Phenylacetate and Phenylbutyrate as Novel, Nontoxic Differentiation Inducers
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Phenylacetate, a common metabolite of phenylalanine, is a natural component of the human plasma and an endogenous growth regulator in plants (1,2). In humans, phenylacetate conjugates glutamine to yield phenylacetylglutamine (PAG), which is subsequently excreted in the urine. The latter, leading to waste nitrogen excretion, has been the basis for using sodium phenylacetate (NaPA) in treatment of hyperammonemia associated with inborn errors of urea synthesis or liver failure (3,4). Clinical experience obtained with these patients indicated that long-term treatment with high doses of NaPA (250–550 mg/kg/day) is well tolerated by both infants and adults, and effective in reducing plasma glutamine levels. These characteristics should be of value in cancer intervention considering the unique dependence of tumor cells on circulating glutamine. Preclinical studies exploring the antitumor efficacy of NaPA revealed that this simple aromatic fatty acid can selectively suppress the growth of various tumors in tissue culture and in animal models (5–7; Samid et al, unpublished). In addition to glutamine depletion in humans, phenylacetate was found to induce tumor cytostasis and differentiation through several other mechanisms (see below). Most importantly, the antitumor activity was observed with pharmacological, non-toxic drug concentrations. The demonstrated antitumor activity, easy administration (oral or IV), and lack of significant adverse effects, made phenylacetate an attractive candidate for clinical use in prevention and treatment of human neoplasms, including those which do not respond to conventional therapies. In the present report we provide a brief summary of the preclinical antitumor activity of NaPA and its derivatives.
KeywordsUrea Synthesis Solid Tumor Cell Line Endogenous Growth Regulator Sodium Phenylbutyrate Demonstrate Antitumor Activity
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