Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma.
Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma.
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DOI：
10.1007/s10637-012-9862-2
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发表时间：
2013-04
影响因子：
3.4
通讯作者：
Wolchok, Jedd D.
中科院分区：
文献类型：
--
作者：
Ott, Patrick A.;Carvajal, Richard D.;Pandit-Taskar, Neeta;Jungbluth, Achim A.;Hoffman, Eric W.;Wu, Bor-Wen;Bomalaski, John S.;Venhaus, Ralph;Pan, Linda;Old, Lloyd J.;Pavlick, Anna C.;Wolchok, Jedd D.
精氨酸脱亚胺酶 (ADI) 是一种降解精氨酸的酶，精氨酸是一种对正常细胞和肿瘤细胞生长和发育很重要的氨基酸。黑色素瘤细胞是精氨酸营养缺陷型的，因为它们缺乏精氨酸琥珀酸合成酶（ASS），精氨酸合成酶是合成精氨酸所需的关键酶。晚期黑色素瘤患者接受 40、80 或 160 IU/m2 ADI-PEG 20 次肌肉注射治疗。每周。主要终点是毒性和肿瘤反应，次要终点包括 18FDG-PET 的代谢反应、药效学 (PD) 对循环精氨酸水平的影响以及免疫组织化学测定的精氨琥珀酸合成酶肿瘤表达。 31 名既往接受过治疗的患者入组。主要毒性为 1 级和 2 级不良事件，包括注射部位疼痛、皮疹和疲劳。没有看到客观的回应。 9 名患者疾病稳定 (SD)，其中 2 名患者持续时间超过 6 个月。 9 名 SD 患者中有 4 名患有葡萄膜黑色素瘤。 PD 分析显示，第 8 天时，30/31 名患者的血浆精氨酸完全耗尽。ADI-PEG 20 的平均血浆水平与 ADI-PEG 20 抗体水平呈负相关。 24 名患者的肿瘤组织中免疫组织化学 ASS 表达分析呈阴性，而 5 名患者的细胞阳性率<5%。 ADI-PEG 20 在晚期黑色素瘤患者中具有良好的耐受性，并导致持续但短暂的精氨酸消耗。尽管没有观察到 RECIST 反应，但葡萄膜黑色素瘤患者的 SD 率令人鼓舞，表明在该黑色素瘤亚组中评估 ADI-PEG 20 可能是值得的。
Arginine deiminase (ADI) is an enzyme that degrades arginine, an amino acid that is important for growth and development of normal and neoplastic cells. Melanoma cells are auxotrophic for arginine, because they lack argininosuccinatesynthetase (ASS), a key enzyme required for the synthesis of arginine. Patients with advanced melanoma were treated with 40, 80 or 160 IU/m2 ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and tumor response, secondary endpoints included metabolic response by 18FDG-PET, pharmacodynamic (PD) effects upon circulating arginine levels, and argininosuccinate synthetase tumor expression by immunohistochemistry. 31 previously treated patients were enrolled. The main toxicities were grade 1 and 2 adverse events including injection site pain, rash, and fatigue. No objective responses were seen. Nine patients achieved stable disease (SD), with 2 of these durable for >6 months. Four of the 9 patients with SD had uveal melanoma. PD analysis showed complete plasma arginine depletion in 30/31 patients by day 8. Mean plasma levels of ADI-PEG 20 correlated inversely with ADI-PEG 20 antibody levels. Immunohistochemical ASS expression analysis in tumor tissue was negative in 24 patients, whereas 5 patients had <5 % cells positive. ADI-PEG 20 is well tolerated in advanced melanoma patients and leads to consistent, but transient, arginine depletion. Although no RECIST responses were observed, the encouraging rate of SD in uveal melanoma patients indicates that it may be worthwhile to evaluate ADI-PEG 20 in this melanoma subgroup.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
5.7
作者：
Tsai WB;Aiba I;Lee SY;Feun L;Savaraj N;Kuo MT
通讯作者：
Kuo MT
影响因子：
45.3
作者：
Izzo, F;Marra, P;Curley, SA
通讯作者：
Curley, SA
影响因子：
6.2
作者：
Dillon, BJ;Prieto, VG;Clark, MA
通讯作者：
Clark, MA
影响因子：
45.3
作者：
Ascierto, PA;Scala, S;Logan, TF
通讯作者：
Logan, TF