Association of African-American ethnic background with survival in men with metastatic prostate cancer. (33/384)

BACKGROUND: African-American men have earlier onset of prostate cancer, higher prostate-specific antigen (PSA) levels, more advanced stage at diagnosis, and higher mortality than white men. It is not known whether the poorer survival of African-American men with prostate cancer reflects their later stage at diagnosis or differences in the basic biology of their disease. To evaluate this question, we examined outcomes of African-American and white men with metastatic prostate cancer in the context of a randomized clinical trial. METHODS: Southwest Oncology Group Study 8894 was a randomized phase III trial that compared orchiectomy with or without flutamide in men with metastatic prostate cancer. Using data from 288 African-American and 975 white men in the trial, we conducted a proportional hazards regression analysis to determine if ethnicity was an independent predictor of survival. All statistical tests were two-sided. RESULTS: African-American men were more likely than white men to have extensive disease and bone pain and had poorer performance status, younger age at study entry, higher Gleason score, and higher PSA levels. After adjustment for these prognostic variables, the hazard ratio (HR) for all-cause mortality for African-American men relative to white men was 1.23 (P: =.018). Further adjustment for initial quality-of-life assessments also resulted in higher HRs associated with African-American ethnicity relative to white ethnicity (HR = 1.39; P: =.007). CONCLUSIONS: African-American men with metastatic prostate cancer have a statistically significantly worse prognosis than white men that cannot be explained by the prognostic variables explored in this study. These data should give increased impetus for efforts to detect the disease early in African-American men and for the development of more effective therapies based on potential biologic differences in this ethnic group.  (+info)

Human CYP1B1 and anticancer agent metabolism: mechanism for tumor-specific drug inactivation? (34/384)

The cytochrome P450 1B1 (CYP1B1) is involved in the metabolism of procarcinogens and xenobiotics. Human CYP1B1 protein has been detected in a variety of tumors but is not detected in adjacent normal tissues or in liver. This suggests that CYP1B1 could biotransform anticancer agents specifically in the target cells. The interaction between CYP1B1 and 12 commonly used anticancer drugs was screened using an ethoxyresorufin deethylase assay. Four agents were competitive inhibitors of CYP1B1 activity: flutamide (K(i) = 1.0 microM), paclitaxel (K(i) = 31.6 microM), mitoxantrone (K(i) = 11.6 microM), and docetaxel (K(i) = 28.0 microM). Doxorubicin (K(i) = 2.6 microM) and daunomycin (K(i) = 2.1 microM) were mixed inhibitors, while tamoxifen was a noncompetitive inhibitor (K(i) = 5.0 microM). Vinblastine, vincristine, 5-fluorouracil, etoposide, and cyclophosphamide did not inhibit CYP1B1 activity. In vitro incubations with flutamide and CYP1B1 produced a metabolite consistent with 2-hydroxyflutamide. Comparison of kinetic parameters (K(m), K(i), V(max)) for flutamide 2-hydroxylation by CYP1B1, CYP1A1, and CYP1A2 indicate that CYP1B1 could play a major role for flutamide biotransformation in tumors. The results obtained indicate that several anticancer agents inhibit CYP1B1 activity. Drug inactivation by CYP1B1 may represent a novel mechanism of resistance, influencing the clinical outcome of chemotherapy.  (+info)

Androgen receptor antagonism by the organophosphate insecticide fenitrothion. (35/384)

Organophosphate insecticides represent one of the most widely used classes of pesticides with high potential for human exposure in both rural and residential environments. We investigated the interaction of the organophosphothioate pesticide fenitrothion (O,O-dimethyl O-(4-nitro-m-tolyl) phosphorothioate) with the human androgen receptor (AR). Fenitrothion blocked dihydrotestosterone-dependent AR activity in a concentration-dependent and competitive manner in HepG2 human hepatoma liver cells transiently transfected with human AR and an AR-dependent luciferase reporter gene. Schild regression analysis yielded an equilibrium dissociation constant value of 2.18 x 10(-8) M. To determine the antiandrogenic potential of fenitrothion in vivo, 7-week-old castrated Sprague-Dawley rats were dosed once a day for 7 days with testosterone propionate (50 microg/day, sc) plus gavage doses of either corn oil vehicle or fenitrothion (15 or 30 mg/kg/day). An additional group of rats was given testosterone propionate and flutamide (50 mg/kg/day). Motor activity and acetylcholinesterase activity in whole blood and brain were also assessed. Both fenitrothion and the reference antiandrogen flutamide caused significant decreases in the ventral prostate, seminal vesicle, and levator ani plus bulbocavernosus muscles tissue weights. In contrast, blood acetylcholinesterase activity, a standard biomarker of organophosphate poisoning, was only inhibited at the higher dose of fenitrothion (30 mg/kg). Our results demonstrate that fenitrothion is a competitive AR antagonist, comparable in potency to the pharmaceutical antiandrogen flutamide and more potent, based on in vitro assays, than the known environmental antiandrogens linuron and p,p'-, 2,2-bis(p-hydroxyphenyl)-1,1-dichloroethylene ( p,p'-DDE).  (+info)

Testosterone inhibits osteoclast formation stimulated by parathyroid hormone through androgen receptor. (36/384)

Androgens play an important role in the regulation of bone metabolism in animals and humans. The present study was performed to investigate whether androgens would affect osteoclast formation stimulated by parathyroid hormone (PTH) in mouse bone cell cultures and its mechanism. Testosterone as well as alpha-dihydrotestosterone (DHT) concentration-dependently inhibited osteoclast formation induced by PTH-(1-34). 10(-8) M ICI 182780, an estrogen receptor inhibitor, did not affect PTH-induced osteoclast formation antagonized by 10(-8) M testosterone, although it completely antagonized the effects of 10(-8) M 17beta-estradiol. Moreover, 3 microM 4-androsten-4-ol-3,17-dione, an aromatase inhibitor, did not affect PTH-induced osteoclast formation antagonized by testosterone. Hydroxyflutamide, an androgen receptor antagonist, concentration-dependently antagonized the inhibitory effects of testosterone as well as DHT on PTH-stimulated osteoclast formation. In conclusion, the present study first demonstrated that testosterone inhibited osteoclast formation stimulated by PTH through the androgen receptor, but not through the production of intrinsic estrogen in mouse bone cell cultures.  (+info)

Sodium-induced rise in blood pressure is suppressed by androgen receptor blockade. (37/384)

Our objective was to test the hypothesis that 1) a high Na (HNa, 3%) diet would increase blood pressure (BP) in male Wistar-Kyoto (WKY) and spontaneously hypertensive Y chromosome (SHR/y) rat strains in a territorial colony; 2) sympathetic nervous system (SNS) blockade using clonidine would lower BP on a HNa diet; and 3) prepubertal androgen receptor blockade with flutamide would lower BP on a HNa diet. A 2 x 4 factorial design used rat strains (WKY, SHR/y) and treatment [0.3% normal Na (NNa), 3% HNa, HNa/clonidine, and HNa/flutamide]. BP increased in both strains on the HNa diet (P < 0.0001). There was no significant decrease in BP in either strain with clonidine treatment. Androgen receptor blockade with flutamide significantly decreased BP in both strains (P < 0.0001) and normalized BP in the SHR/y colony. Neither heart rate nor activity could explain these BP differences. In conclusion, a Na sensitivity was observed in both strains, which was reduced to normotensive values by androgen blockade but not by SNS blockade.  (+info)

Treatment of localized prostate cancer with intermittent triple androgen blockade: preliminary results in 110 consecutive patients. (38/384)

OBJECTIVES: To determine the effectiveness of triple androgen blockade as an alternative to watchful waiting, radical prostatectomy or radiation therapy in the management of patients with clinical stage T1 to T3 prostate cancer. METHODS: The records of 110 consecutive patients were retrospectively evaluated. Patients were treated with a three-drug androgen blockade regimen, consisting of a luteinizing hormone-releasing hormone agonist (leuprolide or goserelin) plus an antiandrogen (flutamide or bicalutamide) plus finasteride (a 5-alpha-reductase inhibitor), followed by finasteride maintenance therapy, as the sole intervention. All patients refused local therapy and had their prostates intact. Determinants of efficacy included serum prostate-specific antigen (PSA) levels and disease-specific survival. RESULTS: Patients were treated for a median of 13 months with triple androgen blockade. At baseline, mean PSA level was 13.2 +/- 1.2 ng/ml (range, 0.39-100 ng/ml), and mean Gleason score was 6.6 +/- 0.1 (range, 4-10). During treatment, PSA levels declined to < or =0.1 ng/ml in all patients, with a median time of 3 months. After a median follow-up of 36 months since initiation of treatment, PSA levels have remained stable in 105 of 110 patients (95.5%). At a median follow-up of 55 months (range, 38-125 months), the mean PSA level for the first 57 patients treated in this series is 1.88 +/- 0.1 (range, 0-11.0 ng/ml). Only 9 of 110 (8.1%) patients have a PSA level > or =4.0 ng/ml. To date, no patient has received a second cycle of hormone blockade. CONCLUSIONS: Although median follow-up is short, triple androgen blockade therapy followed by finasteride maintenance appears to be a promising alternative for the management of patients with clinically localized or locally advanced prostate cancer. Further study of this approach is warranted.  (+info)

Dexamethasone blocks antioestrogen- and oxidant-induced death of pituitary tumour cells. (39/384)

The oestrogen receptor is fundamental to the growth and survival of the rat pituitary tumour cell line, GH(3). Our previous studies have shown that antioestrogens such as RU 58668 and ZM 182780 will reduce the rate of cell division and also induce cell death. Death of these cells in response to antioestrogen treatment appears to be due to a heightened sensitivity to reactive oxygen species (ROS). As part of a study to determine the cross-talk between steroid receptor systems in these cells, we have observed that the glucocorticoid, dexamethasone (Dex), inhibits antioestrogen-induced cell death. Cell death induced by H(2)O(2) is enhanced by ZM 182780 and this effect is also blocked by Dex. As apoptotic cell death in a number of systems involves an early loss of mitochondrial membrane potential (DeltaPsi(m)), we have performed detailed studies on the time-course of DeltaPsi(m) loss in relation to the loss in cell membrane function. These studies have indicated that a loss of DeltaPsi(m) parallels a loss of cell membrane function - this is more characteristic of necrosis than of apoptosis. From microscopic observations of these cells in response to H(2)O(2), it has been noted that early cell membrane blebbing, induced by H(2)O(2), is blocked in the presence of ZM 182780. Cell membrane blebbing can precede necrosis as well as apoptosis and it is thought to involve cytoskeletal changes, for which localised glycolytic reactions provide ATP. These observations, together with those showing that removal of glucose, but not inhibition of mitochondrial function, enhances ROS-induced cell death, prompted studies on the glycolytic pathway. As a strong candidate mechanism, it would appear that, via an effect on one of the rate-limiting glycolytic enzymes, glyceraldehyde-3-phosphate dehydrogenase, Dex is able to overcome the antioestrogen-enhanced loss of glycolytic function following exposure of cells to ROS. This report contributes to the growing body of evidence showing that glucocorticoids provide a survival advantage to both normal and tumour cell types.  (+info)

Testosterone receptor blockade restores cellular immunity in male mice after burn injury. (40/384)

Males are known to have increased risk for septic complications after traumatic injury, which appears to be mediated by the inhibitory effects of testosterone on immune function. The role of testosterone in immunity after burn injury, however, remains unclear. Herein, we examined the effects of a testosterone receptor antagonist, flutamide, on delayed type hypersensitivity response (DTH), splenocyte proliferation, interleukin (IL)-2 secretion, and IL-2 receptor (IL-2R) expression in male BALB/c mice subjected to a 15% total body surface area burn or sham injury. Burn- or sham-injured mice were given flutamide s.c. at 30 min and 24 h after injury. At 48 h, burn injury caused a 48% (P<0.001) decrease in DTH response; however, mice that received flutamide treatment did not demonstrate significant suppression of DTH. Likewise, splenocyte proliferation and IL-2 production were depressed in burned animals in comparison with sham-injured controls, and flutamide treatment resulted in a partial restoration of these responses. In vitro studies indicated that splenocytes from sham- and burn-injured mice were equally sensitive to the suppressive effects of 5alpha-dihydrotestosterone in regard to proliferation and IL-2 production. Further evaluation revealed a decrease in IL-2R expression on splenocytes from burned mice and a partial restoration of this expression with flutamide treatment. Thus blocking testosterone receptor activation improves the cellular immunity in thermally injured mice, possibly through restoration of IL-2 production and IL-2R expression. It remains to be determined whether the effects of testosterone in this injury model are direct or indirect.  (+info)