PHASE IIB STUDY OF PHENYLACETATE IN METASTATIC MELANOMA

苯乙酸酯是一种天然存在的分子，它与谷氨酸结合。 在血浆中。PAG复合体在尿液中排泄，导致 体内总氮的损失。谷氨酰胺也是主要的氮源。 蛋白质合成中的核酸，以及蛋白质合成中能量的底物 快速分裂正常细胞和肿瘤细胞。由于产量的增加 和合成减少，肿瘤细胞在谷氨酰胺的边缘运作 剥夺；因此谷氨酰胺是肿瘤的限速分子 成长。此外，苯乙酸酯已被证明可上调第I类 恶性肿瘤细胞表面分子的表达。其中一个 肿瘤细胞逃避免疫识别和杀伤的机制 是通过下调它们的I类和/或II类分子的表达 在细胞表面。临床前研究表明，上调 这些MHC分子在非免疫原性肿瘤表面的表达 细胞可以诱导免疫识别并导致排斥反应。这项研究 目的是：1)测定苯乙酸酯的抗肿瘤作用， 2)测定苯乙酸乙酯的毒性；3)评价苯乙酸乙酯对小鼠的影响。 I类表达，以及4)评估免疫应答 苯乙酸酯。苯乙酸乙酯的剂量将为450毫克/kd/天 患者理想体重(IBW)。苯乙酸乙酯将被注射 3周以上，连续输液6天，24小时。 第7天不治疗。我们计划累积35分。5分。有 到目前为止已经在这项研究中得到了治疗。没有点。发展显著 认为可归因于苯乙酸乙酯的毒性。1磅。 从转移性病变发展为严重的肺出血 肺脏，不得不从研究中移除。没有证据表明这是客观的 回应。

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. 5 pts. have been treated on this study thus far. No pt. developed significant toxicity 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.