PHASE IIB STUDY OF PHENYLACETATE IN METASTATIC MELANOMA

“苯乙酸酯是一种天然存在的分子

"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."