title: Comparisons of tumor suppressor p53, p21, and p16 gene therapy effects on glioblastoma tumorigenicity in situ.
abstract: The mutation and/or deletion of tumor suppressor genes have been postulated to play a major role in the genesis and the progression of gliomas. In this study, the functional expression and efficacy in tumor suppression of 3 tumor suppressor genes (p53, p21, and p16) were tested and compared in a rat GBM cell line (RT-2) after retrovirus mediated gene delivery in vitro and in vivo. Significant reductions in tumor cell growth rate were found in p16 and p21 infected cells (60 +/- 12% vs 66 +/- 15%) compared to p53 (35 +/- 9%). In vitro colony formation assay also showed significant reductions after p16 and p21 gene delivery (98 +/- 5% vs 91 +/- 10%) compared to p53 (50 +/- 18%). In addition, the tumor suppression efficacy were investigated and compared in vivo. Retroviral mediated p16 and p21 gene deliveries in glioblastomas resulted in more than 90% reductions in tumor growth (92 +/- 26% vs 90 +/- 22%) compared to p53 (62 +/- 18%). Tumor suppressor gene insertions in situ further prolonged animal survival. Overall p16 and p21 genes showed more powerful tumor suppressor effects than p53. The results were not surprising, as p16 and p21 are more downstream in the cell cycle regulatory pathway compared to p53. Moreover, the mechanism involved in each of their suppressor effects is different. This study demonstrates the feasibility of using tumor suppressor genes in regulating the growth of glioma in vitro and in situ.
authors.affiliation: Department of Pediatrics, Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China.
authors.forename: T J
authors.initials: TJ
authors.lastname: Wang
authors.forename: M S
authors.initials: MS
authors.lastname: Huang
authors.forename: C Y
authors.initials: CY
authors.lastname: Hong
authors.forename: V
authors.initials: V
authors.lastname: Tse
authors.forename: G D
authors.initials: GD
authors.lastname: Silverberg
authors.forename: M
authors.initials: M
authors.lastname: Hsiao
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests; D002455:Cell Division / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000627:therapeutic use*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D005909:Glioblastoma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D009368:Neoplasm Transplantation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012190:Retroviridae / Q000235:genetics; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000627:therapeutic use*
chemical_list: C493956:CDKN1A protein, human; C493958:Cdkn1a protein, rat; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53