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The local effect of oestradiol-iyβ on growth and morphology of dunning R3327H prostatic adenocarcinoma may not be receptor-mediated
86s
B-094
DUNNING R3327H MORPHOLOGY OF GROWTH AND THE LOCAL EFFECT OF OESTRADIOL-176 ON PROSTATIC ADENOCARCINOMA MAY NOT BE RECEPTOR-MEDIATED. Landstrom M., Damber J-E., Bergh A., Bostedt L., Stigbrand T. and Tomic R. Departments of Physiology, Urology & Andrology, Pathology and Medical & Physiological Chemistry, University of Umeb. 901 87 Umeh, Sweden. Recently it was shown that oestradiol-176 exerted direct inhibitory effect on tumour growth of the Dunning R3327H prostatic adenocarcinoma in rats. The purpose of the present study was to investigate whether the effects of OE on the Dunning R3327H tumour are oestrogen-receptor-mediatedor not. Method: All rats were castrated on the first day of treatment, and received thereafter dal'ly.c injections of testosterone propionate 0.1 mg (C+T). Some rats were injected daily with oesi,radiol-176(OE) 0.05 mg s.c alone or in combination with the anti-oestrogen tamoxifen, TAM, (C+T+OE,C+T+OE+TAM).One group received TAM without OE (C+T+TAM). TAM was injected s.c twice a week (1 mg tamoxifen in 0.2 ml peanut oil/rat). Tumour volumes were measured weekly. Treatment period lasted for 6 weeks. As an marker of the oestrogen effect the pregnancy-associated murine protein-l (PAMP-1) in plasma was measured. Blood samples were taken for PAMP-1 analysis and pieces of the tumours were taken for morphometric analysis and oestrogen receptor studies. Results: The oestrogen-receptor in the prostatic tumours was blocked efficially by TAM. In both the OE-treatment groups (C+T+OE and C+T+OE+TAM) there were significant inhibition of tumour growth when compared to controls (C+T and C+T+TAM). No differences between the two OE-treatment groups were observed regarding tumour growth and morphology. OE-treatment induced an significant increase in plasma PAMP-1 which was inhibited by TAM. Conclusion: The inhibitory effect of OE on the Dunning R3327H prostatic adenocarcinoma, in contrast to the effect on liver protein synthesis, appears not to be mediated by oestrogenreceptors. B-095 ANDROSTENEDIONE AND PROSTATIC STIMULATION: YODEL STUDIES IN THE RAT Kohlsaat E. and Klein H. DeDartment of Clinical Chemistry, University of Hamburg, D-2000 Hamburg, Germany Controversial discussions about adrenal steroids and their role as a source of androgenic influences on prostatic carcinomas during endocrine therapies have stimulated the interest in the role of androstenedione as precursor of active androgens. Rats were orchiectomized, adrenalectomized, and treated with androstenedione by S.C. implantation of steroid-releasing silicone capsules. Steroid utilization and the resulting effects on the prostate were studied by quantification of steroid concentrations in plasma, prostate, and prostatic subcellular fractions, as Well as activities of prostatic steroid metabolizing enzymes and general narameters of prostatic stimulative response. Treatment with androstenedione resulted in dose-dependent, linear increasing plasma levels of androstenedione (A) and testosterone (T), demonstrating a substantial peripheral conversion of the precursor into the active androgen. The levels of T nearly equaled those of A. There was a non-linear prostatic stimulative response to the concentrations of circulating steroids, resembling that to T alone. By adjusting plasma A and T concentrations to levels comparable to those in castrated men, substantial stimulative effects on the prostate as well as intraorostatic DHT concentrations were observed. However, these effects did not approach the stimulative effects or the intratissular DHT content induced by identical plasma T concentrations not accompanied by A. It is concluded, that 1. in the castrate circulating A is an important source of androgenic stimulation of the prostate via conversion into T, and 2. the perioheral conversion of A into T is of much more importance as source of active androgen available for the orostate than the intraprostatic steroid metabolism. B-096 JQJDR-
MFTABOLISM IN THE PRGSTATEOFCASTRATFDAND PITUITARY c,RAFpEDWISTAR RATS Fjesne HE and Sunde A. Institute of Cancer Research, University Hospital, N-7000 Trondheim, Norway. And.rogenmetabolism in rat ventral(w),lateral(LP) and dorsal labes(DP),and the coagulating glard(cG) has been studied in vitro with the aim of finding differences in the activities of the enzymes 5cl-reductase(5a-RGD),3a-hydroxysteroid oxidoreductase(3a-HSOR),3B-HSORand 17B-HSOR in orchiectunized, hypcphysectmized and pituitary grafted castrated animals, with or without testosterone substitution. In the orchiectmy and the hypophysectany group we found marked atrophy of the prostatic lobes. In grafted animals the lobes were heavier than controls, most clearly seen in unsubstituted animals. Castration caused a fall in all enzyme activities except 3~HSOR (oxidative)with 3cl-androstane-diol as substrate and NADP as added cofactor in VP and LP, which increased. 17@HSGR activity was generally low except LP. There were no significant differences between orchiectany and hypophysectq group. In the grafted animals we found no difference frcracontrol in VP and CC. In I2 hyperprolactinemia caused a decrease of ~wHSOR activity measured reductively and oxidatively (Unsubstituted), seemingly inhibiting the "castration induction" described above. A significant stimulatory effect of hyperprolactinemiawas only found in DP with increased ~~-RHD activity in unsubstituted animals. In our study it seems that both gonadal and pituitary castration results in Similar effects. Hyperprolactinemia seems to affect 3~HSOR activity in LP and 5~RED activity in DP. 'IT-&work was supported by a grant fran the Norwegian Society for Fighting Cancer.
B-094
DUNNING R3327H MORPHOLOGY OF GROWTH AND THE LOCAL EFFECT OF OESTRADIOL-176 ON PROSTATIC ADENOCARCINOMA MAY NOT BE RECEPTOR-MEDIATED. Landstrom M., Damber J-E., Bergh A., Bostedt L., Stigbrand T. and Tomic R. Departments of Physiology, Urology & Andrology, Pathology and Medical & Physiological Chemistry, University of Umeb. 901 87 Umeh, Sweden. Recently it was shown that oestradiol-176 exerted direct inhibitory effect on tumour growth of the Dunning R3327H prostatic adenocarcinoma in rats. The purpose of the present study was to investigate whether the effects of OE on the Dunning R3327H tumour are oestrogen-receptor-mediatedor not. Method: All rats were castrated on the first day of treatment, and received thereafter dal'ly.c injections of testosterone propionate 0.1 mg (C+T). Some rats were injected daily with oesi,radiol-176(OE) 0.05 mg s.c alone or in combination with the anti-oestrogen tamoxifen, TAM, (C+T+OE,C+T+OE+TAM).One group received TAM without OE (C+T+TAM). TAM was injected s.c twice a week (1 mg tamoxifen in 0.2 ml peanut oil/rat). Tumour volumes were measured weekly. Treatment period lasted for 6 weeks. As an marker of the oestrogen effect the pregnancy-associated murine protein-l (PAMP-1) in plasma was measured. Blood samples were taken for PAMP-1 analysis and pieces of the tumours were taken for morphometric analysis and oestrogen receptor studies. Results: The oestrogen-receptor in the prostatic tumours was blocked efficially by TAM. In both the OE-treatment groups (C+T+OE and C+T+OE+TAM) there were significant inhibition of tumour growth when compared to controls (C+T and C+T+TAM). No differences between the two OE-treatment groups were observed regarding tumour growth and morphology. OE-treatment induced an significant increase in plasma PAMP-1 which was inhibited by TAM. Conclusion: The inhibitory effect of OE on the Dunning R3327H prostatic adenocarcinoma, in contrast to the effect on liver protein synthesis, appears not to be mediated by oestrogenreceptors. B-095 ANDROSTENEDIONE AND PROSTATIC STIMULATION: YODEL STUDIES IN THE RAT Kohlsaat E. and Klein H. DeDartment of Clinical Chemistry, University of Hamburg, D-2000 Hamburg, Germany Controversial discussions about adrenal steroids and their role as a source of androgenic influences on prostatic carcinomas during endocrine therapies have stimulated the interest in the role of androstenedione as precursor of active androgens. Rats were orchiectomized, adrenalectomized, and treated with androstenedione by S.C. implantation of steroid-releasing silicone capsules. Steroid utilization and the resulting effects on the prostate were studied by quantification of steroid concentrations in plasma, prostate, and prostatic subcellular fractions, as Well as activities of prostatic steroid metabolizing enzymes and general narameters of prostatic stimulative response. Treatment with androstenedione resulted in dose-dependent, linear increasing plasma levels of androstenedione (A) and testosterone (T), demonstrating a substantial peripheral conversion of the precursor into the active androgen. The levels of T nearly equaled those of A. There was a non-linear prostatic stimulative response to the concentrations of circulating steroids, resembling that to T alone. By adjusting plasma A and T concentrations to levels comparable to those in castrated men, substantial stimulative effects on the prostate as well as intraorostatic DHT concentrations were observed. However, these effects did not approach the stimulative effects or the intratissular DHT content induced by identical plasma T concentrations not accompanied by A. It is concluded, that 1. in the castrate circulating A is an important source of androgenic stimulation of the prostate via conversion into T, and 2. the perioheral conversion of A into T is of much more importance as source of active androgen available for the orostate than the intraprostatic steroid metabolism. B-096 JQJDR-
MFTABOLISM IN THE PRGSTATEOFCASTRATFDAND PITUITARY c,RAFpEDWISTAR RATS Fjesne HE and Sunde A. Institute of Cancer Research, University Hospital, N-7000 Trondheim, Norway. And.rogenmetabolism in rat ventral(w),lateral(LP) and dorsal labes(DP),and the coagulating glard(cG) has been studied in vitro with the aim of finding differences in the activities of the enzymes 5cl-reductase(5a-RGD),3a-hydroxysteroid oxidoreductase(3a-HSOR),3B-HSORand 17B-HSOR in orchiectunized, hypcphysectmized and pituitary grafted castrated animals, with or without testosterone substitution. In the orchiectmy and the hypophysectany group we found marked atrophy of the prostatic lobes. In grafted animals the lobes were heavier than controls, most clearly seen in unsubstituted animals. Castration caused a fall in all enzyme activities except 3~HSOR (oxidative)with 3cl-androstane-diol as substrate and NADP as added cofactor in VP and LP, which increased. 17@HSGR activity was generally low except LP. There were no significant differences between orchiectany and hypophysectq group. In the grafted animals we found no difference frcracontrol in VP and CC. In I2 hyperprolactinemia caused a decrease of ~wHSOR activity measured reductively and oxidatively (Unsubstituted), seemingly inhibiting the "castration induction" described above. A significant stimulatory effect of hyperprolactinemiawas only found in DP with increased ~~-RHD activity in unsubstituted animals. In our study it seems that both gonadal and pituitary castration results in Similar effects. Hyperprolactinemia seems to affect 3~HSOR activity in LP and 5~RED activity in DP. 'IT-&work was supported by a grant fran the Norwegian Society for Fighting Cancer.