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PubMed1996

Flutamide hepatotoxicity.

PURPOSE: Observed and expected reporting rates were compared in patients who died or were hospitalized due to hepatotoxicity associated with the use of flutamide. MATERIALS AND METHODS: Case series were submitted to the MedWatch Spontaneous Reporting System of the Food and Drug Administration. Reporting rates for serious hepatotoxicity due to flutamide were calculated and compared to rates for hospitalized patients with acute idiopathic hepatitis in the medical literature. RESULTS: After the marketing of flutamide in the United States, between February 1989 and December 1994 the Food and Drug Administration received reports of 20 patients who died and 26 who were hospitalized for hepatotoxicity due to flutamide. The rate of approximately 3 per 10,000 flutamide users exceeds by 10-fold or more the expected rate of hospitalizations for acute noninfectious liver injury of 2.5 per 100,000 men 65 years and older. Autopsies in 6 cases revealed marked to massive hepatic necrosis as the predominant feature. CONCLUSIONS: Flutamide is a potent hepatotoxin in certain patients. Serial blood aminotransferase levels should be monitored during the first few months of flutamide treatment. Before beginning use of this drug patients should be instructed to report immediately to physicians any episodes of nausea, vomiting, fatigue and jaundice so that flutamide can be promptly discontinued to avoid progression of possible liver injury.

Adverse Drug Reaction Reporting Systems↗
PubMed1997

Flutamide versus orchidectomy in the treatment of metastatic prostate carcinoma.

PURPOSE: To compare in a randomized clinical trial the therapeutic efficacy of the nonsteroidal antiandrogen flutamide 250 mg tid to testicular androgen suppression by orchidectomy in patients with metastatic prostate cancer. PATIENTS AND METHODS: Between 1989 and 1991, 104 patients aged 74 +/- 8 years with newly diagnosed metastatic prostate cancer, an ECOG performance status 0-2 and no prior hormone manipulation or chemotherapy, were randomized to receive flutamide 250 mg tid (54 patients) or orchidectomy (50 patients). Patients were evaluated at entry and at months 3, 6, 12, 18 and 24. The primary endpoint was duration of progression-free survival, progression being defined as an increase in PSA> 50% over the nadir value at 2 consecutive months or a single PSA rise > 50% over the nadir value with another objective parameter. At progression, the treatment was left to the discretion of the attending urologist. RESULTS: 16 patients (10 flutamide, 6 orchidectomy) are not evaluable. 86 had a minimum follow-up of 36 months, 36/42 and 41/44 have progressed in the orchidectomy and flutamide group with a time of failure of 419 and 496 days (p = 0.32); median time to progression was almost identical in both groups (370 vs. 396 days p = 0.9); overall survival at 69 months irrespective of treatment at relapse was identical in both groups. Side effects were dominated by gynecomastia, hot flushes in both groups, breast tenderness and diarrhea in the flutamide group. Overall, 4 (10%) of the patients in the flutamide group withdrew from therapy because of side effects. The impact of flutamide on sexual potency was not assessed because of the advanced age of the patients. Serum testosterone rose by 50% over baseline level at month 3 to plateau at 25% over baseline level at month 12. CONCLUSION: Although affected by the lack of a clear statistical power due to the small number of patients in each arm, this study shows that in spite of a constant elevation of serum testosterone (25% over baseline) flutamide 250 mg tid may be a reasonable alternative to castration in highly selected patients with well to moderately differentiated low volume metastatic prostate cancer and wishing to avoid the side effects of androgen deprivation, provided they are closely monitored and ready to switch to standard androgen deprivation in the presence of untolerable side effects or suboptimal treatment efficacy as assessed by the inability to achieve a low PSA nadir.

Aged↗
PubMed1999

Maximum androgen-blockade with medical or surgical castration in advanced prostate cancer: A meta-analysis of nine published randomized controlled trials and 4128 patients using flutamide.

With the recent Southwest Oncology Group (SWOG) publication of their metastatic prostate cancer clinical trial results, which concluded that orchiectomy and flutamide as maximal androgen blockade (MAB) therapy vs orchiectomy alone does not significantly improve survival (NCI 0105), and the 1989 publication from the same cooperative group indicating a 24% improvement in survival for MAB therapy with leuprolide and flutamide versus leuprolide alone (NCI 0036), clinicians may well be undecided about the likelihood of clinical benefits with flutamide in combination with medical or surgical castration. To better characterize this important therapeutic decision, we assessed the survival benefit of MAB therapy with flutamide through a meta-analysis of up-to-date information from studies reported/conducted from 1989 through 1998. All peer-reviewed published randomized controlled trials comparing treatment with flutamide plus either lutenizing hormone releasing hormone (LhRH) agonists or orchiectomy as MAB treatment with LhRH or orchiectomy alone were included. The primary objective of the study was to form a combined estimate and confidence interval for the hazard ratio (as measured by the relative risk (RR) of survival in a comparison of castration vs MAB) summarizing the effect of flutamide treatment on overall survival. Directly extracted estimates of the log hazard ratio were used if available (1 study); if not, either an estimate of the RR based on a reported P-value from a log rank test (7 studies) or a discrete proportional hazards approximation based on reconstructed annual life tables for the treatment arms (1 study) were used. Nine studies with 4128 patients with advanced prostate cancer were included in these analyses. Pooled estimates demonstrated a 10% improvement in overall survival with flutamide as MAB therapy (relative risk (RR)=0.90, 95% Confidence Interval=0.79, 1.00). The currently available updated evidence from randomized trials shows a 10% benefit in overall survival with flutamide as MAB therapy in comparison to conventional castration, almost identical to the estimate reported in the recently published Southwest Oncology Group Study (NCI 0105).

Journal Article↗
PubMed1993

Mechanism of action and pure antiandrogenic properties of flutamide.

Although treatment of intact adult male rats with the pure antiandrogen flutamide or a luteinizing hormone-releasing hormone (LHRH) agonist alone leads to partial inhibition of ventral prostate weight, maximal inhibition is achieved by combination of the two drugs. Potentializing effects of the two compounds were observed even on prostatic ornithine decarboxylase activity. Because LHRH agonists are widely used to achieve medical castration in men treated for prostate cancer, it is of interest to observe that in the dog, known for being the best model for studies of the action of LHRH agonists, flutamide does not interfere with the potent desensitizing action of the LHRH agonist on pituitary LH secretion, thus supporting the combined use of flutamide with an LHRH agonist for maximal androgen blockade without loss of efficiency of the LHRH agonist. Because prostate cancer is known to show a high degree of heterogeneity of its sensitivity to androgens, we analyzed the effect of combined antiandrogen therapy on parameters more sensitive to androgens than ventral prostatic weight itself. In agreement with its pure antiandrogenic characteristics, flutamide alone has no stimulatory effect on the intraprostatic level of mRNA encoding the C1 or C3 component of prostatic binding protein (PBP), whereas cyproterone acetate (CPA), megestrol acetate (MEG), and, especially, medroxyprogesterone acetate (MPA) markedly stimulate PBP-C1 and PBP-C3 mRNA levels, an effect reversed by flutamide, thus further supporting the intrinsic androgenic activity of all these steroidal derivatives. Similar androgenic effects of the steroidal derivatives were observed on prostatic ornithine decarboxylase activity. Androgen-sensitive Shionogi tumor cells were then used to assess the antiandrogenic/androgenic properties of flutamide and the above-indicated steroidal derivatives. MPA, MEG, CPA as well as spironolactone-stimulated cell proliferation under both in vivo and in vitro conditions, thus illustrating the intrinsic androgenic activity of all these compounds. Flutamide was inactive by itself and reversed the stimulatory effect of all other compounds, thus indicating its pure antiandrogenic activity. Although castration reduces intraprostatic dihydrotestosterone (DHT) to undetectable levels in the rat and guinea pig, the concentration remains at about 50% of the value found in intact men after castration, thus indicating an important contribution of the adrenals to DHT in the human prostate, a finding that requires the addition of an antiandrogen to block the action of this important amount of DHT remaining after castration.

Androgen Antagonists↗
PubMed1993

Flutamide-mediated androgen blockade evokes osteopenia in the female rat.

Androgens are believed to play a role in building and maintaining bone in the female, as well as in the male. The antiandrogen drug flutamide inhibits responses to androgens from both the gonads and the adrenals. Antiandrogens prevent androgens stimulating bone cell proliferation and differentiation in vitro, but effects of androgen blockade on bone metabolism in vivo have not been tested. The present study was undertaken to determine whether androgen blockade with flutamide (15 mg/kg body weight orally daily) would influence bone turnover or bone composition (1) in female rats with intact ovaries and (2) in rats made estrogen-deficient with the luteinizing hormone releasing hormone (LHRH) agonist, buserelin (25 micrograms/kg body weight per day SC). Four groups of rats with 45Ca-labeled skeletons were studied for 4 weeks: group A, placebo; group B, buserelin; group C, flutamide; group D, flutamide+buserelin. Total-body calcium values (mean +/- SD) were (mg) 2007 +/- 109, 1779 +/- 138 (P < 0.01 versus group A), 1818 +/- 140 (P < 0.01 versus group A), and 1690 +/- 75 (P < 0.01 versus group A) in groups A-D, respectively. Thus both buserelin and flutamide induced osteopenia. Skeletal 45Ca changes suggested buserelin-mediated estrogen deficiency bone loss was due to increased bone resorption, but flutamide-mediated androgen deficiency bone thinning was caused principally by reduced bone formation. These findings support the view that androgens play an important role in preserving bone mass in the female rat. Importantly, adequate estrogen status did not compensate for flutamide-mediated osteopenia.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗
PubMed1994

Effect of early exposure of flutamide on subsequent growth of transplantable rat prostatic tumor (dunning R-3327).

Rat transplantable prostatic tumors (Dunning R-3327) were treated with flutamide before tumors grew palpable, in order to examine the effect of short term treatment of antiandrogen for prostatic cancer in latent period on the growth after appearance of tumor. Flutamide delayed an appearance of the tumor nodule and retarded the growth rate in proportion as treatment began earlier. Flutamide also reduced final tumor volume. Flutamide-treated tumors histologically consisted of small or dilated glandular structure with an increase in stromal area, but androgen receptors were preserved. Flutamide-treated tumor showed slow growth with androgen sensitivity when transplanted to intact rats, showing prolonged influences of antiandrogen on tumor growth. There was no significant difference between flutamide-treated and control groups in weight of accessory sex organs and serum androgen or estrogen levels. In conclusion, flutamide treatment may retard an appearance of prostatic cancer concomitant in benign prostatic hyperplasia.

Animals↗
PubMed1988

The pharmacokinetics of flutamide and its major metabolites after a single oral dose and during chronic treatment.

Flutamide is a nonsteroidal antiandrogen used in the treatment of prostatic carcinoma. We have investigated the disposition of flutamide and its two major metabolites in ten urological in-patients without significant liver or renal disease. After oral administration flutamide is absorbed from the gastrointestinal tract with a tmax of about 2 h. Flutamide undergoes extensive first-pass metabolism, and its major metabolites are 2-hydroxyflutamide and the hydrolysis product 3-trifluoromethyl-4-nitroaniline. After the oral administration of a single dose of 250 mg or 500 mg maximum flutamide plasma concentrations of 0.02 and 0.1 micrograms.ml-1 respectively were observed. Maximum plasma concentrations of 2-hydroxyflutamide for the same flutamide doses were 1.3 and 2.4 micrograms.ml-1 (mean of n = 2 or n = 3). Steady-state concentrations of the biologically active metabolite 2-hydroxyflutamide (0.94 +/- 0.23 micrograms.ml-1, mean +/- SD, n = 5) were found at 2-4 days after the administration of 250 mg every 8 h. The area under the plasma concentration time curve for 2-hydroxyflutamide averaged 11.4 (10.6 and 12.1) and 24.3 (21.5-29.4, n = 3) micrograms.ml-1.h for 250 mg and 500 mg flutamide orally. 2-Hydroxyflutamide and 3-trifluoromethyl-4-nitroaniline were eliminated monoexponentially with half-times of 4.3-21.9 and 4.3-17.2 h (n = 5) respectively.

Administration, Oral↗
PubMed2006

Flutamide in unresectable pancreatic adenocarcinoma: a randomized, double-blind, placebo-controlled trial.

PURPOSE: To evaluate the impact of flutamide on survival of patients with unresectable pancreatic cancer. METHODS: This single institution, randomized, double-blind, placebo controlled study compared flutamide in the dose of 250 mg three times daily (n = 23) versus placebo (n = 23) in patients with histologically proven, previously untreated unresectable pancreatic adenocarcinoma. The primary end point was overall survival; secondary endpoints included 6-month and 1-year survival rates, performance status and response rate. RESULTS: Both the groups were well matched with regards to demographic, disease related and treatment variables. This small sample sized study, failed to demonstrate a dramatic effect on survival with the use of flutamide. Median overall survival was 151 days with the use of flutamide as compared to 136 with placebo (p = 0.51). The 6-month survival rate was 39.13% in both arms of study and 1-year survival was 4.35% versus 13.04% for the flutamide group. There was no statistically significant difference in time to deterioration of performance status (flutamide 90 days versus placebo 68 days, p = 0.59) and all patients died as a result of tumor progression. CONCLUSIONS: Anti-androgen drug flutamide in the dose of 250 mg three times daily does not appear to prolong overall survival in unresectable pancreatic cancer.

Adenocarcinoma↗
PubMed2005

Is combined androgen blockade with bicalutamide cost-effective compared with combined androgen blockade with flutamide?

OBJECTIVES: To determine the cost-effectiveness of combined androgen blockade (CAB) with bicalutamide versus CAB with flutamide in men with Stage D2 prostate cancer. Both bicalutamide and flutamide are commonly used in CAB for prostate cancer. Although the cost of bicalutamide is more than that of flutamide, it is important that the efficacy, quality of life, and side effects are also considered when determining whether CAB with bicalutamide is a cost-effective option. METHODS: A decision model was created to compare treatment strategies. Survival and side-effect information was based on a randomized trial that directly compared bicalutamide and flutamide. The costs and quality-of-life effects related to therapy were determined from published sources. RESULTS: The incremental cost per quality-adjusted life year gained for bicalutamide versus flutamide was 22,000 dollars and 16,000 dollars at 5 and 10 years, respectively. If a quality adjustment was not included, the incremental cost-effectiveness ratio for CAB with bicalutamide compared with CAB with flutamide was even more favorable (20,000 dollars/life year gained at 5 years). One-way sensitivity analysis demonstrated that the cost-effectiveness estimates were most sensitive to drug costs and survival (baseline survival was not significantly different between therapies). Multi-way uncertainty analysis revealed that the median value of the incremental cost-effectiveness ratio at 5 years was 13,637 dollars/quality-adjusted life year when all the parameters were varied over a clinically reasonable range. CONCLUSIONS: Bicalutamide is cost-effective compared with flutamide when used for androgen blockade as part of CAB for men with advanced prostate cancer.

Androgen Antagonists↗
PubMed1992

Treatment of hirsutism in women with flutamide.

OBJECTIVE: To explore the clinical usefulness of the antiandrogen flutamide in the treatment modality for hirsutism in women. DESIGN: Nine women with hirsutism were assessed before and then monthly for 3 months on a regimen of flutamide 250 mg three times a day as the sole therapeutic agent. Blood samples were taken at each assessment time for a battery of androgenic parameters. SETTING: Patients were followed in the Out-Patient Department of the Hospital das Clinicas, Sao Paulo, Brazil. Hormonal assays were performed in the Hormone Laboratories of Hospital das Clinicas and the Endocrine Research Laboratory at Newark Beth Israel Medical Center, Newark, New Jersey. PATIENTS: Nine women with moderate hirsutism were treated with flutamide. Six women were previously diagnosed as having idiopathic hirsutism, and three women were diagnosed as having polycystic ovary syndrome. INTERVENTION: All women were treated with flutamide 250 mg three times a day for 3 months. MAIN OUTCOME MEASURE: Improvement of hirsutism was assessed using the Ferriman-Gallwey hair density index. Side effects of drug therapy (deterioration of menses and dry skin) were explored. Androgen parameters included testosterone (T), sex hormone-binding globulin, bound, nonbound, and free T, androstanediol glucuronide, and others. RESULTS: After 3 months of flutamide alone, Ferriman-Gallwey scores improved in seven of nine women with mean scores decreasing from 28.1 +/- 0.6 to 24.5 +/- 0.6. None of the androgenic parameters changed during this period of time. Follicle-stimulating hormone and luteinizing hormone response to gonadotropin-releasing hormone was unchanged after flutamide. CONCLUSION: Flutamide favorably influenced hirsutism in women, with differences noted after only 3 months of therapy. More prolonged and detailed studies of this drug as the sole therapeutic agent for treatment of hirsutism seems warranted.

Adult↗
PubMed1999

Prospective randomized study comparing the long-acting gonadotropin-releasing hormone agonist triptorelin, flutamide, and cyproterone acetate, used in combination with an oral contraceptive, in the treatment of hirsutism.

OBJECTIVE: To compare triptorelin, cyproterone acetate (CPA), and flutamide, in combination with an oral contraceptive, in the treatment of hirsutism. DESIGN: Prospective randomized study. SETTING(S): Tertiary care hospital. PATIENT(S): Thirty-nine hirsute women with idiopathic or functional ovarian hyperandrogenism. INTERVENTION(S): Patients were randomly assigned to receive triptorelin (3.75 mg IM every 28 days), CPA (100 mg/d orally on days 1-10 of the menstrual cycle), or flutamide (250 mg orally twice daily). All the patients also received a triphasic oral contraceptive. MAIN OUTCOME MEASURE(S): Before and after 3 and 9 months of treatment, the Ferriman-Gallwey score, hepatic function, and gonadal and adrenal steroid profiles were evaluated. RESULTS: Thirty-three patients completed the 9-month study period. The Ferriman-Gallwey score decreased in all the groups. In the patients treated with CPA or flutamide, a decrease in the hirsutism score was noted as soon as after 3 months of treatment. This decrease was more pronounced after 9 months of treatment, especially in the patients who received flutamide, who had lower hirsutism scores compared with the other treatment groups. None of the patients had abnormal liver function test results. There was a mild increase in serum lipid concentrations, mostly in the group treated with triptorelin. CONCLUSION(S): Triptorelin, CPA, and flutamide are effective drugs for the treatment of hirsutism. Flutamide results in a greater reduction in the hirsutism score, but CPA also offers satisfactory results at a much lower cost. Triptorelin has no advantages over flutamide and CPA, and is the most expensive of the three drugs tested.

Adult↗
PubMed1993

Response to flutamide withdrawal in advanced prostate cancer in progression under combination therapy.

The effect of flutamide withdrawal was studied in 40 patients with stage D2 prostate cancer showing progression of the disease after an initial and long (average 3.9 years) period of positive response to combination therapy with flutamide associated with medical (luteinizing hormone-releasing hormone agonist) or surgical castration. Using the criteria of response of the United States National Prostatic Cancer Project, 1 complete, 3 partial and 26 stable responses were observed, while 10 patients continued to have progression after discontinuation of flutamide. The average durations of previous treatment with combination therapy were 1,794 days for the 30 responders (complete, partial and stable responses), compared to 1,726 days for the 10 nonresponders. The average duration of response after the arrest of flutamide was 440 days. Serum prostate specific antigen, which was elevated in all patients, decreased by 90% or more in 19 of the 30 responders (63%) and returned to normal in 17 (57%). The concentration of testosterone binding globulin increased after discontinuation of flutamide, thus also suggesting the suppression of an androgenic influence, while the serum levels of testosterone and dihydrotestosterone, as well as their main metabolites, did not change after withdrawal of flutamide. Alteration of local sensitivity to androgens is a probable explanation for the paradoxical positive response to the arrest of flutamide suggested in the present preliminary study.

Adenocarcinoma↗
PubMed1995

Estimating the cost effectiveness of total androgen blockade with flutamide in M1 prostate cancer.

OBJECTIVES: Although combined androgen blockade with flutamide plus medical or surgical castration is effective in metastatic prostate cancer, debate exists over whether it is cost effective. METHODS: Decision analysis model of hypothetical cohorts of 70-year-old men presenting with metastatic prostate cancer, using a societal perspective, calculated anticipated survival and incremental cost per life-year gained. Time to progression and survival rate were from the Intergroup 0036 trial. Costs were based on Medicare data and wholesale drug pricing. Flutamide was estimated to reduce the relative risk of progressive disease by 25% (range, 0 to 50%). Costs and survival benefits were discounted at a 5% annual rate. RESULTS: In our model for minimal disease, median survival increased from 42.3 to 49.4 months with flutamide and average survival by 5.2 months at an incremental cost of $25,300 per life-year gained. If the efficacy were as high as 50%, the benefit would be 12 months at a cost of $13,700 per life-year gained. At a 10% efficacy, the benefit would be 1.9 months at a cost of $60,900 per life-year gained. For severe disease, the model estimated the median survival increased from 29.5 to 34.3 months with flutamide and average survival by 4.0 months at an incremental cost of $20,000 per life-year gained. At worst-case 10% efficacy, the benefit decreased to 1.5 months at an incremental cost of $47,500 per life-year gained. Total costs for patients treated with an orchiectomy and flutamide compared to leuprolide alone were similar if severe disease was present and actually lowered costs if there was minimal disease. CONCLUSIONS: Flutamide has an incremental cost effectiveness more favorable than most accepted therapies. If drug costs are covered under health care reform, flutamide should be initiated and covered for all good performance status patients.

Aged↗
PubMed1995

A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Casodex Combination Study Group.

OBJECTIVES: To compare the efficacy and safety of bicalutamide and flutamide, each used in combination with luteinizing hormone-releasing analogue (LHRH-A) therapy, in patients with untreated metastatic (Stage D2) prostate cancer. METHODS: Randomized, double-blind (for antiandrogen therapy), multicenter study with a 2 x 2 factorial design. Eight hundred thirteen patients were allocated 1:1 to bicalutamide (50 mg once daily) and flutamide (250 mg three times daily) and 2:1 to goserelin acetate (3.6 mg every 28 days) and leuprolide acetate (7.5 mg every 28 days). RESULTS: With a median duration of follow-up of 49 weeks, time to treatment failure, the primary endpoint, was significantly (P = 0.005) better for the bicalutamide plus LHRH-A group than for the flutamide plus LHRH-A group. Patients in the flutamide plus LHRH-A group were 34% more likely to fail treatment over the given time period, as indicated by the hazard ratio of 0.749 (95% confidence interval, 0.61 to 0.92) for bicalutamide plus LHRH-A to flutamide plus LHRH-A. Results for secondary endpoints (survival, quality of life, and subjective response) were similar between groups. Diarrhea occurred in 24% of patients in the flutamide plus LHRH-A group, compared with 10% of patients in the bicalutamide plus LHRH-A group (P < 0.001). CONCLUSIONS: In patients with metastatic prostate cancer, bicalutamide plus LHRH-A is well tolerated and provides superior efficacy to flutamide plus LHRH-A with respect to time to treatment failure. Assessment of the effects of these regimens on longer term survival requires additional time for follow-up.

Adenocarcinoma↗
PubMed1991

Perinatal flutamide and mounting and lordosis behavior in adult female Wistar and Sprague-Dawley rats.

The present study was designed to investigate the possible role of perinatal androgens acting via the androgen receptor, as opposed to the estrogen receptor, for the differentiation of adult mounting and lordosis behavior in female rats. Female Wistar (W) and Sprague-Dawley (SD) rats were exposed to the anti-androgen flutamide prenatally (days 11-22 of pregnancy) and/or neonatally (days 1-10). The females were ovariectomized in adulthood and repeatedly tested for mounting and lordosis behavior. Flutamide, given both pre- and neonatally to SD rats, reduced adult T-induced female mounting. Flutamide administered only prenatally or only neonatally did not lower adult mounting behavior of SD rats. Mounting behavior of female W rats, following pre- and/or neonatal flutamide treatment was not affected. Lordosis behavior was also not altered by perinatal flutamide treatment of either strain. The results of the present study, no effect of prenatal flutamide, do not support the hypothesis that female rats require prenatal androgen receptor-mediated actions of testosterone in the organization of neural tissues for the occurrence of adult mounting and lordosis behavior. Only in SD rats androgenic organization of adult mounting behavior via the androgen receptor seems to occur both pre- and neonatally. Since clear behavioral effects of prenatal flutamide treatment have been published earlier in Long-Evans females, we suggest strain differences in sensitivity for perinatal androgenization in female rats. Future research into that possibility is needed.

Animals↗
PubMed2004

Effects of the antiandrogen flutamide on the expression of protein kinase C isoenzymes in LNCaP and PC3 human prostate cancer cells.

Flutamide is a nonsteroidal antiandrogen that is frequently used for total androgen blockage in the treatment of advanced prostate cancer. We investigated the effect of this antiandrogen on the expression of protein kinase C (PKC) isoenzymes (alpha, beta1, epsilon, zeta) that are involved in cell growth, apoptosis and neoplastic transformation. Androgen-dependent (LNCaP) and independent (PC3) human prostate cancer cells were cultured in a medium that contained fetal bovine serum (FBS) or charcoal-stripped serum (CSS) and treated with 10 microM flutamide. The expression of PKC isoenzymes and the androgen receptor (AR) were analyzed by Western blot and RT-PCR, respectively. Serum steroids differentially regulate the expression of PKC isoenzymes in LNCaP and PC3 cells. Flutamide up-regulated the expression of alpha, beta1 and zeta, but not epsilon, PKC isoenzymes in CSS-LNCaP cells. These results were not homogeneously reproduced in the presence of androgens. We observed an opposite effect of flutamide, compared to CSS, on PKCbeta1 isoform expression in CSS-LNCaP suggesting that this antiandrogen exerts an agonistic effect. In PC3 cells flutamide potentiated the expression of the four PKC isoenzymes in almost all conditions tested (FBS- and CSS-cultured cells). Such effect of flutamide in PC3 cells is independent of AR since no expression of AR was detected. These results provide new evidence on antagonistic/agonistic responses of prostate cancer cells to antiandrogen drugs that are widely used in therapy and show that flutamide can elicit responses in prostate cancer cells that do not express AR.

Androgen Antagonists↗
PubMed2003

Low-dose combination of flutamide, metformin and an oral contraceptive for non-obese, young women with polycystic ovary syndrome.

BACKGROUND: The endocrine-metabolic status of non-obese, young women with polycystic ovary syndrome (PCOS) is normalized more effectively by combined treatment with flutamide and metformin than by either of these drugs in monotherapy. In this follow-up study, we assess whether the endocrine-metabolic benefits of combined flutamide-metformin treatment are maintained in the presence of a low-dose oral contraceptive (OC). METHODS: To a population of non-obese, young PCOS women already receiving flutamide-metformin (125 mg/day and 1275 mg/day), a low-dose OC (ethinyl estradiol 20 microg + gestodene 75 microg) was administered to reduce the risk of pregnancy. A total of 12 women elected to receive the OC and this subgroup (OC+) was matched to a subgroup continuing on flutamide-metformin alone (OC-), for a total study population of 24 women (mean age +/- SEM 18.7 +/- 0.3 years; body mass index, 21.8 +/- 0.5 kg/m(2)). Endocrine-metabolic indices were assessed before any treatment (0 months), on flutamide-metformin (12 months), and again after a further 6 months with or without additional OC (18 months). RESULTS: In OC- and OC+ women, the beneficial effects of flutamide-metformin on hyperandrogenaemia, hyperinsulinaemia and dyslipidaemia were maintained. In OC+ women, there was an additional increase in sex hormone-binding globulin (SHBG), and thus a further drop in the free androgen index. CONCLUSION: When a low-dose OC is administered with a low-dose flutamide-metformin combination in women with PCOS, the beneficial effects are maintained on hyperinsulinaemia-dyslipidaemia, which are key determinants of long-term complications. Hence, in daily practice, such a low-dose quatuor may become a therapeutic option of first choice for young women with PCOS.

Adult↗
PubMed2002

Evaluation of the 20-day pubertal female assay in Sprague-Dawley rats treated with DES, tamoxifen, testosterone, and flutamide.

The Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC) has recommended the rodent pubertal female assay as a Tier I test to detect potential endocrine disrupters (EDs). This assay is designed to screen estrogenic activity in immature rats exposed to chemicals during sexual maturation. The aim of this study was to evaluate whether this assay can detect the EDs with effects brought about through various mechanisms. Immature Sprague-Dawley female rats (21 days of age) were dosed daily for 20 days by oral gavage (DES, tamoxifen, and flutamide) or sc injection (testosterone). The mean age at vaginal opening (VO) was 32.3 +/- 0.5 days in control rats. Although VO was unaffected by DES at doses of 0.2 and 1.0 microg/kg, a high dose of DES (5.0 microg/kg) significantly advanced the age at VO to 24 days. Both tamoxifen (50 and 200 microg/kg) and flutamide (25 mg/kg) also significantly accelerated VO to 27.8 +/- 0.5, 25.1 +/- 0.1, and 26.1 +/- 0.1, respectively. However, testosterone dose-dependently delayed VO (exposure to 1.0 mg/kg extended VO to 37.3 +/- 0.8 days, and VO did not occur in 2 of 10 animals by the time of necropsy at 41 days of age). Estrous cyclicity was monitored in rats from VO to necropsy. Irregular cycles were observed in the groups treated with DES (5.0 microg/kg), tamoxifen (200 microg/kg), testosterone (1.0 mg/kg), and flutamide (25 mg/kg). High dose of DES showed a persistent estrus state throughout the entire observation period. In addition, the number of days in diestrus was increased by tamoxifen (200 microg/kg) and flutamide (25 mg/kg) treatments. Significant decreases in ovarian weight were observed in 5.0 microg/kg DES (64% of control), 25 mg/kg flutamide (76% of control), and 200 microg/kg tamoxifen (47% of control). Testosterone also significantly decreased the ovarian weights in all treatment groups. Uterine weights were also decreased significantly at high doses of tamoxifen (200 microg/kg, 39% of control) or testosterone (1.0 mg/kg, 47% of control). In hormone analysis, tamoxifen significantly increased serum E(2) levels at 50 microg/kg. The mean serum levels of TSH were significantly increased in tamoxifen (10 and 50 microg/kg), testosterone (0.2 mg/kg), and flutamide (1.0 and 25 mg/kg) treatment groups compared with the control. However, serum T(4) levels were significantly reduced by testosterone. Furthermore, serum T(3) levels were significantly increased in DES, tamoxifen (10 and 50 microg/kg), testosterone (1.0 mg/kg), and flutamide (1.0 and 5 mg/kg). Our data demonstrate that the rodent pubertal female assay is useful for identifying potential EDs having not only estrogenic/antiestrogenic but also androgenic/antiandrogenic activities. However, further validation study is necessary to identify chemicals that operate through other action mechanisms, including steroid biosynthesis inhibitors and thyroid inhibitors. Moreover, additional data on other compounds with weak endocrine disrupting activity will be required to further characterize the sensitivity of the female pubertal assay.

Administration, Oral↗