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Drug resistance and apoptosis in ENU-induced rat brain tumors treated with anti-cancer drugs

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Abstract

To cast light on the mechanisms of drug-resistance, experimental brain tumors were immunohistochemically evaluated for expression of glutathione S-transferase (GST)-α, µ, π, p-glycoprotein and apoptosis-related factors, such as bcl-2 and p53, as well as by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) method. Rat brain tumors induced by means of prenatal exposure to ethylnitrosourea (ENU) were treated with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and/or vincristine. Tumors more than 2 mm in size were considered to be drug resistant. The expression of GST-µ was strongly positive in ACNU-treated brain tumors, while p-glycoprotein was overexpressed in vincristine-treated brain tumors. Neither p53 nor bcl-2 expression directly correlated with apoptosis identified by TUNEL method, but tumors lacking apoptotic cells always demonstrated the expression of either GST-µ or p-glycoprotein. These results indicate that tumors resistant to chemotherapy might not be susceptible to induction of apoptosis, and therefore that mechanisms of drug resistance are related to programmed cell death in brain tumors.

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Authors and Affiliations

  1. Nara Medical University, Nara

    Toru Yabuno, Mitsutoshi Nakamura, Toshihide Tsuzuki & Toshisuke Sakaki

  2. Second Department of Pathology, Nara Medical University, Nara

    Noboru Konishi & Yoshio Hiasa

  3. Department of Space and Life Sciences, College of Integrated Arts and Sciences, Osaka Prefectural University, Osaka, Japan

    Shigeru Tsunoda

Authors
  1. Toru Yabuno
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  2. Noboru Konishi
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  3. Mitsutoshi Nakamura
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  4. Toshihide Tsuzuki
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  5. Shigeru Tsunoda
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  6. Toshisuke Sakaki
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  7. Yoshio Hiasa
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Yabuno, T., Konishi, N., Nakamura, M. et al. Drug resistance and apoptosis in ENU-induced rat brain tumors treated with anti-cancer drugs. J Neurooncol 36, 105–112 (1998). https://doi.org/10.1023/A:1005878402133

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