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Enhancement of ACNU cytotoxicity by pretreatment withO 6-methylguanine in ACNU-resistant brain tumors

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Summary

O 6-Methylguanine is a substrate of the DNA repair enzymeO 6-methylguanine-DNA methyltransferase, which is involved in the repair mechanism of DNA damage induced by chloroethylnitrosoureas such as 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). We tested the enhancement effect ofO 6-methylguanine pretreatment on ACNU cytotoxicity in ACNU-resistant brain tumors. Exposure toO 6-methylguanine at various times ranging from 2 to 48 hours increased the cytotoxic effects of ACNU on C6-1 cells, and this effect was highest at higher concentrations 500 and 1,000 μM. Colorimetric cytotoxicity assay revealed at least a two-fold increase in ACNU cytotoxicity relative to controls withoutO 6-methylguanine. Intraarterial ACNU after treatment withO 6-methylguanine (two intravenous bolus injections of 80 and 40 mg/kg) significantly (P < 0.05 or P < 0.01) reduced the proliferation activity of transplanted C6-1 tumors for 96 hours after injection, whereas intravenous ACNU together withO 6-methylguanine significantly (P < 0.05) reduced C6-1 activity for only 48 hours. Thus, pretreatment withO 6-methylguanine prolonged the suppression effect of ACNU. The C6-1 tumors treated only with intravenous or intraarterial ACNU showed transient inhibition and rapid regrowth for 24 hours after treatment. These results indicate thatO 6-methylguanine increases ACNU cytotoxicity in anin vitro andin vivo brain tumor model.

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Authors and Affiliations

  1. Neurosurgical Service, Akita University Hospital, Akita, Japan

    Katsuyoshi Mineura, Ichiro Izumi, Katsuo Watanabe & Masayoshi Kowada

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  1. Katsuyoshi Mineura
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  2. Ichiro Izumi
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  3. Katsuo Watanabe
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  4. Masayoshi Kowada
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Mineura, K., Izumi, I., Watanabe, K. et al. Enhancement of ACNU cytotoxicity by pretreatment withO 6-methylguanine in ACNU-resistant brain tumors. J Neuro-Oncol 19, 51–59 (1994). https://doi.org/10.1007/BF01051048

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