Abstract
The DNA-repair proteinO 6-alkylguanine-DNA alkyltransferase is known to protect tumor cells from the antitumor effects of carmustine (BCNU). This repair protein was inactivated in Copenhagen rat prostate tumors by treatment withO 6-benzylguanine in attempts to increase the effectiveness of BCNU therapy. The alkyltransferase activity in the liver, kidney, lung, and prostate of Copenhagen rats was 66, 37, 65, and 122 fmol/mg protein, respectively. The activity in the Dunning R3327G rat prostate tumor was found to be 129 and 126 fmol/mg protein from intact and castrated animals, respectively. The level of this protein remained low in the tissues and tumors of rats for up to 24 h and slowly began to rise at 36 h following an i. p. injection of 80 mg/kgO 6-benzylguanine. Animal survival and body weight as well as tumor volumes were monitored in rats bearing prostate tumors in the flank area that had received no treatment,O 6-benzylguanine alone, BCNU alone (5.5–60 mg/kg), or 80 mg/kgO 6-benzylguanine 1 h prior to BCNU (5.5 mg/kg). WhenO 6-benzylguanine was combined with BCNU therapy, there was a regression in tumor growth that was not observed in animals treated with an equal dose of BCNU alone. A similar regression in tumor growth was observed in animals treated with a higher dose of BCNU alone (45 mg/kg); however, this regimen was more toxic thanO 6-benzylguanine plus BCNU (5.5 mg/kg) as determined by animal weight loss. The mean weight loss observed in animal treated with BCNU alone and in those given the combination was 24% and 6%, respectively. Histopathology revealed that animals receiving either BCNU alone or the combination had a decrease in all types of bone marrow cells, a loss of intestinal crypts, and a decreased number of lymphocytes in the spleen. The enhancement of the antitumor effect on BCNU by pretreatment withO 6-benzylguanine supports a role for this therapy in the treatment of prostate cancer.
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Abbreviations
- AGT:
-
O 6-alkylguanine-DNA alkyltransferase
- BCNU:
-
1,3-bis(2-chloroethyl)-l-nitrosourea
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Dolan, M.E., Pegg, A.E., Biser, N.D. et al. Effect ofO 6-benzylguanine on the response to 1,3-bis(2-chloroethyl)-1-nitrosourea in the Dunning R3327G model of prostatic cancer. Cancer Chemother. Pharmacol. 32, 221–225 (1993). https://doi.org/10.1007/BF00685839
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DOI: https://doi.org/10.1007/BF00685839