Molecular targeting chemotherapy for glioblastoma

DOI Web Site 参考文献6件 オープンアクセス
  • Okamura Tatsunori
    Department of Neurosurgery, Hiroshima University School of Medicine
  • Nishiyama Masahiko
    Department of Biochemistry and Biophysics, Research Institute for Radiation Biology and Medicine, Hiroshima University
  • Suzuki Katsuyuki
    Department of Biochemistry and Biophysics, Research Institute for Radiation Biology and Medicine, Hiroshima University
  • Yamamoto Wataru
    Department of Biochemistry and Biophysics, Research Institute for Radiation Biology and Medicine, Hiroshima University
  • Kurisu Kaoru
    Department of Neurosurgery, Hiroshima University School of Medicine

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We investigated the critical determinants of cytotoxic activity for cisplatin (CDDP), mitomycin C (MMC), and nimustine hydrochloride (ACNU), which are commonly used to treat malignant glioma. In 10 human cancer cell lines, glutathione S-transferase (GST) was a significant resistance factor for CDDP. MMC activity was found to be determined through the balance between activation by NADPH: quinone oxidoreductase (DTD) and inactivation by GST, while NADPH: cytochrome P450 reductase (P-450) was important in ACNU resistance. Two glioblastoma cell lines, T98G and U-251 MG, showed remarkably high levels of these 3 enzymes and glutathione (GSH), thus being moderately sensitive to MMC and resistant to CDDP and ACNU. Inhibition of these target enzymes caused an increase of the efficacy of each drug. KW2149, a novel MMC analogue activated by GSH, was active against T98G and U-251MG cells due to their high GSH levels. Molecular targeting to seek the best treatment modality or the most active drug may contribute to improving the effectiveness of glioma chemotherapy.

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