title: Distinct radiochemotherapy protocols differentially influence cellular proliferation and expression of p53 and Bcl-2 in glioblastoma multiforme relapses in vivo.
abstract: Several protocols for the adjuvant treatment of glioblastoma multiforme (GBM) are currently being evaluated. In this context, little is known about the influence of radiochemotherapy on apoptosis and the expression of apoptosis-related proteins in vivo. We have analyzed the incidence of apoptosis using in situ nick translation (ISNT) and expression of Ki-67 (MIB- 1), p53 (DO-1 and DO-7), Bcl-2 and transglutaminase II (TGase II) by immunohistochemistry in 41 patients with GBM and their matched relapses. Sixteen patients received radiochemotherapy, 18 irradiation and 7 no treatment. Radiochemotherapy resulted in an increase in Bcl-2+ cells (p = 0.013). Irradiation caused the reduction of MIB-1+ (p = 0.0015), DO-7+ (p = 0.0043) and the increase of Bcl-2+ cells (p = 0.016). We calculated a positive correlation between high TGase II scores in patients preceding radiochemotherapy (p = 0.0186) and no treatment (p = 0.0158), low ISNT scores (p = 0.0018) and high DO-1 scores (p = 0.0233) in patients preceding irradiation and short time to progression. These data show that distinct postsurgical radiochemotherapy protocols differentially alter cellular proliferation and expression of p53 and Bcl-2 in GBM relapses. Furthermore, we show that ISNT, DO-I and TGase II labeling scores are therapy-specific predictors of time to progression in GBM patients.
authors.affiliation: Institute of Brain Research, University of Tuebingen Medical School, Germany. hirnforschung@uni-tuebingen.de
authors.forename: M H
authors.initials: MH
authors.lastname: Deininger
authors.forename: E
authors.initials: E
authors.lastname: Grote
authors.forename: J
authors.initials: J
authors.lastname: Wickboldt
authors.forename: R
authors.initials: R
authors.lastname: Meyermann
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015415:Biomarkers; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy / Q000601:surgery; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D003561:Cytarabine / Q000008:administration & dosage; D018450:Disease Progression; D005260:Female; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D005796:Genes / Q000187:drug effects / Q000528:radiation effects; D019254:Genes, bcl-2 / Q000187:drug effects / Q000528:radiation effects; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy / Q000601:surgery; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis / Q000235:genetics; D015993:Life Tables; D008130:Lomustine / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000528:radiation effects; D015376:Nimustine / Q000008:administration & dosage / Q000627:therapeutic use; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D018714:Radiotherapy, Adjuvant; D016019:Survival Analysis; D013713:Teniposide / Q000008:administration & dosage; D011503:Transglutaminases / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D003561:Cytarabine; D015376:Nimustine; D008130:Lomustine; D003520:Cyclophosphamide; D013713:Teniposide; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; C003726:trofosfamide