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The mechanism and overcoming of resistance in ACNU-resistant sublines of C6 and 9L rat glioma

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Abstract

In order to study the mechanism of the resistance to chemotherapeutic agents, especially ACNU [1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride], two variant cell lines (C6/ACNU and 9L/ACNU) resistant to ACNU were selected in vivo from rat C6 and 9L glioma, respectively. Uptake and efflux of ACNU in these resistant cells were studied with Ethylene[14C]ACNU. The result indicated that the resistance exhibited by both sublines were due to both the reduced uptake of the drug and the increased efflux. The study of the effects of oxidative phosphorylation inhibitor, DNP (2,4-dinitrophenol), on the uptake and retention of ACNU suggested that there is an active outward transport mechanism for ACNU in both glioma sublines and that enhanced activity of this efflux mechanism renders cells highly resistant to the cytotoxic action of ACNU. In an attempt to clarify the more detailed biochemical mechanisms of this active efflux system, we surveyed various membrane-modifying agents which potentiate the sensitivity of these resistant cells to ACNU. Among a number of membrane-modifying agents, reserpine was found to retain ACNU in the resistant cells and to enhance the action of ACNU on these resistant cell lines. It may be concluded that drugs such as reserpine may overcome a mechanism of ACNU resistance.

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Abbreviations

PBS:

phosphate-buffered saline consisting of 0.02 M sodium phosphate, 0.15 M NaCl pH 7.4

IC50 :

concentration of drug required for 50% inhibition of cell growth

C6/ACNU:

C6 glioma cells resistant to ACNU

9L/ACNU:

9L glioma cells resistant to ACNU

CAP-2:

2-(gamma-chloropropyl)2-chloromethylpyrimidine hydrochloride

BCNU:

1,3-bis(2-chloroethyl)-1-nitrosourea

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Authors and Affiliations

  1. Department of Neurosurgery, Osaka University Medical School, 1-1-50, Fukushima, 553, Osaka City, Japan

    Tatsuo Yoshida, Keiji Shimizu, Yukitaka Ushio, Toru Hayakawa & Heitaro Mogami

  2. Institute of Cancer Research, Osaka University Medical School, 1-1-50, Fukushima, 553, Osaka City, Japan

    Yukiya Sakamoto

Authors
  1. Tatsuo Yoshida
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  2. Keiji Shimizu
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  3. Yukitaka Ushio
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  4. Toru Hayakawa
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  5. Heitaro Mogami
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  6. Yukiya Sakamoto
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Yoshida, T., Shimizu, K., Ushio, Y. et al. The mechanism and overcoming of resistance in ACNU-resistant sublines of C6 and 9L rat glioma. J Neuro-Oncol 5, 195–203 (1987). https://doi.org/10.1007/BF00151222

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