title: Mild hyperthermia plus adenoviral p53 over-expression additively inhibits the viability of human malignant glioma cells.
abstract: Adenoviral replacement of the p53 gene has already been proved effective for the treatment of various tumours, including malignant gliomas. However, it is difficult to treat malignant glioma with p53 gene therapy alone because of problems with resistance or a less-than-satisfactory response to the treatment. This study investigated whether heat shock at 43 degrees C (mild hyperthermia) augments the cytotoxic effect of p53 gene transfer on malignant glioma cells expressing wild-type p53 (D54) or mutant p53 (U373-MG and U251-MG). The combination of mild hyperthermia and adenoviral p53 over-expression had an additive inhibitory effect on cellular proliferation in all three cell lines studied. Further, both cell cycle analysis and a DNA fragmentation assay showed that apoptosis was induced by p53 over-expression alone but not by heat shock at 43 degrees C alone. However, p53 over-expression followed by mild hyperthermia additively increased the proportion of cells in which apoptosis was induced, regardless of the endogenous p53 status of the tumour cells. Interestingly, a caspase-independent mechanism was observed to be involved in the p53-induced apoptosis in U251-MG and D54 cells. Taken together, the findings showed that combining adenoviral p53 transfer with mild hyperthermia inhibits the proliferation of malignant glioma cells in an additive manner, irrespective of their endogenous p53 status, suggesting a novel treatment strategy for this malignancy.
authors.affiliation: Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nashimoto
authors.forename: Tadashi
authors.initials: T
authors.lastname: Komata
authors.forename: Takao
authors.initials: T
authors.lastname: Kanzawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aoki
authors.forename: Shin
authors.initials: S
authors.lastname: Endo
authors.forename: Takashi
authors.initials: T
authors.lastname: Kon
authors.forename: Takeo
authors.initials: T
authors.lastname: Uzuka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Seiji
authors.initials: S
authors.lastname: Kondo
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Tanaka
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D061945:Caspase Inhibitors; D002470:Cell Survival / Q000502:physiology*; D003131:Combined Modality Therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D016158:Genes, p53; D015316:Genetic Therapy; D005910:Glioma / Q000628:therapy*; D006801:Humans; D006979:Hyperthermia, Induced; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; C493956:CDKN1A protein, human; D061945:Caspase Inhibitors; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone