acid-phosphatase and bicalutamide

To evaluate the efficacy, tolerability, endocrinological effects and the pharmacokinetics of Casodex, when given as monotherapy during daily dosing of 10-200 mg to patients with advanced prostate cancer.. A total of 390 patients with advanced prostate cancer were treated for a minimum of 12 weeks with a daily monotherapy dose of Casodex. The doses ranged from 10 to 200 mg. Objective assessments of efficacy included: review of measurable metastases, prostate dimension, prostatic acid phosphatase and prostate-specific antigen (PSA) levels. Subjective assessments of efficacy included review of urological symptoms, performance status, bone scan and analgesic requirement. Pharmacokinetic samples were taken at various time points up to 3 months, and assayed using an achiral HPLC method.. Clear objective responses were observed, particularly at doses of 50 mg and above. Specifically, the median percentage decrease in PSA at 50 mg was 90.0%, and at 100 and 200 mg it was 93.4 and 94.8%, respectively. Up to 53% of symptomatic patients demonstrated a subjective response at 3 months. Casodex was well tolerated at all doses with no effect on haematological or cardiovascular parameters and no effect on renal function. The expected pharmacological effects of potent antiandrogen therapy, such as breast tenderness (58%), gynaecomastia (48%), and hot flushes (17%), were reported, but these incidences reflected the direct eliciting of these events. The intrinsic efficacy of Casodex was demonstrated despite increases of 60% in testosterone levels. However, this increase reached a plateau after 4-12 weeks of therapy, but the majority of values remained within the normal range. Casodex has a half-life of approximately 1 week, enabling once-daily dosing with no effect of age or renal impairment on its pharmacokinetics.. Casodex has a favourable side effect profile compared with the known safety profiles of other antiandrogens and has demonstrated intrinsic efficacy. Casodex warrants further investigation as a monotherapy for the management of advanced prostate cancer.

Topics: Acid Phosphatase; Androgen Antagonists; Anilides; Antineoplastic Agents; Dose-Response Relationship, Drug; Estradiol; Follicle Stimulating Hormone; Humans; Liver Function Tests; Luteinizing Hormone; Male; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Tosyl Compounds

The safety, efficacy, and pharmacokinetics of the nonsteroidal antiandrogen bicalutamide were investigated in a Phase II trial in 150 patients with metastatic prostate cancer.. Patients took bicalutamide, 50 mg daily, in an open-label multicenter North American trial.. The objective response rate (modified European Organization on Research and Treatment of Cancer [EORTC] criteria) was 70% (57% partial, 13% stable); 59 (39%) of 150 patients had either a > 90% decrease in prostate-specific antigen (PSA) levels or a decline to < 4 ng/mL. Extent of disease on the bone scan was a significant predictor of response. Patients with < 6 metastatic lesions were more likely to respond. Breast pain and gynecomastia occurred in 76% and 60% of patients, respectively. Gastrointestinal toxicity was very infrequent (diarrhea, 5%) The mean drug plasma concentration was 8528 (+/- 2928) ng/mL.. Bicalutamide, 50 mg daily, was well tolerated and has efficacy in metastatic prostate cancer. The percentage of men who had > 90% decline in PSA levels is less than observed with surgical or medical castration and has led to trials using this antiandrogen at higher doses as monotherapy.

Topics: Acid Phosphatase; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Humans; Male; Middle Aged; Nitriles; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Tosyl Compounds

The safety, efficacy and pharmacokinetics of bicalutamide were investigated in 150 patients with stage D2 prostate cancer.. Patients received 50 mg. bicalutamide daily in an open label multicenter North American trial.. The objective response rate (modified European Organization for Research in Cancer Therapy criteria) was 70%. Of 150 patients 59 (39%) met prostate specific antigen criteria for partial response, and 88 (59%) reached treatment failure end points and withdrew. Extent of disease was a significant predictor of response but baseline testosterone was not. Breast pain and gynecomastia developed in 76% and 60% of patients, respectively. Mean drug plasma concentration was 8,528 +/- 2,928 ng/ml.. Bicalutamide (50 mg.) daily was well tolerated and efficacious. However, suboptimal effects on prostate specific antigen have led to additional trials to evaluate monotherapy at higher doses.

Topics: Acid Phosphatase; Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Staging; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Time Factors; Tosyl Compounds

Abnormal differentiation in epithelial stem cells or their immediate proliferative progeny, the transiently amplifying population (TAP), may explain malignant pathogenesis in the human prostate. These models are of particular importance as differing sensitivities to androgen among epithelial cell subpopulations during differentiation are recognised and may account for progression to androgen independent prostate cancer. Androgens are crucial in driving terminal differentiation and their indirect effects via growth factors from adjacent androgen responsive stroma are becoming better characterised. However, direct effects of androgen on immature cells in the context of a prostate stem cell model have not been investigated in detail and are studied in this work. In alpha2beta1hi stem cell enriched basal cells, androgen analogue R1881 directly promoted differentiation by the induction of differentiation-specific markers CK18, androgen receptor (AR), PSA and PAP. Furthermore, treatment with androgen down-regulated alpha2beta1 integrin expression, which is implicated in the maintenance of the immature basal cell phenotype. The alpha2beta1hi cells were previously demonstrated to lack AR expression and the direct effects of androgen were confirmed by inhibition using the anti-androgen bicalutamide. AR protein expression in alpha2beta1hi cells became detectable when its degradation was repressed by the proteosomal inhibitor MG132. Stratifying the alpha2beta1hi cells into stem (CD133(+)) and transient amplifying population (TAP) (CD133(-)) subpopulations, AR mRNA expression was found to be restricted to the CD133(-) (TAP) cells. The presence of a functional AR in the TAP, an androgen independent subpopulation for survival, may have particular clinical significance in hormone resistant prostate cancer, where both the selection of immature cells and functioning AR regulated pathways are involved.

Topics: AC133 Antigen; Acid Phosphatase; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antigens, CD; Cell Differentiation; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Epithelial Cells; Fibroblast Growth Factor 7; Glycoproteins; Humans; Integrin alpha2beta1; Keratin-18; Leupeptins; Male; Metribolone; Middle Aged; Neoplastic Stem Cells; Nitriles; Peptides; Phenotype; Prostate-Specific Antigen; Prostatic Neoplasms; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Tyrosine Phosphatases; Receptors, Androgen; RNA, Messenger; Signal Transduction; Testosterone Congeners; Tosyl Compounds

Sleep-related erections in 5 patients with stage T3N0M0 prostate cancer treated with a new nonsteroidal antiandrogen, Casodex, were evaluated with continuous monitoring of penile tumescence and rigidity on multiple nights. Mean serum luteinizing hormone levels were 7.2 +/- 1.2 IU/l. before therapy and increased to 14 +/- 3.6 IU/l. after 6 months of therapy. Serum testosterone and estradiol levels also increased from a basal level of 5.05 +/- 1.9 ng./ml. and 102 +/- 18 pmol./l., respectively, to 8.04 +/- 1.32 ng./ml. and 175 +/- 20 pmol./l., respectively, after 6 months of therapy. No significant modifications in regard to number of nocturnal penile tumescence episodes, maximum penile circumference and total rigidity time were found before and after therapy. Only 1 patient reported a decrease in sexual drive and libido. All patients presented with stable disease (National Prostatic Cancer Treatment Group criteria) and an unmodified performance status (Eastern Cooperative Oncology Group) after 6 months. Pure antiandrogen therapy did not seem to interfere significantly with the erectile capability of men with prostate cancer.

Topics: Acid Phosphatase; Androgen Antagonists; Anilides; Antigens, Neoplasm; Estradiol; Humans; Male; Middle Aged; Nitriles; Penile Erection; Prostate-Specific Antigen; Prostatic Neoplasms; Sleep; Testosterone; Tosyl Compounds

Following promising results in animal studies, Casodex (ICI 176,334) has been studied in the treatment of patients with advanced prostate cancer. At doses of 10, 30 and 50 mg, the drug was found to be well tolerated, with a moderate effect on sex hormone levels. The 50 mg dose of Casodex (daily) reduced previously elevated acid phosphatase levels by 50% or more in 71% of patients.

Topics: Acid Phosphatase; Aged; Androgen Antagonists; Anilides; Estradiol; Follicle Stimulating Hormone; Humans; Male; Middle Aged; Nitriles; Prostatic Neoplasms; Testosterone; Tosyl Compounds