纳酶耐受性良好，表现出一致且可逆的临床毒性模式，不会诱发大多数化疗药物相关的毒性（如骨髓抑制和脱发），并且鉴于在患有耐药实体瘤的患者中观察到其客观临床活性，已启动并正在进行II期临床试验。
