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 ...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.展开更多
Although Sirt2 is primarily expressed in oligodendrocytes of the central nervous system,its role in oligodendroglial lineage differentiation is not fully understood.Our findings demonstrate that the transcription fac...Although Sirt2 is primarily expressed in oligodendrocytes of the central nervous system,its role in oligodendroglial lineage differentiation is not fully understood.Our findings demonstrate that the transcription factor Nkx2.2 binds to the Sirt2 promoter via histone deacetylase 1(HDAC-1),the binding site for Nkx2.2 maps close to the start codon of the Sirt2 gene,and Nkx2.2 negatively regulates Sirt2 expression in CG4 cells,an oligodendroglial precursor cell line.HDAC-1 knock-down not only significantly attenuates the binding capacity of Nkx2.2 to the Sirt2 promoter but also releases repression of Sirt2 expression by Nkx2.2.Nkx2.2 overexpression down-regulates Sirt2 expression and delays differentiation of CG4 cells;in contrast,up-regulation of Sirt2 does not impact Nkx2.2 expression level.Sirt2 knock-down via RNAi or inhibition of Sirt2 by sirtinol,a Sirt2 activity inhibitor,blocks CG4 cell differentiation.Over-expression of Sirt2 facilitates CG4 cell differentiation at both molecular and cellular levels,enhancing expression of myelin basic protein and facilitating the growth of cell processes.We have conclusively demonstrated that Sirt2 enhances CG4 oligodendroglial differentiation and report a novel mechanism through which Nkx2.2 represses CG4 oligodendroglial differentiation via Sirt2.展开更多
文摘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.
文摘Although Sirt2 is primarily expressed in oligodendrocytes of the central nervous system,its role in oligodendroglial lineage differentiation is not fully understood.Our findings demonstrate that the transcription factor Nkx2.2 binds to the Sirt2 promoter via histone deacetylase 1(HDAC-1),the binding site for Nkx2.2 maps close to the start codon of the Sirt2 gene,and Nkx2.2 negatively regulates Sirt2 expression in CG4 cells,an oligodendroglial precursor cell line.HDAC-1 knock-down not only significantly attenuates the binding capacity of Nkx2.2 to the Sirt2 promoter but also releases repression of Sirt2 expression by Nkx2.2.Nkx2.2 overexpression down-regulates Sirt2 expression and delays differentiation of CG4 cells;in contrast,up-regulation of Sirt2 does not impact Nkx2.2 expression level.Sirt2 knock-down via RNAi or inhibition of Sirt2 by sirtinol,a Sirt2 activity inhibitor,blocks CG4 cell differentiation.Over-expression of Sirt2 facilitates CG4 cell differentiation at both molecular and cellular levels,enhancing expression of myelin basic protein and facilitating the growth of cell processes.We have conclusively demonstrated that Sirt2 enhances CG4 oligodendroglial differentiation and report a novel mechanism through which Nkx2.2 represses CG4 oligodendroglial differentiation via Sirt2.
