Ascierto Paolo A, Scala Stefania, Castello Giuseppe, Daponte Antonio, Simeone Ester, Ottaiano Alessandro, Beneduce Gerardo, De Rosa Vincenzo, Izzo Francesco, Melucci Maria Teresa, Ensor C Mark, Prestayko Archie W, Holtsberg Frederick W, Bomalaski John S, Clark Mike A, Savaraj Niramol, Feun Lynn G, Logan Theodore F
Pascale National Cancer Institute, Naples, Italy.
J Clin Oncol. 2005 Oct 20;23(30):7660-8. doi: 10.1200/JCO.2005.02.0933.
Individuals with metastatic melanoma have a poor prognosis. Many human melanomas are auxotrophic for arginine, and arginine is not an essential amino acid in humans. We hypothesized that this auxotrophy may be therapeutically exploited. A novel amino acid-degrading enzyme (arginine deiminase) conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw) was used to lower plasma arginine in individuals with metastatic melanoma.
Two cohort dose-escalation studies were performed. A phase I study in the United States enrolled 15 patients, and a phase I to II study in Italy enrolled 24 patients. The Italian patients also received two subsequent cycles of treatment, each consisting of four once-weekly injections of 160 U/m2. The goals of these studies were to determine pharmacokinetics (PK), pharmacodynamics (PD), safety, and the antitumor activity of ADI-SS PEG 20,000 mw.
PK and PD studies indicated that a dose of 160 U/m2 lowered plasma arginine from a resting level of approximately 130 micromol/L to less than 2 micromol/L for at least 7 days; nitric oxide levels also were lowered. There were no grade 3 or 4 toxicities directly attributable to the drug. Six of 24 phase I to II patients responded to treatment (five partial responses and one complete response; 25% response rate) and also had prolonged survival. CONCLUSION Elimination of all detectable plasma arginine in patients with metastatic melanoma was well tolerated and may be effective in the treatment of this cancer. Further testing of ADI-SS PEG 20,000 mw in a larger population of individuals with metastatic melanoma is warranted.
转移性黑色素瘤患者预后较差。许多人类黑色素瘤对精氨酸营养缺陷，而精氨酸在人类中并非必需氨基酸。我们推测这种营养缺陷可能具有治疗价值。一种与聚乙二醇（分子量20,000道尔顿的ADI-SS PEG）偶联的新型氨基酸降解酶（精氨酸脱亚氨酶）被用于降低转移性黑色素瘤患者的血浆精氨酸水平。
进行了两项队列剂量递增研究。美国的一项I期研究纳入了15名患者，意大利的一项I/II期研究纳入了24名患者。意大利患者还接受了随后的两个治疗周期，每个周期包括每周一次注射160 U/m²，共注射四次。这些研究的目的是确定分子量20,000道尔顿的ADI-SS PEG的药代动力学（PK）、药效动力学（PD）、安全性和抗肿瘤活性。
PK和PD研究表明，160 U/m²的剂量可使血浆精氨酸从约130微摩尔/升的静息水平降至低于2微摩尔/升，且至少持续7天；一氧化氮水平也有所降低。没有直接归因于该药物的3级或4级毒性。24名I/II期患者中有6名对治疗有反应（5名部分缓解和1名完全缓解；缓解率为25%），且生存期延长。结论：转移性黑色素瘤患者消除所有可检测到的血浆精氨酸耐受性良好，可能对该癌症的治疗有效。有必要在更多转移性黑色素瘤患者中对分子量20,000道尔顿的ADI-SS PEG进行进一步测试。
