Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flutamide is a potent antiandrogen used for the treatment of prostatic cancer. Flutamide undergoes extensive first-pass metabolism to the pharmacologically active metabolite 2-hydroxyflutamide. A simple, sensitive, precise, accurate and specific HPLC method, using carbamazepine as the internal standard, for the determination of 2-hydroxyflutamide in human plasma was developed and validated. After addition of the internal standard, the analytes were isolated from human plasma by liquid-liquid extraction. The method was linear in the 25 to 1,000 ng/ml concentration range (r>0.999). Recovery for 2-hydroxyflutamide was greater than 91.4% and for internal standard was 93.6%. The limit of quantitation was 25 ng/ml. Inter-batch precision, expressed as the relative standard deviation (RSD), ranged from 4.3 to 7.9%, and accuracy was better than 93.9%. Analysis of 2-hydroxyflutamide concentrations in plasma samples from 16 healthy volunteers following oral administration of 250 mg of flutamide provided the following pharmacokinetic data (mean+/-SD): Cmax, 776 +/- 400 ng/ml; AUC(0-infinity), 5,368 +/- 2,689 ng h/ml; AUC(0-t) 5,005 +/- 2,605 ng h/ml; Tmax 2.6 +/- 1.6 h; elimination half-life, 5.2 +/- 2.0 h.
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PMID:Determination of 2-hydroxyflutamide in human plasma by high-performance liquid chromatography and its application to pharmacokinetic studies. 1149 24

Disseminated intravascular clotting (DIC) is a well-recognized complication of malignancy. Prostatic cancer can produce chronic DIC as well as acute severe DIC. Treatment of DIC are general supportive measures including heparin, transfusion of blood, platelets and clotting factors, but the most important aspect is correction of underlying malignant diseases i.e. cancer of the prostate gland. For metastatic prostatic cancer presenting with an emergency oncologic condition, the treatment of choice is surgical orchiectomy, but surgery may not be possible in the presence of severe DIC. Ketoconazole and Flutamide are drugs with different mechanisms for hormonal manipulation of this cancer. Due to severe DIC, we combined both drugs trying to put maximum therapeutic effect on this life threatening profound DIC patient.
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PMID:Ketoconazole and Flutamide in the treatment of disseminated intravascular clotting from prostate cancer: a case report and review. 1180 62

The acquired serum Chromogranin A (CgA) positivity was followed-up during 15 months in 79 prostate cancer patients referred to maximal androgen blockade (Mab.) In all patients normal CgA values were initially measured. This study was also performed on 24 Stage C-D1 prostate cancer patients left without therapy through their own choice and in 20 controls with benign prostatic hypertrophy. In all these subjects serum PSA, %FPSA and CgA concentrations were measured at three-month intervals and bone scans were performed 1-2 times during the overall monitoring period. After nine months of monitoring, no differences in CgA-positivity between two prostate cancer patient groups had been observed. However, during the last six months of monitoring, the acquired CgA-positivity was statistically significant in treated patients when compared to the untreated group (p<<0.001). Bone metastases were found in 38% of CgA-positive prostate cancer patients (regardless of the therapy status) and in only 6% of studied patients with a steady normal serum CgA concentration. According to the data reported herein we advocate the assessment of serum CgA concentrations at 3-month intervals during hormonal manipulation. The reported results may reawaken the idea of intermittent hormone therapy and, in particular, the replacement of Mab after 9 months by Casodex (Flutamide) monotherapy for a 6-month period.
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PMID:Acquired neuroendocrine-positivity during maximal androgen blockade in prostate cancer patients. 1217 56

Androgen blockage, with either orchiectomy or luteinizing hormone releasing hormone (LHRH) analogs combined with an antiandrogen drug, is the standard treatment for metastatic prostate cancer. Flutamide is a non-steroidal antiandrogen drug that is frequently used for total androgen blockage. We report on a 54-yr-old man with metastatic prostate cancer who developed nonoliguric acute renal failure (ARF) during treatment with flutamide. Following discontinuation of flutamide therapy, his renal functions returned to normal limits within 4 wk. After a rechallenge with flutamide, serum levels of BUN and creatinine increased again. His renal function recovered completely after the cessation of the drug for the second time. This observation confirm that ARF may be clearly attributed to flutamide therapy. Although very rare, flutamide-induced ARF should be considered.
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PMID:Flutamide-induced acute renal failure in a patient with metastatic prostate cancer. 1218 Apr 80

Epidemiological reports suggest that Asians consuming a diet high in soy have a low incidence of clinically manifested prostate cancer. We have tested the hypothesis that life-time exposure to genistein, the primary isoflavone component of soy, is responsible for this protective effect. Lobund-Wistar rats were exposed to 0, 25 and 250 mg genistein/kg AIN-76A diet, starting at conception and continued until necropsy at 11 months. Male offspring were injected s.c. with Flutamide on days 50-66 and with testosterone on days 67-69, injected with N-methylnitrosourea (NMU) into the dorsal prostate on day 70, and given testosterone implants, starting at day 77. Genistein in the diet inhibited the development of NMU-induced prostate invasive adenocarcinomas, in a dose-dependent manner. Genistein did not alter body, prostate and testes weights. Male rats fed 0, 25 and 250 mg genistein/kg diet had serum genistein concentrations of 9, 60 and 861 pmol/ml, and prostate genistein concentrations of 85, 230 and 775 pmol/g tissue. We conclude that lifetime dietary genistein protected against chemically induced prostate cancer development in rats.
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PMID:Dietary genistein suppresses chemically induced prostate cancer in Lobund-Wistar rats. 1218 70

Flutamide is an antiandrogen and frequently used for the treatment of prostatic cancer. Severe hepatotoxicity occurs in few patients but may be fatal. We report on two patients with prostatic cancer who received a therapy with flutamide. They showed different degrees of liver damage. One patient recovered completely after withdrawal of Flutamide under medication with steroids. Clinical symptoms and laboratory findings returned to normal within four weeks. Despite immediate withdrawal of Flutamide, the other patient showed a severe course with progressive liver dysfunction and hepatorenal syndrome. He finally died under the clinical picture of fulminant hepatic coma. This case represents the first death associated with flutamide in Germany. The literature concerning the metabolism of flutamide and the published cases of hepatotoxicity of this drug are reviewed.
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PMID:[Toxic hepatitis and liver failure under therapy with flutamide]. 1499 10

A prior comparison of 750 mg flutamide daily to 500 mg daily with an LHRH analog or orchiectomy showed no difference in effect on prostate specific antigen (PSA). However, any difference was likely masked by hypogonadism from concomitant LHRH analog or orchiectomy. We sought to evaluate different flutamide dosing schedules without this confounding factor. We recruited 50 men with advanced prostate cancer who elected to receive hormonal therapy to be randomized to 1 of 3 flutamide treatment groups: 1) 250 mg once daily, 2) 250 mg twice daily, or 3) 250 mg 3 times daily for 3 months, after which the therapy of their choice was instituted. Serum samples at the initiation of therapy and at the 1- and 3-month time point were assessed for PSA, testosterone, liver function tests, hematology, and renal function. Prostate volume, androgen deficiency symptoms, and a compliance diary were also recorded. Testosterone and PSA levels show a dose-dependent response to flutamide monotherapy. Loss of libido and erectile dysfunction occurred in all 3 treatment groups, with a trend toward worsening sexual function with higher flutamide dosing, but this trend did not reach statistical significance. Prostate volumes decreased by an average of 34.3% in the patients receiving 250 mg flutamide 3 times daily, 27.8% in patients receiving 250 mg flutamide twice daily, and 19.2% in those receiving a once daily dose of 250 mg flutamide. There was a significant difference between the once daily group and the 3 times daily group (P =.047). Flutamide at 500 mg did not result in significant changes in testosterone, PSA, prostate volume, or androgen deficiency symptoms compared to 750 mg daily after 3 months.
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PMID:Flutamide administration at 500 mg daily has similar effects on serum testosterone to 750 mg daily. 1522 52

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.
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PMID:Effects of the antiandrogen flutamide on the expression of protein kinase C isoenzymes in LNCaP and PC3 human prostate cancer cells. 1549 29

This study deals with the study of the optimization of the volume of organic phase (X1), the volume of aqueous phase (X2), and the drug:phosphotidylcholine (PC): cholesterol (Chol) molar ratio (X3) using 3(3) factorial 26-term logit model to maximize the Flutamide absorption at the target site in the treatment of prostatic cancer by maximizing the entrapment of Flutamide (FLT) in the preparation of FLT liposomes. FLT liposomes are expected to be an excellent carrier for FLT to the prostatic cancer site based on the use of liposomes with other drugs. A 3(3) factorial 26-term logit model for coded factors X1, X2, and X3 is used to develop a second-order response surface regression equation for predicting percent entrapment efficiency (%EE) for FLT. In turn, the regression equation is used to develop contour plots that show the %EE is maximized at the level of 1:15:2 of the drug: PC: Chol molar ratio with the volume of organic phase (chloroform: methanol) (1:2) at 5 mL and the volume of distilled water at 1.5 mL.
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PMID:Optimization of formulation parameters for the preparation of flutamide liposomes by 3(3) factorial 26-term logit model. 1558 Oct 73

Resistance to antiandrogen therapy in patients with metastatic prostate cancer poses a major challenge, which, if overcome, may lead to significant advances in the treatment of these patients. Hormone resistance of prostate cancer develops, in part, from upregulation of antiapoptotic genes after androgen deprivation. Given the accumulating evidence that Survivin, a new member of the inhibitor of apoptosis (IAP) family, is associated with both cancer progression and drug resistance, we hypothesized that Survivin plays a potentially important role in hormone therapy resistance, and that targeting of Survivin may enhance sensitivity to antiandrogen therapy in prostate cancer. Patterns of Survivin expression were assessed in three prostate cancer cell lines LNCaP, PC-3, and DU-145 using quantitative Western analysis. All three cell lines were found to strongly express Survivin. In LNCaP cells with intact androgen receptors (ARs), it was observed that androgen stimulation with 5alpha-dihydrotestosterone (DHT) increased Survivin expression. Conversely, treatment with Flutamide decreased Survivin expression in LNCaP cells. We next studied the functional effect of Survivin on sensitivity to Flutamide. LNCaP cells were infected with replication-deficient adenoviruses encoding either wild-type Survivin pAd-S(WT) or a phosphorylation-defective Survivin Thr34 --> Ala dominant-negative mutant pAd-S(T34A), and then treated with Flutamide. Cell viability and apoptosis were assessed in vitro and in vivo. It was determined that Survivin can mediate resistance to such antiandrogen therapies based on our assays. Direct androgen stimulation resulted in pan-cell cycle expression of Survivin, which was found to be mediated by AKT, as it was determined that exogenous insulin-like growth factor-1 (IGF-1), a known activator of AKT signaling, could increase Survivin expression and result in pan-cell cycle expression even in AR-negative prostate cancer cell lines PC-3 and DU-145. Given this alternative mechanism of Survivin expression and our findings that Survivin can mediate resistance to Flutamide treatment, we further investigated whether IGF-1-mediated activation of Survivin via AKT could mediate resistance to antiandrogen therapy. Both in vitro and in vivo, this was found to be the case, supporting a novel mechanism of resistance to antiandrogen therapy. Our study indicates that upregulation of Survivin via IGF-1 signaling confers resistance to Flutamide in prostate cancer cells. Targeted inhibition of Survivin appears to enhance the therapeutic effects of Flutamide in vitro and in vivo, revealing a novel strategy to enhance sensitivity to androgen ablation therapy.
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PMID:Survivin mediates resistance to antiandrogen therapy in prostate cancer. 1573 3


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