Effect ofO 6-benzylguanine on the response to 1,3-bis(2-chloroethyl)-1-nitrosourea in the Dunning R3327G model of prostatic cancer |
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| Authors: | M. Eileen Dolan Anthony E. Pegg Neil D. Biser Robert C. Moschel Hugh F. English |
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| Affiliation: | (1) Division of Hematology-Oncology, The University of Chicago Medical Center, 5841 S. Maryland Ave., Box MC2115, 60637 Chicago, IL, USA;(2) Department of Medicine (HFE, NDB), Cellular and Molecular Physiology and of Pharmacology (AEP), Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, P. O. Box 850, 17033 Hershey, PA, USA;(3) Carcinogen-Modified Nucleic Acid Chemistry, ABL-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, P. O. Box B, 21702 Frederick, MD, USA |
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| Abstract: | The DNA-repair proteinO6-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 withO6-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/kgO6-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,O6-benzylguanine alone, BCNU alone (5.5–60 mg/kg), or 80 mg/kgO6-benzylguanine 1 h prior to BCNU (5.5 mg/kg). WhenO6-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 thanO6-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 withO6-benzylguanine supports a role for this therapy in the treatment of prostate cancer.Abbreviations AGT O6-alkylguanine-DNA alkyltransferase - BCNU 1,3-bis(2-chloroethyl)-l-nitrosourea |
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