EFFECT OF O6-BENZYLGUANINE ON THE RESPONSE TO 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA IN THE DUNNING-R3327G MODEL OF PROSTATIC-CANCER

被引:41
作者
DOLAN, ME
PEGG, AE
BISER, ND
MOSCHEL, RC
ENGLISH, HF
机构
[1] NCI,FREDERICK CANC RES & DEV CTR,ABL BASIC RES PROGRAM,FREDERICK,MD 21702
[2] PENN STATE UNIV,MILTON S HERSHEY MED CTR,COLL MED,DEPT MED,HERSHEY,PA 17033
[3] PENN STATE UNIV,MILTON S HERSHEY MED CTR,COLL MED,DEPT CELLULAR & MOLEC PHYSIOL,HERSHEY,PA 17033
[4] PENN STATE UNIV,MILTON S HERSHEY MED CTR,COLL MED,DEPT PHARMACOL,HERSHEY,PA 17033
关键词
D O I
10.1007/BF00685839
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The DNA-repair protein O6-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 with O6-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/kg O6-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/kg O6-benzylguanine 1 h prior to BCNU (5.5 mg/kg). When O6-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 than O6-benzylguanine plus BCNU (5.5 mg/kg) as determined by animal weight loss. The mean weight loss observed in animals 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 with O6-benzylguanine supports a role for this therapy in the treatment of prostate cancer.
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页码:221 / 225
页数:5
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