PHASE IIB STUDY OF PHENYLACETATE IN METASTATIC MELANOMA

“苯乙酸是一种天然存在的分子 与血浆中的谷氨酸结合PAG复合物是 通过尿液排出，导致体内总氮的损失。 谷氨酰胺也是玉米中核酸的主要氮源。 蛋白质合成以及快速分裂中的能量底物 正常细胞和肿瘤细胞。由于产量增加， 合成减少，肿瘤细胞在谷氨酰胺的边缘运作 因此，谷氨酰胺是一种限速分子， 肿瘤生长此外，苯乙酸已被证明 上调I类分子在细胞表面的表达， 恶性肿瘤肿瘤细胞用来 逃避免疫识别和杀伤是通过下调 它们的I类和/或II类分子在细胞表面上的表达。 临床前研究表明，上调这些基因的表达， 非免疫原性肿瘤细胞表面的MHC分子可以 诱导免疫识别并导致排斥。研究 目的是：1）确定抗肿瘤反应 苯乙酸，2）确定毒性，3）评价 苯乙酸对I类表达的影响，以及4）评估 对苯乙酸的免疫反应苯乙酸的剂量 根据患者的理想体重，将为450 mg/kd/天 （IBW）。苯乙酸将在三周内给药，其中6 连续输注24天，随后24小时。没有治疗 在第七天。我们计划增加35个百分点。7分。接受治疗 到目前为止，这项研究。1分。显着（等级 2)神经毒性，认为这是由于苯乙酸。1 PT.出现了严重的转移性肺出血 肺部病变，不得不从研究中移除。有 没有客观反应的证据。"

"Phenylacetate is a naturally occurring molecule which conjugates glutamate in the plasma. The PAG complex is excreted in the urine leading to the loss of total body nitrogen. Glutamine is also the major nitrogen source for nucleic acid in protein synthesis as well as a substrate for energy in rapidly dividing normal and tumor cells. Due to the increased production and decreased synthesis, tumor cells operate on the edge of glutamine deprivation; glutamine is therefore a rate- limiting molecule for tumor growth. In addition, phenylacetate has been shown to upregulate class I molecule expression on the cell surface of malignant tumors. One of the mechanisms that tumor cells use to escape immune recognition and killing is by down-regulating the expression of their class I and/or II molecules on the cell surface. Preclinical studies have shown that upregulating expression of these MHC molecules on the surface of nonimmunogenic tumor cells can induce immunorecognition and lead to rejection. The study objectives are: 1) to determine the antitumor response of phenylacetate, 2) determine the toxicities, 3) evaluate the effects of phenylacetate on class I expression, and 4) evaluate the immunologic response to phenylacetate. The dose of phenylacetate will be 450 mg/kd/day based on the patient's ideal body weight (IBW). Phenylacetate will be administered over three weeks, with 6 days of continuous infusion followed by 24 hrs. without treatment on the 7th day. We plan to accrue 35 pts. 7 pts. have been treated on this study thus far. 1 pt. developed significant (grade 2)neurotoxicity which was felt to be attributable to phenylacetate. 1 pt. developed significant pulmonary hemorrhage from metastatic lesions to the lung and had to be removed from study. There was no evidence of objective response."