Sodium Phenylacetate (NaPA) was found to induce tumor cell differentiation in vitro at concentrations that have been achieved in humans with no significant adverse effects. The goal of this project is to explore the mechanisms of action and the efficacy of phenylacetate, its prodrug phenylbutyrate, and analogs in treatment of malignant and non-malignant disorders of cell differentiation. The major observations are: 1. Differentiation Models. NaPA induced granulocyte differentiation in promyelocytic leukemia HL60 cells following rapid decline of myc oncogene expression; erythroid maturation in K562 leukemia; and, adipocyte conversion in immortalized mesenchymal C3H 10T1/2 cultures. NaPA was neither cytotoxic nor carcinogenic. 2. Molecular Marker of Cell Response. In K562 cells, differentiation was associated with increased production of the fetal form of hemoglobin (HbF). With HbF as a marker, we were able to demonstrate activity in humans. Patients with urea cycle disorders treated with the pro-drug, phenylbutyrate, were examined for red cells containing HbF (F cells); the mean % F cells was found to be significantly higher than that of normal subjects, indicating the validity of our experimental models. 3. Activity in Solid Tumors. Impressive activities were observed in cell lines established from hormone-refractory prostate carcinoma, glioblastoma, lung adenocarcinoma, and melanoma NaPA caused selective cytostasis and phenotypic reversion, as evident by altered gene expression, and loss of invasiveness and tumorigenicity. A pilot study involving systemic NaPA treatment of rats with intracerebral gliomas showed tumor suppression in vivo. Our data suggest that phenylacetates, used alone or in combination with other drugs, may offer safe and effective new approach to treatment of some hematopoietic and solid neoplasms, and of severe hemoglobinopathies. Clinical protocol """"""""Phase 1 Trial of Intravenous Phenylacetate in Adults with Cancer"""""""" has been IRB approved (#92-C-140A) and is IND pending.
