title: Inactivation of p53 sensitizes astrocytic glioma cells to BCNU and temozolomide, but not cisplatin.
abstract: p53 inactivation sensitizes U87MG astrocytic glioma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TMZ), drugs used clinically to treat high-grade astrocytomas. In this report, we examined the effect of p53 inactivation on the chemosensitivity of two additional human astrocytic glioma cell lines, D54 and A172, in order to assess whether sensitization is a general property of astrocytic tumor cells. Compared to control cells with intact p53 function, derived lines in which p53 was inactivated displayed significantly reduced clonogenic survival after exposure to BCNU and TMZ. Sensitization to both BCNU and TMZ was associated with failure of p21(WAF1) induction, lack of a sustained G2 cell cycle arrest and significant tumor cell death. These findings suggest that enhanced sensitivity to BCNU and TMZ is a general property of human astrocytic glioma cells in which p53 was disrupted. In contrast, p53 inactivation rendered D54 and U87MG cells significantly more resistant to cis-dichlorodiamminoplatinum (CDDP), another chemotherapeutic to which high-grade astrocytomas sometimes respond. These results indicate that p53 status influences the chemosensitivity of astrocytic glioma cells in a drug-type specific manner, a finding that may have implications for the selection of drug treatments for patients with astrocytic gliomas.
authors.affiliation: Department of Oncology, University of Western Ontario, London, Ontario, Canada.
authors.forename: G Wei
authors.initials: GW
authors.lastname: Xu
authors.forename: Joe S
authors.initials: JS
authors.lastname: Mymryk
authors.forename: J Gregory
authors.initials: JG
authors.lastname: Cairncross
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001254:Astrocytoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002330:Carmustine / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020868:Gene Silencing; D006801:Humans; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D003606:Dacarbazine; D002945:Cisplatin; D002330:Carmustine; D000077204:Temozolomide