AIM： To develop a conditionally replicative gene-viral vector system called CNHK500-p53, which contains dual promoters within the E1 region, and combines the advantages of oncolytic virus and gene therapies for hepat...AIM： To develop a conditionally replicative gene-viral vector system called CNHK500-p53, which contains dual promoters within the E1 region, and combines the advantages of oncolytic virus and gene therapies for hepatocellular carcinoma （HCC）. METHODS： CNHK500-p53 was constructed by using human telomerase reverse transcriptase （hTERT） promoter to drive adenovirus E1a gene and hypoxia response element （HRE） promoter to drive adenovirus E1b gene. p53 gene expressing cassette was inserted into the genome of replicative virus. Viral replication experiments, cytopathic effect （CPE） and methyl thiazolyl tetrazolium （MTT） assay were performed to test the selective replication and oncolytic efficacy of CNHK500-p53. RESULTS： Immunohistochemistry verified that infection with CNHK500-p53 was associated with selective replication of adenovirus and production of p53 protein in telomerase-positive and hypoxia-inducible factordependent HCC cells, p53 protein secreted from HepG2, infected with CNHK500-p53 was significantly higher than that infected with nonreplicative adenovirus Ad-p53 in vitro （388 ± 34.6 μg/L vs 76.3 ± 13.17 μg/L）. Viral replication experiments showed that replication of CNHK500-p53 and CNHK500 or WtAd5, was much stronger than that of Ad-p53 in tested HCC cell lines. CPE and H1-F assay indicated that CNHK500-p53 selectively replicated in and killed HCC cells while leaving normal cells unaffected. CONCLUSION： A more efficient gene-viral system is developed by combining selective oncolysis with exogenous expression of p53 against HCC cells.展开更多
Patients with brain tumors,specifically,malignant forms such as glioblastoma,medulloblastoma and ependymoma,exhibit dismal survival rates despite advances in treatment strategies.Chemotherapeutics,the primary adjuvant...Patients with brain tumors,specifically,malignant forms such as glioblastoma,medulloblastoma and ependymoma,exhibit dismal survival rates despite advances in treatment strategies.Chemotherapeutics,the primary adjuvant treatment for human brain tumors following surgery,commonly lack efficacy due to either intrinsic or acquired drug resistance.New treatments targeting epigenetic factors are being explored.Post-translational histone modification provides a critical regulatory platform for processes such as chromosome condensation and segregation,apoptosis,gene transcription,and DNA replication and repair.This work reviews how aberrant histone modifications and alterations in histone-modifying enzymes can drive the acquisition of drug resistance in brain tumors.Elucidating these mechanisms should lead to new treatments for overcoming drug resistance.展开更多
基金Supported by the Major State Basic Research Development Program (973 Program) of China, No. 2003CB515507
文摘AIM： To develop a conditionally replicative gene-viral vector system called CNHK500-p53, which contains dual promoters within the E1 region, and combines the advantages of oncolytic virus and gene therapies for hepatocellular carcinoma （HCC）. METHODS： CNHK500-p53 was constructed by using human telomerase reverse transcriptase （hTERT） promoter to drive adenovirus E1a gene and hypoxia response element （HRE） promoter to drive adenovirus E1b gene. p53 gene expressing cassette was inserted into the genome of replicative virus. Viral replication experiments, cytopathic effect （CPE） and methyl thiazolyl tetrazolium （MTT） assay were performed to test the selective replication and oncolytic efficacy of CNHK500-p53. RESULTS： Immunohistochemistry verified that infection with CNHK500-p53 was associated with selective replication of adenovirus and production of p53 protein in telomerase-positive and hypoxia-inducible factordependent HCC cells, p53 protein secreted from HepG2, infected with CNHK500-p53 was significantly higher than that infected with nonreplicative adenovirus Ad-p53 in vitro （388 ± 34.6 μg/L vs 76.3 ± 13.17 μg/L）. Viral replication experiments showed that replication of CNHK500-p53 and CNHK500 or WtAd5, was much stronger than that of Ad-p53 in tested HCC cell lines. CPE and H1-F assay indicated that CNHK500-p53 selectively replicated in and killed HCC cells while leaving normal cells unaffected. CONCLUSION： A more efficient gene-viral system is developed by combining selective oncolysis with exogenous expression of p53 against HCC cells.
基金Supported by the Rory David Deutsch Foundationthe Surgical Neuro-oncology Research Fund of Ann&Robert H Lurie Children’s Hospital(A&RLCH) of Chicagothe Dr.Ralph and Marian C.Falk Medical Research Trust
文摘Patients with brain tumors,specifically,malignant forms such as glioblastoma,medulloblastoma and ependymoma,exhibit dismal survival rates despite advances in treatment strategies.Chemotherapeutics,the primary adjuvant treatment for human brain tumors following surgery,commonly lack efficacy due to either intrinsic or acquired drug resistance.New treatments targeting epigenetic factors are being explored.Post-translational histone modification provides a critical regulatory platform for processes such as chromosome condensation and segregation,apoptosis,gene transcription,and DNA replication and repair.This work reviews how aberrant histone modifications and alterations in histone-modifying enzymes can drive the acquisition of drug resistance in brain tumors.Elucidating these mechanisms should lead to new treatments for overcoming drug resistance.
