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PubMed1993

Hormonal chemoprevention of cancer in women.

The use of oral contraceptives in the United States during the past three decades has led to a dramatic decline in the incidence of cancers of the ovary and endometrium. The magnitude of these declines was predictable both from epidemiologic data and from the biologic effects of oral contraceptives on these tissues. Although the incidence of breast cancer has not been substantially affected by current oral contraceptives, it may be possible to develop alternative forms of contraception that provide protection against all three cancers. The major goal of hormonal chemoprevention of cancer is to reduce cell proliferation in the relevant epithelial tissue. New chemopreventive agents such as tamoxifen exemplify the application of this principle.

5-alpha Reductase Inhibitors↗
PubMed1977

Physiological effects of an antimycotic azasterol on cultures of Saccharomyces cerevisiae.

The yeast Saccharomyces cerevisiae has been studied during cultivation with a naturally occurring antimycotic azasterol. At very low concentrations (1.0 to 10.0 ng/ml), where growth retardation is not observed, an unusual sterol, ergosta-8,14-dien-3beta-ol, accumulates in high concentrations. Upon removal of the azasterol from the culture, the 8,14-diene is converted to ergosterol. Much smaller amounts of another 8,14-sterol, but with an additional unsaturation, have also been observed. Total sterol accumulation is higher in cultures containing subinhibitory levels of the antimycotic agent than the amounts of normal sterol accumulation in control cultures. With between 10 and 100 ng of azasterol per ml a transitory cessation of growth is observed from which the culture is able to recover. At much higher concentrations growth inhibition and even cell lysis results. Competitive inhibition of sterol 24(28)methylene reductase is demonstrated.

Antifungal Agents↗
PubMed1976

Homoazasterol-mediated inhibition of yeast sterol biosynthesis.

A naturally occurring azasterol has been shown to inhibit sterol transmethylation in both in vitro and in vivo in the yeast Saccharomyces cerevisiae. The inhibition was competitive, with a calculated dissociation constant of 43 muM. The compound prevented the accumulation of ergosterol in aerobically adapting cells. Cultures forced to gain energy by respiration were found to be much more sensitive to growth inhibition by the azasterol than those cells fermenting glucose. The growth inhibition is reversible at low concentrations of the azasterol.

Azasteroids↗
PubMed2006

What can metabolic myopathies teach us about exercise physiology?

Exercise physiologists are interested in metabolic myopathies because they demonstrate how knocking out a component of a specific biochemical pathway can alter cellular metabolism. McArdle's disease (myophosphorylase deficiency) has often been studied in exercise physiology to demonstrate the influence of removing the major anaerobic energy supply to skeletal muscle. Studies of patients with McArdle's disease have shown the increased reliance on blood-borne fuels, the importance of glycogen to maximal aerobic capacity, and the use of nutritional strategies to bypass metabolic defects. Myoadenylate deaminase deficiency is the most common metabolic enzyme deficiency in human skeletal muscle. It is usually compensated for endogenously and does not have a major influence on high-energy power output. Nutritional interventions such as carbohydrate loading and carbohydrate supplementation during exercise are essential components of therapy for patients with fatty acid oxidation defects. Cases of mitochondrial myopathies illustrate the importance of peripheral oxygen extraction for maximal aerobic capacity and show how both exercise and nutritional interventions can partially compensate for these mutations. In summary, metabolic myopathies provide important insights into regulatory and nutritional aspects of the major biochemical pathways of intermediary metabolism in human skeletal muscle.

Azasteroids↗
PubMed2005

Effect of dutasteride therapy on Doppler US evaluation of prostate: preliminary results.

PURPOSE: To prospectively determine the effect of short-term therapy with dutasteride on the suppression of Doppler ultrasonographic (US) signal in benign prostate tissue and thus on improvement in the depiction of prostate cancer with Doppler US-guided core-needle biopsy. MATERIALS AND METHODS: After institutional review board approval and informed consent were obtained as part of this HIPAA-compliant study, 11 men (age range, 59-77 years) were evaluated with gray-scale, color, and power Doppler US at baseline and weekly for up to 3 weeks while taking 0.5 mg of dutasteride per day. Flow intensity in the periurethral, transition, and peripheral zones was subjectively scored by using a four-point scale. The Wilcoxon matched-pairs signed-ranks test was used to compare pre- and posttherapy scores. After flow was reduced to "diminished" or "none" with at least a 1-score difference on the four-point scale, up to four targeted cores were obtained from areas of persistent flow within the peripheral zone, followed by laterally directed sextant biopsy. RESULTS: Doppler US flow suppression occurred in 11 of 11 patients after 1 week of dutasteride therapy (P < .01). Further suppression was noted after 2 weeks in eight of 10 patients (P = .04) and after 3 weeks in two of two patients. Biopsy was performed after 1 (n = 1), 2 (n = 8), or 3 (n = 2) weeks of therapy. Flow suppression was greatest in the peripheral zones (mean decrease: 0.64 and 0.76 after weeks 1 and 2, respectively) and least in the periurethral zones (mean decrease: 0.30 after 1 week). Cancer was detected in eight (20%) of 40 targeted cores and in five (8%) of 66 sextant cores. Four patients had cancer at targeted biopsy, and three of these four patients had cancer at sextant biopsy. In the four men with cancer, targeted cores were 5.9 times more likely to be positive (P = .027). Selective suppression of flow in benign tissue was observed in two of the four men with cancer. CONCLUSION: Short-term dutasteride therapy reduces Doppler US flow in the prostate and may improve depiction of hypervascular cancer.

Aged↗
PubMed1993

Androgen regulation of thromboxane A2/prostaglandin H2 receptor expression in human erythroleukemia cells.

Thromboxane A2 (TxA2), a platelet aggregator and vasoconstrictor, has been implicated as a potential mediator of cardiovascular diseases. Abuse of androgenic steroids has been associated with thrombotic cardiovascular diseases. Human erythroleukemia (HEL) cells, a megakaryocyte-like cell line, express functional TxA2/prostaglandin H2 (PGH2) receptors with characteristics similar to those seen in platelets. This study characterized testosterone regulation of HEL cell TxA2/PGH2 receptors. TxA2/PGH2 receptor affinity (Kd) and density (Bmax) were determined via equilibrium binding experiments using the radiolabeled TxA2 mimetic (1S-[1 alpha,2 beta(5Z),3 alpha(1E,3R*),4 alpha])-7-(3-[3-hydroxy-4-(4'- iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]heptan-2-yl)-5-he ptenoic acid (125I-labeled BOP). Testosterone (200 nM) but not estradiol increased Bmax from 108 +/- 9 fmol/mg protein to 157 +/- 9 fmol/mg protein (n = 7 experiments; P < 0.01) without any significant change in Kd. Testosterone had no significant effect on alpha 2-adrenergic receptor density. The maximum increase in intracellular free calcium induced by the TxA2 agonists I-BOP or U-46619 was significantly (P < 0.005) greater in testosterone-treated cells compared with controls. Hydroxyflutamide (1 microM), an androgen-receptor antagonist, completely blocked the effect of testosterone (P < 0.01). Dihydrotestosterone, the active metabolite of testosterone, also increased Bmax in a concentration-dependent manner and was more potent than testosterone. The effect of testosterone to increase Bmax was significantly (P < 0.01) inhibited by coincubation with cycloheximide (0.1 microgram/ml) or actinomycin D (10 ng/ml). These results indicate that androgenic steroids regulate the expression of functional TxA2/PGH2 receptors in HEL cells. These findings may have relevance to cardiovascular disease.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2006

Pharmacologic basis for the enhanced efficacy of dutasteride against prostatic cancers.

PURPOSE: Prostatic dihydrotestosterone (DHT) concentration is regulated by precursors from systemic circulation and prostatic enzymes of androgen metabolism, particularly 5alpha-reductases (i.e., SRD5A1 and SRD5A2). Therefore, the levels of expression SRD5A1 and SRD5A2 and the antiprostatic cancer growth response to finasteride, a selective SRD5A2 inhibitor, versus the dual SRD5A1 and SRD5A2 inhibitor, dutasteride, were compared. EXPERIMENTAL DESIGN: Real-time PCR and enzymatic assays were used to determine the levels of SRD5A1 and SRD5A2 in normal versus malignant rat and human prostatic tissues. Rats bearing the Dunning R-3327H rat prostate cancer and nude mice bearing LNCaP or PC-3 human prostate cancer xenografts were used as model systems. Tissue levels of testosterone and DHT were determined using liquid chromatography-mass spectrometry. RESULTS: Prostate cancer cells express undetectable to low levels of SRD5A2 but elevated levels of SRD5A1 activity compared with nonmalignant prostatic tissue. Daily oral treatment of rats with the SRD5A2 selective inhibitor, finasteride, reduces prostate weight and DHT content but did not inhibit R-3327H rat prostate cancer growth or DHT content in intact (i.e., noncastrated) male rats. In contrast, daily oral treatment with even a low 1 mg/kg/d dose of the dual SRD5A1 and SRD5A2 inhibitor, dutasteride, reduces both normal prostate and H tumor DHT content and weight in intact rats while elevating tissue testosterone. Daily oral treatment with finasteride significantly (P < 0.05) inhibits growth of LNCaP human prostate cancer xenografts in intact male nude mice, but this inhibition is not as great as that by equimolar oral dosing with dutasteride. This anticancer efficacy is not equivalent, however, to that produced by castration. Only combination of dutasteride and castration produces a greater tumor inhibition (P < 0.05) than castration monotherapy against androgen-responsive LNCaP cancers. In contrast, no response was induced by dutasteride in nude mice bearing androgen-independent PC-3 human prostatic cancer xenografts. CONCLUSIONS: These results document that testosterone is not as potent as DHT but does stimulate prostate cancer growth, thus combining castration with dutasteride enhances therapeutic efficacy.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2006

In vivo efficacy of STX213, a second-generation steroid sulfatase inhibitor, for hormone-dependent breast cancer therapy.

PURPOSE: Steroid sulfatase (STS) inhibitors that can decrease or prevent the biosynthesis of estrogenic steroids via the sulfatase route may play an important role in the treatment of breast cancer. We compare the in vivo efficacy of two potent STS inhibitors, STX64 and STX213, in a xenograft breast cancer model. EXPERIMENTAL DESIGN: MCF-7 cells stably expressing STS cDNA (MCF-7STS) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of estradiol sulfate (E2S) and bearing both MCF-7STS and wild-type MCF-7 (MCF-7WT) tumors were orally treated with STX64 and STX213. Treatment was given for 49 days followed by a recovery period of 35 days in which animals received only E2S. Mice were weighed, and tumor measurements were taken weekly. RESULTS: STX64 and STX213 exhibited potent STS inhibition in vivo. However, STX213 showed a greater duration of activity. In vehicle-treated nude mice receiving E2S, tumor volumes increased 5.5-fold for MCF-7WT and 3.8-fold for MCF-7STS after 49 days compared with day 0. MCF-7WT tumor growth was reduced by 56% by STX213 over the dosing period, and subsequent growth was retarded during the recovery period. All treatments fully inhibited growth of MCF-7STS tumors, and recovery of these tumors was significantly retarded (P<0.01). All compounds completely inhibited liver and tumor STS activity. Additionally, STS mRNA expression in the MCF-7STS tumors directly correlated with the corresponding STS enzyme activity. CONCLUSIONS: This study indicates that STS inhibitors attenuate hormone-dependent human breast cancer growth and therefore offer a potentially novel treatment for this condition.

Animals↗
PubMedDate not supplied

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. 20% in PNU-156765-treated and 51% in flutamide-treated groups). The effect of the combination was similar to that of castration (75% inhibition). Ventral prostate weight was more markedly reduced by PNU 156765 than by flutamide, and combined treatment was as effective as castration. Prostatic dihydrotestosterone content was markedly reduced by PNU 156765 while prostatic testosterone increased. Concomitant treatment with flutamide antagonized the testosterone increase induced by PNU 156765. These data indicate a role for 5 alpha-reductase inhibitors in the therapy of prostate cancer, in combination with antiandrogens, in order to achieve adequate androgen blockade with minimal side effects.

Androgen Antagonists↗
PubMedDate not supplied

Enhanced cytogenetic and antineoplastic effects by the combined action of two esteric steroidal derivatives of nitrogen mustards.

The authors studied the effect of two modified steroids containing different proportions (%) of alkylating agents alone or in combination on sister chromatid exchange (SCE) rates and on human lymphocyte proliferation kinetics. The antitumor activity of these compounds was tested on leukemia P388- and leukemia L1210-bearing mice. The two chemicals in mixtures enhance SCE induction and antitumor activity in a synergistic manner. The homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenyl acetic acid was found to be more effective than the homo-aza-steroidal ester of o-bis(2-chloroethyl)aminobenzoic acid in causing cytogenetic damage and antineoplastic activity. A correlation was observed between the magnitude of the SCE response and the depression of the cell proliferation index. The order of the antitumor effectiveness of the five different treatments tested coincided with the order of the cytogenetic effects they induced.

Animals↗
PubMedDate not supplied

Testosterone metabolism in human skin cells in vitro and its interaction with estradiol and dutasteride.

Since the limited knowledge of cutaneous drug metabolism can impair the development of specifically acting topical dermatics and transdermal application systems, the cell-type-specific androgen metabolism in human skin and its inhibition by drugs were investigated. Cultured human foreskin and scalp skin keratinocytes and fibroblasts as well as occipital scalp dermal papilla cells (DPC) were incubated with testosterone 10(-6) and 10(-8)M alone and in the presence of 17alpha-estradiol, 17beta-estradiol or dutasteride for 24 h. Androgens extracted from culture supernatants were subjected to thin-layer chromatography and quantified by beta-counting. In keratinocytes and DPC, dihydrotestosterone (DHT) was only formed to a low extent while androstenedione was the main metabolite. In fibroblasts, DHT formation was pronounced following 10(-8)M testosterone. Dutasteride 10(-8)M completely suppressed 5alpha-dihydro metabolite formation. 17alpha-Estradiol and 17beta-estradiol at nontoxic concentrations decreased 17-ketometabolites. Human skin regulates testosterone action by cell-type-specific activation or deactivation. Effects of 17alpha-estradiol in androgenetic alopecia are not due to 5alpha-reductase inhibition. Dutasteride may be useful in acne and androgenetic alopecia.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1989

Role of steroid 5 alpha-reductase activity in sexual differentiation of the guinea pig.

The possible role of 5 alpha-reduction of steroids in the sexual differentiation of guinea pigs was determined by treating pregnant guinea pigs with a 5 alpha-reductase activity (5 alpha RA) inhibitor (17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one, 4MA, 10 mg/day) from day 30 to 55 of gestation. 5 alpha RA in fetal diencephalon tissue obtained from 4MA-treated mothers on day 55 of gestation was suppressed compared to that of control tissue. Four litters receiving 4MA were carried to term along with an equal number of litters receiving the vehicle alone. Males that received 4MA in utero (n = 6) had altered external genitalia, i.e., hypospadias and reduced anogenital distances, but their adult copulatory behavior did not differ from that of controls (n = 7). In order to evaluate treatment effects on the hypothalamic-pituitary axis, all animals were challenged with estradiol benzoate (EB, 10 micrograms in oil, s.c.) 2 weeks after gonadectomy. Serial plasma samples were obtained and analyzed for luteinizing hormone (LH) using an heterologous radioimmunoassay. Control females (n = 13) and 4MA-treated females (n = 5) released LH in surge quantities about 42 h after EB treatment. Plasma from 4MA-treated females differed from controls in that it contained greater overall quantities of LH (p less than 0.05) and greater amounts at the time of the LH surge (p less than 0.05). Regardless of treatment males did not respond to EB.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1997

Activity and inhibition of 3-beta-hydroxysteroid dehydrogenase/delta-5-4-isomerase in human skin.

Activity and inhibition of 3 beta-hydroxysteroid dehydrogenase/delta 5-4-isomerase, a key example of biosynthesis of androgenic steroids, in human skin were studied. Whole-width dermal tissue specimens excised from various regions of the male and female body were investigated with an in vitro radioenzyme assay method using dehydroepiandrosterone as substrate. The Michaelis-Menten constant of the enzyme was found to be Km = 10nM and the maximal velocity was Vmax = 0.625 pmol produced 4-androstene-3,17-dione/mg protein/20 min. Activity of 3 beta-hydroxysteroid dehydrogenase/delta 5-4-isomerase in male inguinal skin (n = 8) was 0.132-0.412, in female abdominal skin (n = 4) 0.140-0.255, in perineal skin (n = 4) 0.138-0.962 pmol/mg protein/20 min. The synthetic steroids cyproterone acetate, 4-MA and epostane proved to be potent inhibitors, IC50 values were 150, 6.2 and 1.45 nM, respectively.

Adult↗
PubMed1982

Activity of 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstane-17-oic-13,17-lactam(p-(bis(2-chloroethyl)amino)-phenyl) acetate(NSC 290205) in murine solid tumors.

The modified steroidal alkylating agent, 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstane-17-oic-13,17-lactam[p-[bis(2-chloroethyl)amino]-phenyl]acetate showed excellent activity in treatment of there murine solid tumors. Colon 26-bearing CD2F1 mice lived twice as long as controls with tumor free survivors at the end of the 70-day observation period. CD8F1 mammary tumor growth was suppressed greater than 90% compared to controls. B16 melanoma-bearing B6D2F1 mice lived 50% longer than controls. This agent had previously been shown to be active in treatment of the Theagenion-Bahner angiosarcoma, the T8 Guerin tumor, L1210 leukemia and P388 leukemia.

Animals↗
PubMed1986

Further studies on the antineoplastic activity of homo-aza-steroidal esters.

The modified steroidal alkylating agents, 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4- one(p-[bis(2-chloroethyl)amino]phenyl)butyrate(1),3 alpha-hydroxy- 13,17-seco-5 alpha- butyrate(2),3 beta-hydroxy-13,17-seco-5-androsten-17-oic- 13,17-lactam(p-[bis-(2-chloroethyl)amino]phenyl)butyrate(3) and and (p-[bis(2-chloroethyl)amino]phenyl)butyric acid(4) have been tested against L1210, P388, Ehrlich ascites tumors (EAT), Lewis lung (LL) carcinoma and adenocarcinoma CA-755. Of four compounds evaluated in L1210 leukemia, none displayed antileukemic activity. Almost all of the four compounds were more or less active against P388 leukemia. Compound 2 possesses a slight antitumor activity in EAT, while only compound 1 appears to be active in LL carcinoma. The antitumor activity of the three modified steroidal esters on adenocarcinoma CA-755 seems to be interesting.

Animals↗
PubMed1986

Synthesis of a new nor-aza-steroidal ester of p-N,N-bis-(2-chloroethyl)aminophenylbutyric acid and in vitro study of its mutagenicity and clastogenicity.

A new nor-aza-steroidal ester of chlorambucil has been synthesized. The study of the mitotic index in CHO and HeLa cells treated with this compound showed that it may be a cytostatic drug. It was also found that treatment of CHO cells with a dose as low as 5 micrograms/ml induces a large number of sister chromatid exchanges. A great number of abnormal metaphases has been observed when CHO cells were treated with the compound at a dose of 25 micrograms/ml. When the compound was tested in the Ames/Salmonella microsome assay, it was found to be mutagenic in strains TA100 and TA1535, both with and without metabolic activation.

Animals↗