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  • Author or Editor: Kazunari Yoshida x
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Shigeo Ohba, Yuichi Hirose, Kazunari Yoshida, Takahito Yazaki and Takeshi Kawase

Object

The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas. A considerable number of glioblastoma cases are refractory to TMZ, however, and the development of novel chemotherapeutic regimens is needed. The authors of previous studies have revealed that hsp90 is expressed at higher levels in human neoplastic tissues, including gliomas, than in normal tissues. Heat shock protein 90 is involved in a cytoprotective mechanism against cellular stressors such as DNA damage, and the authors hypothesized that hsp90 inhibitors might act as antitumor agents against gliomas and potentiate the cytotoxicity of DNA-damaging agents.

Methods

The authors examined the cytotoxicity of an hsp90 inhibitor, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), both alone and in combination with 1 of 3 DNA-damaging agents (cisplatin, 1,3-bis(2-chloroethyl)-1-nitrosourea, and TMZ) in human glioma cell lines. The cytotoxicity of these agents to glioma cells was measured using a colony formation assay. The cell cycle phase distribution, protein expression, and number of apoptotic cells were measured using a fluorescence-activated cell sorting assay, immunoblot assays, and double staining with annexin V and propidium iodide. In an in vivo experiment, 17-AAG, cisplatin, or 17-AAG and cisplatin were administered intraperitoneally to mice with xenografted U87MG cells, and the resulting tumor volumes were measured.

Results

The authors found that 17-AAG reduced the clonogenicity of U87MG cells, and at a low concentration (< 100 nM) potentiated the cytotoxicity of the DNA-crosslinking agents cisplatin and 1,3-bis(2-chloroethyl)-1-nitrosourea, but not that of the DNA-methylating agent TMZ. This 17-AAG–induced potentiation of DNA crosslinking agent–induced cytotoxicity was a consequence of prolonged G2-M arrest accompanied by the suppression of cdc2 and cdc25C and of increased apoptotic cell death accompanied by the degradation of the antiapoptosis proteins Akt and survivin. Similar effects were observed when cells were treated with radicicol, another hsp90 inhibitor. The 17-AAG–induced enhancement of DNA crosslinking agent–induced cytotoxicity was also observed in other cell lines. In addition, 17-AAG sensitized xenografted U87MG cells to cisplatin in nude mice.

Conclusions

Heat shock protein 90–targeted therapy may be an effective strategy for potentiating chemotherapy using DNA-crosslinking agents for TMZ-refractory gliomas.

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Shigeo Ohba, Kazunari Yoshida, Yuichi Hirose, Eiji Ikeda, Yoichi Nakazato and Takeshi Kawase

This 32-year-old woman, 27 weeks pregnant, harbored a cystic mass with a solid component in the left frontal lobe. Histologically, the lesion was hypercellular and contained a diffuse sheet of eosinophilic cells of various sizes. The cells were almost round and had a few prominent, eccentrically placed, hyperchromatic nuclei of various sizes. Immunohistochemically, the tumor was reactive for vimentin, epithelial membrane antigen, cytokeratin AE1/AE3, smooth muscle actin, and BAF47/INI-1, and negative for glial fibrillary acidic protein, neurofilament protein, S100 protein, CK7, CK20, HMB-45, MIC2, and Bcl-2. The Ki 67 labeling index was 4.2%. Comparative genomic hybridization analysis revealed aberrations of the chromosomal copy number of +7 and −10. This tumor could not be categorized according to the present World Health Organization classification. Results of staining with glial fibrillary acidic protein were not consistent with a glioma, and staining with INI-1 was inconsistent with atypical teratoid/rhabdoid tumor. The tumor was therefore designated as a “cerebral tumor with extensive rhabdoid features.”