Combined treatment of Dunning R3327 rat prostatic tumor with the 5alpha-reductase inhibitor PNU 157706 and the antiandrogen bicalutamide.

Unlabelled: PNU 157706 [N-(1,1,1,3,3,3-hexafluorophenyl-propyl)-3-oxo-4-aza- 5alpha-androst-1-ene-17beta-carboxamide], a novel, potent and selective dual 5alpha-reductase inhibitor, was reported to be effective in inhibiting the growth of established tumors in the Dunning R3327 rat prostatic carcinoma model.

Purpose: We investigated the efficacy of treatment with PNU 157706 in combination with the antiandrogen bicalutamide in this prostatic tumor model.

Methods: Rats with tumor diameters of about 1 cm were treated orally 6 days a week for 9 weeks with PNU 157706 (10 mg/kg per day) alone or in combination with bicalutamide (0.

Combined treatment with the 5 alpha-reductase inhibitor PNU 157706 and the antiandrogen flutamide on the Dunning R3327 prostatic carcinoma in rats.

The steroid 5 alpha-reductase enzyme catalyzes the conversion of testosterone to the potent androgen 5 alpha-dihydrotestosterone (DHT). PNU 157706, a novel, potent and selective dual 5 alpha-reductase inhibitor, was reported to be effective in inhibiting the growth of established tumors in the Dunning R3327 rat prostatic carcinoma model. We have studied the efficacy of combined treatment with PNU 157706 and the antiandrogen flutamide in this prostatic tumor in rats.

Effect of the 5 alpha-reductase inhibitor PNU 156765, alone or in combination with flutamide, in the Dunning R3327 prostatic carcinoma model in rats.

The efficacy of treatment with the 5 alpha-reductase inhibitor PNU 156765 (FCE 28260) was investigated in the Dunning R3327 prostatic tumor in rats. The compound, given orally at the doses of 10 and 50 mg/kg/day, for 8 weeks, reduced the growth of established tumors by 49-50%, an effect similar to that of flutamide at 5 mg/kg/day (46% inhibition). In a further experiment, the combination of PNU 156765 10 mg/kg/day and flutamide 5 mg/kg/day resulted in greater inhibition than either treatment alone (70 vs.

Effect of early treatment of prostate cancer with the 5alpha-reductase inhibitor turosteride in Dunning R3327 prostatic carcinoma in rats.

Background: Turosteride, a selective 5alpha-reductase inhibitor, was reported to be effective in inhibiting the growth of established tumors in the Dunning R3327 rat prostatic carcinoma model. We evaluated the preventive effect of turosteride when administered during the latency period in this prostatic tumor model.

Methods: Turosteride was given orally, 6 days a week for 10-15 weeks, starting at different times: 1) 5 weeks after tumor implantation, when tumors were not yet palpable, or 2) 1 day after tumor implantation.

Effect of the dual 5alpha-reductase inhibitor PNU 157706 on the growth of dunning R3327 prostatic carcinoma in the rat.

PNU 157706 [N-(1,1,1,3,3,3-hexafluorophenylpropyl)-3-oxo-4-aza-5alpha-androst-1-ene-17beta-carboxamide] is a novel, potent and selective dual 5alpha-reductase inhibitor. We have investigated its effect on tumor growth, endocrine organ weights and prostatic dihydrotestosterone (DHT) content in rats bearing the androgen dependent Dunning R3327 prostatic carcinoma. Animals with tumor diameters of about 1 cm were treated orally for 9 weeks with PNU 157706 (2 and 10 mg/kg/day, 6 days a week) or they were castrated, to check the hormone responsiveness of the tumor.

PNU 157706, a novel dual type I and II 5alpha-reductase inhibitor.

PNU 157706 is a novel dual inhibitor of 5alpha-reductase (5alpha-R), the enzyme responsible for the conversion of testosterone (T) to 5alpha-dihydrotestosterone (DHT). Tested on a crude preparation of human or rat prostatic 5alpha-R, PNU 157706 caused enzyme inhibition with IC50 values of 20 and 34 nM, respectively, compared to the values of 32 and 58 nM shown by finasteride. Furthermore, PNU 157706 was highly potent in inhibiting human recombinant 5alpha-R type I and II isozymes, showing IC50 values of 3.

Effect of turosteride, a 5 alpha-reductase inhibitor, on the Dunning R3327 rat prostatic carcinoma.

Background: Turosteride (FCE 26073) is a new, potent, and selective 5 alpha-reductase inhibitor. We have investigated its effect on tumor growth, organ weight, and serum hormone levels in rats bearing the androgen sensitive Dunning R3327 prostatic carcinoma.

Methods: Animals with tumor diameters of 0.

FCE 28260, a new 5 alpha-reductase inhibitor: in vitro and in vivo effects.

FCE 28260 is a novel inhibitor of 5 alpha-reductase (5 alpha R), the enzyme responsible for the conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT). The compound caused inhibition of rat and human prostatic enzymes, with IC50 values of 15 and 16 nM, respectively, compared to the values of 30 and 52 nM shown by finasteride. Furthermore, FCE 28260 was highly potent in inhibiting human recombinant 5 alpha R type 2 and 1 isozymes, showing IC50 values of 3.

Novel aromatase and 5 alpha-reductase inhibitors.

Inhibitors of aromatase and 5 alpha-reductase may be of use for the therapy of postmenopausal breast cancer and benign prostatic hyperplasia, respectively. FCE 27993 is a novel steroidal irreversible aromatase inhibitor structurally related to exemestane (FCE 24304). The compound was found to be a very potent competitive inhibitor of human placental aromatase, with a Ki of 7.

Detection and estimation of mRNA levels using a nonlinear model in neurons labeled by in situ hybridization histochemistry.

In situ hybridization histochemistry (ISHH) is an anatomical technique used to monitor gene expression at the cellular level via detection of steady-state levels of mRNA. Previously, densitometric analysis of ISHH-generated autoradiographic material has provided a relatively quantitative measure of the level of a specific mRNA distributed in any given anatomical region. The present study details the development of a parametric modeling technique used to automate the quantitative aspects of ISHH.

Inhibitory effect of combined treatment with the aromatase inhibitor exemestane and tamoxifen on DMBA-induced mammary tumors in rats.

The antitumor effect of exemestane (FCE 24304), an irreversible aromatase inhibitor, given alone or in combination with tamoxifen, was investigated in rats with 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors. The compounds were given once daily, 6 days a week for 4 weeks. Exemestane, given at the dose of 20 mg/kg/day s.

Antitumor activity of the aromatase inhibitor FCE 24928 on DMBA-induced mammary tumors in ovariectomized rats treated with testosterone.

The antitumor activity of the irreversible aromatase inhibitor FCE 24928 (4-aminoandrosta-1,4,6-triene-3,17-dione) was studied in ovariectomized and testosterone propionate (TP)-treated rats bearing 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors. This experimental condition was used as a model of postmenopausal breast cancer. TP was given s.

Selective in situ hybridization histochemical analyses of alternatively spliced mRNAs encoding beta- and gamma-preprotachykinins in rat central nervous system.

The present study describes the development of an in situ hybridization histochemistry (ISHH) procedure which was employed to selectively monitor cellular distributions of the 2 major alternatively spliced beta- and gamma-species of mRNA encoding preprotachykinin (PPT) molecules found in rat CNS. For these purposes, 2 custom-designed oligodeoxynucleotide probes were synthesized corresponding to complementary sequences of beta- and gamma-PPT mRNAs. In particular, the gamma-selective probe was demonstrated to hybridize to the contiguous regions of RNA flanking the splice site formed by exclusion of exon 4.

Comparison of the effects of the irreversible aromatase inhibitor exemestane with atamestane and MDL 18962 in rats with DMBA-induced mammary tumours.

The antitumour activity of the steroidal aromatase inhibitors exemestane (FCE 24304), MDL 18962 and atamestane (SH 489) was evaluated on 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumours in rats. The compounds were given subcutaneously at daily doses of 10 and 50 mg/kg for 4 weeks. Exemestane was also given orally, at daily doses of 100 and 200 mg/kg.

Antiestrogenic and antitumor properties of the new triphenylethylene derivative toremifene in the rat.

The effects of toremifene, a new triphenylethylene derivative, on the uterus and DMBA-induced mammary tumors in rats were compared to tamoxifen. The ability of toremifene to compete with [3H]estradiol for cytoplasmic estrogen receptor from rat uterus was similar to tamoxifen, the IC50 being 26 and 23 microM respectively. In immature intact rats the two compounds, administered orally for three consecutive days, had similar intrinsic partial estrogenic efficacy, at 50 mg/kg, about 40% of that of estradiol benzoate (EB).

Aromatase inhibition and experimental antitumor activity of FCE 24304, MDL 18962 and SH 489.

Human placental aromatase inhibitory properties of FCE 24304, MDL 18962, SH 489 and 4-hydroxyandrostenedione (4-OHA) were compared. The compounds caused time-dependent enzyme inactivation with t1/2 values of 13.9, 13.

Effect of the irreversible aromatase inhibitor FCE 24304 on DMBA-induced mammary tumors in ovariectomized rats treated with testosterone.

The antitumor activity of the irreversible aromatase inhibitor FCE 24304 (6-methylenandrosta-1,4-diene-3,17-dione) was studied in ovariectomized, testosterone propionate (TP)-treated rats with 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors that were used as a postmenopausal tumor model. When given s.c.

A new irreversible aromatase inhibitor, 6-methylenandrosta-1,4-diene-3,17-dione (FCE 24304): antitumor activity and endocrine effects in rats with DMBA-induced mammary tumors.

The antitumor activity of the new irreversible aromatase inhibitor 6-methylenandrosta-1,4-diene-3,17-dione (FCE 24304) was studied in rats with 7,12-dimethylbenzanthracene (DMBA)-induced tumors; several endocrine parameters were evaluated in these animals. The compound was given s.c.

Antitumor activity of FCE 21336, a new prolactin lowering drug, on the MXT mouse mammary carcinoma.

The effect of a new prolactin-lowering drug, FCE 21336 [1-ethyl-3-(3'-dimethylaminopropyl)-3-(6'allylergoline-8'-beta-car bonyl)-urea diphosphate] was evaluated on the hormone-dependent MXT mouse mammary carcinoma. The compound at doses of 0.02, 0.

Combined and sequential treatment using FCE 21336, a new prolactin-lowering drug, and medroxyprogesterone acetate (MPA) in DMBA-induced tumors in rats.

The effect of the new, prolactin-lowering ergoline derivative FCE21336 and medroxyprogesterone acetate (MPA) given alone and in combination was tested on DMBA-induced mammary tumors in rats. FCE 21336 (0.05 and 0.

Correlation between inhibitory effect on prolactin secretion and antitumor activity of new ergoline compounds on DMBA-induced tumors in rats.

Five recently synthesized (355/1057, 355/1000, 355/1101, 355/1138 and FCE 21336) and 4 well-known (bromocriptine, metergoline, 1-demethylmetergoline and pergolide) prolactin-lowering ergoline derivatives and 1 ergoline (nicergoline) without antiprolactin activity were tested against 7-12-dimethyl-benzanthracene (DMBA)-induced mammary carcinomas in rats. Nicergoline did not show any activity, while the other compounds, tested at doses inhibiting prolactin secretion, proved active against established tumors and on the onset of new tumors. The activity of 3 of the new ergolines (355/1000, 355/1057 and FCE 21336) and of bromocriptine and pergolide was also tested at different oral doses and was correlated with serum prolactin levels 24 hr after the last dose.