Glutamine is a non-essential amino acid and the major nitrogen source for nucleic acid and protein synthesis. It is also an important energy substrate in rapidly dividing cells. Tumor cells are significantly more sensitive to glutamine depletion than normal cells, as they function on limiting levels of glutamine availability due to their increased utilization and accelerated catabolism. The glutamine depleting enzyme glutaminase, as well as some glutamine antimetabolites have shown promising antineoplastic activity, but their clinical usefulness has been limited by their unacceptable side effects and toxicity.
Phenylbutyrate depletes the cells of glutamine without affecting the glutamine utilizing enzymes. In its metabolized form it is capable of conjugating glutamine to yield PAG (phenylacetyl glutamine), which is then excreted in the urine, and the tumor cells will not have enough "fuel" to continue to grow and multiply. Normal cells are not affected by the used dosages. It has been shown (Samid 1992) that Phenylbutyrate arrests tumor growth and induces differentiation of pre-malignant and malignant cells through this non-toxic mechanism.
Differentiation therapy is becoming an attractive alternative in cancer treatment, as neoplastic transformation is considered to be a result from defects in cellular differentiation.
Phenylbutyrate has been shown to be a non-toxic differentiation inducer, promoting maturation of various types of malignant cells. Maturation makes the cells less aggressive, causing them to cease dividing and eventually die.
Differentiation therapy is also a therapeutic potential for other diseases such as inherited anemias. Some exceptional results have been shown in using Phenylbutyrate in the treatment of Sickle Cell Anemia/ Thalassemia, raising the HbF levels. Recent experimental research has furthermore indicated both an inhibiting effect of Phenylbutyrate on HIV replication, due to its glutamine depleting effect, and encouraging results of in vitro studies on Cystic Fibrosis, where Phenylbutyrate was able to restore the missing cellular protein.
A Possible Preventative for Cancer?
Due to the above-mentioned non-toxic working mechanisms for Phenylbutyrate, it has been suggested that it may be an effective preventative for Cancer at a much lower dosage than would be needed for treatment. Clinical Studies to explore this theory are yet to be conducted.
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