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Results: 31 to 36 of 36

Publication Record


Is combined androgen blockade with bicalutamide cost-effective compared with combined androgen blockade with flutamide?
Ramsey S, Veenstra D, Clarke L, Gandhi S, Hirsch M, Penson D
(2005) Urology 66: 835-9
MeSH Terms: Androgen Antagonists, Anilides, Antineoplastic Agents, Cost-Benefit Analysis, Drug Therapy, Combination, Flutamide, Humans, Male, Nitriles, Prostatic Neoplasms, Tosyl Compounds
Show Abstract · Added March 5, 2014
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.
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11 MeSH Terms
Molecular alterations in primary prostate cancer after androgen ablation therapy.
Best CJ, Gillespie JW, Yi Y, Chandramouli GV, Perlmutter MA, Gathright Y, Erickson HS, Georgevich L, Tangrea MA, Duray PH, González S, Velasco A, Linehan WM, Matusik RJ, Price DK, Figg WD, Emmert-Buck MR, Chuaqui RF
(2005) Clin Cancer Res 11: 6823-34
MeSH Terms: Aged, Androgen Antagonists, Androgens, Antineoplastic Agents, Hormonal, Biopsy, Cell Adhesion, Chromosome Deletion, Chromosome Mapping, Chromosomes, Cluster Analysis, Disease Progression, Down-Regulation, Gene Deletion, Gene Expression Regulation, Gene Expression Regulation, Neoplastic, Genome, Humans, Interleukin-6, Lasers, Male, Middle Aged, Models, Statistical, Neoplasm Metastasis, Oligonucleotide Array Sequence Analysis, Oxidative Stress, Principal Component Analysis, Prostatic Neoplasms, RNA, Signal Transduction, Up-Regulation
Show Abstract · Added June 11, 2010
PURPOSE - After an initial response to androgen ablation, most prostate tumors recur, ultimately progressing to highly aggressive androgen-independent cancer. The molecular mechanisms underlying progression are not well known in part due to the rarity of androgen-independent samples from primary and metastatic sites.
EXPERIMENTAL DESIGN - We compared the gene expression profiles of 10 androgen-independent primary prostate tumor biopsies with 10 primary, untreated androgen-dependent tumors. Samples were laser capture microdissected, the RNA was amplified, and gene expression was assessed using Affymetrix Human Genome U133A GeneChip. Differential expression was examined with principal component analysis, hierarchical clustering, and Student's t testing. Analysis of gene ontology was done with Expression Analysis Systematic Explorer and gene expression data were integrated with genomic alterations with Differential Gene Locus Mapping.
RESULTS - Unsupervised principal component analysis showed that the androgen-dependent and androgen-independent tumors segregated from one another. After filtering the data, 239 differentially expressed genes were identified. Two main gene ontologies were found discordant between androgen-independent and androgen-dependent tumors: macromolecule biosynthesis was down-regulated and cell adhesion was up-regulated in androgen-independent tumors. Other differentially expressed genes were related to interleukin-6 signaling as well as angiogenesis, cell adhesion, apoptosis, oxidative stress, and hormone response. The Differential Gene Locus Mapping analysis identified nine regions of potential chromosomal deletion in the androgen-independent tumors, including 1p36, 3p21, 6p21, 8p21, 11p15, 11q12, 12q23, 16q12, and 16q21.
CONCLUSIONS - Taken together, these data identify several unique characteristics of androgen-independent prostate cancer that may hold potential for the development of targeted therapeutic intervention.
1 Communities
2 Members
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30 MeSH Terms
The cost-effectiveness of combined androgen blockade with bicalutamide and luteinizing hormone releasing hormone agonist in men with metastatic prostate cancer.
Penson DF, Ramsey S, Veenstra D, Clarke L, Gandhi S, Hirsch M
(2005) J Urol 174: 547-52; discussion 552
MeSH Terms: Androgen Antagonists, Anilides, Cost-Benefit Analysis, Decision Support Techniques, Drug Therapy, Combination, Gonadotropin-Releasing Hormone, Humans, Male, Nitriles, Prostatic Neoplasms, Quality of Life, Sensitivity and Specificity, Tosyl Compounds
Show Abstract · Added March 5, 2014
PURPOSE - Combined androgen blockade therapy (CAB) has been shown to have a small survival advantage over luteinizing hormone releasing hormone LH-RH agonists (LH-RHa) alone in men with metastatic prostate cancer. The goal of this study was to assess the cost-effectiveness of CAB with bicalutamide and LH-RH agonist therapy to LH-RH agonist therapy alone.
MATERIALS AND METHODS - A macro-simulation model was developed to compare the cost-effectiveness of 2 interventions for stage D2 prostate cancer, 1) CAB with bicalutamide 50 mg per day and monthly dosing of an LH-RHa or 2) monthly LH-RH agonist therapy. Cost and outcomes are tabulated in 5 and 10-year time horizons. Model assumptions were taken from the published literature. Appropriate 1-way and multi-way sensitivity analyses were performed.
RESULTS - At 5 years, the incremental cost-effectiveness ratio (ICER) for CAB, when compared with LH-RHa monotherapy, was US dollars 33,677 per quality-adjusted life-year. In other words, for every additional quality-adjusted life year that a patient lived because he received CAB, it cost US dollars 33,677. At 10 years the ICER for CAB was US dollars 20,053 (well within the accepted cost-effectiveness threshold). If quality adjustment was not included, the ICER for CAB was even more favorable (US dollars 20,489 at 5 years and US dollars 13,313 at 10 years). The model was most sensitive to the estimates of effectiveness (survival) of LH-RHa therapy alone and CAB therapy. The model was also fairly sensitive to the quality of life effect of having late stage prostate cancer and the cost of bicalutamide.
CONCLUSIONS - CAB with bicalutamide is cost-effective when compared with LH-RH monotherapy in men with stage D2 prostate cancer.
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13 MeSH Terms
Use of the probasin promoter ARR2PB to express Bax in androgen receptor-positive prostate cancer cells.
Andriani F, Nan B, Yu J, Li X, Weigel NL, McPhaul MJ, Kasper S, Kagawa S, Fang B, Matusik RJ, Denner L, Marcelli M
(2001) J Natl Cancer Inst 93: 1314-24
MeSH Terms: Adenoviridae, Androgen Antagonists, Androgen-Binding Protein, Animals, Apoptosis, Arabidopsis Proteins, Blotting, Western, DNA-Binding Proteins, Flutamide, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Promoter Regions, Genetic, Prostatic Neoplasms, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Receptors, Androgen, Transcription Factors, Transplantation, Heterologous, Tumor Cells, Cultured, Up-Regulation, bcl-2-Associated X Protein
Show Abstract · Added June 11, 2010
BACKGROUND - Adenovirus-mediated overexpression of the apoptosis-inducing protein Bax can induce apoptosis in prostate cancer cell lines. Constitutive overexpression of Bax could result in unwanted apoptosis in every site of accidental Bax accumulation in vivo. Therefore, we developed an adenoviral construct (Av-ARR2PB-Bax) in which the probasin promoter, modified to contain two androgen response elements, drives Bax expression. This promoter would be expected to limit expression of Bax to cells expressing the androgen receptor.
METHODS - A variety of androgen receptor (AR)-positive and -negative cell lines of prostatic or nonprostatic origin were infected with Av-ARR2PB-Bax or a control virus, Av-ARR2PB-CAT, in which the same promoter drives expression of the chloramphenicol acetyl transferase-reporter gene. Bax expression and apoptosis in vitro were assessed by western blot analysis. Tumor size and apoptosis in vivo were assessed after four weekly injections of Av-ARR2PB-Bax or Av-ARR2PB-CAT into subcutaneous LNCaP xenografts growing in uncastrated male mice. All statistical tests were two-sided.
RESULTS - Bax was overexpressed in an androgen-dependent way in AR-positive cell lines of prostatic origin but not in AR-positive cells of nonprostatic origin or in AR-negative cell lines of either prostatic or nonprostatic origin. The androgen dihydrotestosterone activated apoptosis in LNCaP cells infected with Av-ARR2PB-Bax but not in those infected with Av-ARR2PB-CAT. Av-ARR2PB-Bax-injected LNCaP xenograft tumors decreased in tumor size from 34.1 mm3 (95% confidence interval [CI] = 25.1 mm3 to 43.1 mm3) to 24.6 mm3 (95% CI = -2.5 mm3 to 51.7 mm3), but the difference was not statistically significant (P =.5). Tumors injected with Av-ARR2PB-CAT increased in size, from 28.9 mm3 (95% CI = 12.7 mm3 to 45.1 mm3) to 206 mm3 (95% CI = 122 mm3 to 290 mm3) (P =.002) and contained statistically significant more apoptotic cells (23.3% [95% CI = 21.1% to 25.6%] versus 9.5% [95% CI = 8.0% to 11.1]) (P<.001).
CONCLUSIONS - Av-ARR2PB-Bax induces androgen-dependent therapeutic apoptosis in vitro and in vivo by activating apoptosis in AR-positive cells derived specifically from prostatic epithelium and does not affect nonprostatic cells.
1 Communities
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23 MeSH Terms
Mutations at the boundary of the hinge and ligand binding domain of the androgen receptor confer increased transactivation function.
Buchanan G, Yang M, Harris JM, Nahm HS, Han G, Moore N, Bentel JM, Matusik RJ, Horsfall DJ, Marshall VR, Greenberg NM, Tilley WD
(2001) Mol Endocrinol 15: 46-56
MeSH Terms: Adenocarcinoma, Androgen Antagonists, Androgens, Animals, Binding Sites, COS Cells, Cell Line, DNA, Dihydrotestosterone, Estradiol, Flutamide, Humans, Male, Mice, Mice, Transgenic, Models, Molecular, Mutagenesis, Mutation, Progesterone, Prostatic Neoplasms, Protein Structure, Secondary, Receptors, Androgen, Structure-Activity Relationship, Transcriptional Activation, Transfection
Show Abstract · Added June 11, 2010
The androgen receptor (AR), a member of the steroid receptor superfamily of nuclear transcription factors, mediates androgen signaling in diverse target tissues. Here we report AR gene mutations identified in human prostate cancer and the autochthonous transgenic adenocarcinoma of the mouse prostate model that colocate to residues (668)QPIF(671) at the boundary of the hinge and ligand-binding domain, resulting in receptors that exhibit 2- to 4-fold increased activity compared with wild-type AR in response to dihydrotestosterone, estradiol, progesterone, adrenal androgens, and the AR antagonist, hydroxyflutamide, without an apparent effect on receptor levels, ligand binding kinetics, or DNA binding. The expression of these or similar variants could explain the emergence of hormone refractory disease in a subset of patients. Homology modeling indicates that amino acid residues (668)QPIF(671) form a ridge bordering a potential protein-protein interaction surface. The naturally occurring AR gene mutations reported in this study result in decreased hydrophobicity of this surface, suggesting that altered receptor-protein interaction mediates the precocious activity of the AR variants.
1 Communities
1 Members
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25 MeSH Terms
Inhibition of androgen action by dehydroepiandrosterone sulfotransferase transfected in PC-3 prostate cancer cells.
Chan J, Song CS, Matusik RJ, Chatterjee B, Roy AK
(1998) Chem Biol Interact 109: 267-78
MeSH Terms: Adenocarcinoma, Androgen Antagonists, Androgens, Animals, Chloramphenicol O-Acetyltransferase, Dihydrotestosterone, Humans, Luciferases, Male, Mammary Tumor Virus, Mouse, Plasmids, Prostatic Neoplasms, Rats, Repetitive Sequences, Nucleic Acid, Sulfotransferases, Transcriptional Activation, Transfection, Tumor Cells, Cultured
Show Abstract · Added June 11, 2010
Age-dependent loss of androgen sensitivity of the rat liver is associated with a marked increase in dehydroepiandrosterone/hydroxysteroid sulfotransferase (rStd) activity. Sulfonated steroid hormones are known to be ineffective in binding receptor proteins. These observations suggest that intracellular androgen sulfonation can physiologically influence androgen action. We have examined the inhibitory effect of rStd on androgen action in the human prostate cancer-derived PC-3 cells transfected with the rat androgen receptor (AR) expression plasmid and two androgen-responsive promoter reporter constructs (murine mammary tumor long-terminal repeat ligated to chloramphenicol acetyltransferase (CAT) gene and rat probasin androgen response element (ARE) ligated to firefly luciferase (LUC) gene). These transfected cells were dependent on 5alpha-dihydrotestosterone (DHT) for the activation of both reporter genes and showed about a 200- and a 800-fold increase of CAT and LUC activity, respectively, at 10(-10) M DHT over the no-hormone control. Expression of the sulfonating enzyme in this cell transfection system via the rStd expression plasmid caused a dose-dependent decline in the reporter activity with approximately 90% inhibition of androgen action at a rStd:AR plasmid ratio of 100. From these results we conclude that irrespective of a high level of AR, changes in the Std expression can markedly alter the androgen sensitivity of target cells.
1 Communities
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18 MeSH Terms