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RC: Phenylbutyrate and related aromatic fatty acids are some of the least appreciated agents with solid scientific evidence, established efficacy, low toxicity as well as oral bioavailability for cancer treatment. It is a potent differentiating agent effective in inducing apoptosis, and in the class of histone deacetylase inhibitors (HDACs) and has anti-tumor activity in part based on modification of chromatin structure, modulation of protein kinase C, attenuating the expression of Bcl-X(L), DNA-PK, caveolin-1, and VEGF (See Ref) and also via activation of PPAR gamma receptor (See Ref), although the exact mechanisms involved are still obscure perhaps by regulation of DNA transcription. Studies/Trials have shown HDAC cancer inhibitory effects in cell culture (eg malignant B cells as in CLL or NHL, retinoblastoma, neuroblastoma, melanoma, glioma, myeloma, cervical, lung, breast, ovarian, colon and prostate cancers) animal models (acute leukemias APL and AML, liver, breast, colon cancers) and in human with both hematological and solid tumors, and phenylbutyrate has been demonstrated to have clinical efficacy in patient with glioblastoma (one published case of complete remission) and in preventing leukemic transformation in myeloproliferative conditions. The agent is available in this country as an investigational agent for cancer or an orphan drug for a rare inborn error of metabolism in children. Given orally, it can achieve biologically effective and meaningful blood levels at relatively low doses and has limited side-effects (MA Carducci at Hopkins did much work on this drug: See his review as well as his report on the phase I trial of oral phenylbutyrate in refractory solid tumors. It has been demonstrated to potentiate chemotherapeutic agents synergistic with cytarabine, etoposide, topotecan, BCNU, FUDR and hydroxyurea Phenylbutyrate is also synergistic with retinoic acid (another differentiating agent) (See Ref) and may be synergistic with PPARgamma agonists (See Ref), cox-2 inhibitors and interferons (See Ref) as well. It may also have other anti-cancer effects such as antiangiogenesis as well.

Phenylbutyrate is an ingredient of Burzynski's "Antineoplaston" therapy but its efficacy and low toxicity as well as oral availability justifies much wider usage, but I find it particularly applicable for hematologic and childhood malignancies, retinoblastoma and neuroblastoma, as well as glioblastoma and medullary thyroid cancers. It can be used in cocktail fashion as treatment to enhance survival (even while on certain chemotherapies such as BCNU, 5FU and others above) or as a preventative in the adjuvant setting for patients who are in remission after cytoreductive therapies. Our patients can obtain pure phenylbutyrate from reputable compounding pharmacies under our prescription after carefully considering their therapeutic options and signing the requisite consents for a compassionate trial. The only downside to this treatment is relative expense and the large number of capsules to swallow each day [depending on dose]. Other HDAC inhibitors that may potentially be useful includes the anti-seizure medication valproic acid (See Ref) which may be particularly appropriate to use in cocktail fashion in brain tumors.