Antineoplastons work as molecular switches, which regulate expression of genes p53 and p21 through demethylation of promoter sequences and acetylation of histones. They also inhibit the uptake of growth-critical amino acids, such as 1-glutamine and 1-leucine in neoplastic cells. Phase II trials indicate efficacy of antineoplastons in low-grade glioma, brain stem glioma, high-grade glioma, adenocarcinoma of the colon, and hepatocellular carcinoma. The best results were observed in children with low-grade glioma, where 74% of patients obtained objective response, and in patients with adenocarcinoma of the colon with liver metastases whose survival rate of more than 5 years is 91% versus 39% in controls on chemotherapy. Gene array studies will explain antineoplaston-induced changes in gene expression.

Antineoplastons are peptide and amino acid derivatives that occur naturally in the human body. They inhibit the growth of neoplastic cells without growth inhibition of normal cells. Phenylacetylglutaminate (PG) is an active ingredient of antineoplastons A10 and AS2-1 (ANP) and is also a metabolic by-product of phenylbutyrate (PB). The formulation of antineoplaston AS2-1 is a 4:1 mixture of phenylacetate (PN) and PG. Antineoplaston A10 is a 4:1 mixture of PG and isoPG. This study investigates the molecular mechanism of action of PG and PN. The Human U87 glioblastoma (GBM) cell line was used as the model system in this study. A total human gene array screen using the Affymetrix Human Genome plus 2.0 oligonucleotide arrays was performed using mRNA derived from U87 cells exposed to PG and PN. Pathway analysis was performed to allow the visualization of effect on metabolic pathways and gene interaction networks. Our preliminary results indicate that PG and PN interrupt signal transduction in RAS/MAPK/ERK and PI3K/AKT/PTEN pathways, interfere with cell cycle, decrease metabolism and promote apoptosis in human U87 GBM cells. The effect on multiple cellular pathways and targets, suggests that ANP and PB are promising candidates for clinical studies in GBM.

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Recurrent GBM (RGBM) has a highly unfavorable prognosis with majority of patients dying within 6 months and no standard treatments available. Antineoplaston (ANP) A10 and AS2-1 injections underwent Phase II trials in RGBM patients, which reported a long-term overall survival (OS) in a small percentage of patients. The additional Phase II studies BT-07, and BT-21 with ANP in GBM also revealed cases of a long-term OS. ANP shares active ingredients with metabolites of sodium phenylbutyrate (PB), which was used in private practice setting in combination of targeted and chemotherapeutic agents for the treatment of RGBM. The treatment contributed to cases of rapid complete response (CR) and significant OS. This paper provides case studies of three patients treated with ANP under Phase II protocols and two patients treated with PB in combination with targeted therapy, who obtained CR and long-term OS. Based on these studies and basic research on the effects of ANP and PB on the genome of GBM and review of results of preclinical and clinical research on targeted agents, the authors suggest a new strategy for successful treatment of RGBM. They propose Phase I/II clinical trials with ANP and PB in combination with targeted agents, bevacizumab (BVZ), pazopanib, dasatinib and everolimus in patients with RGBM after failure of standard surgery, radiation therapy (RT) and chemotherapy including temozolomide (TMZ) to be conducted to evaluate survival, response and toxicity in these patients.