Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new casodex research articles will be listed here shortly after becoming available to us.
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Medical research on casodex
Eur J Histochem. 2008 Apr-Jun; 52(2): 127-34
Shi C, Zhou G, Zhu Y, Su Y, Cheng T, Zhau HE, Chung LW
Semiconductor quantum dots (QDs) are bright fluorescent nanoparticles that have been successfully used for the detection of biomarker expression in cells. The objective of the present study is to use this technology in a multiplexing manner to determine at a single cell level the expression of a cell-specific bio-marker, prostate-specific antigen (PSA) expressed by human prostate cancer LNCaP and ARCaP cell lines. Here we compared the sensitivity of immunohistochemistry (IHC) and QD-based detection of AR and PSA expression in these cell lines. Further, we conducted multiplexing QD-based detection of PSA and androgen receptor (AR) expression in LNCaP cells subjecting to androgen (R1881) stimulation. The involvement of AR in PSA regulation in LNCaP cells, at a single cell level, was confirmed by the co-incubation of LNCaP cells in the presence of both R1881 and its receptor antagonist, bicalutamide (Casodex). We showed here the superior quality of QDs, in comparison to IHC, for the detection of AR and PSA in cultured LNCaP and ARCaP cells. Multiplexing QDs technique can be used to detect simultaneously AR and PSA expression induced by R1881 which promoted AR translocation from its cytosolic to the nuclear compartment. We observed AR antagonist, bicalutamide, inhibited AR nuclear translocation and PSA, but not AR expression in LNCaP cells.
Bioorg Med Chem. 2008 Jun 18;
Wakabayashi KI, Imai K, Miyachi H, Hashimoto Y, Tanatani A
Various 4-(anilino)pyrrole-2-carboxamides were designed and synthesized as novel androgen receptor (AR) antagonists without steroidal or anilide structure, based on our strategy for developing full antagonists of nuclear receptors. Introduction of a bulky N-alkyl group, such as a cyclohexylmethyl or benzyl group, increased the binding affinity for wild-type AR and the potency for growth inhibition of androgen-dependent SC-3 cells. Among the compounds obtained, N-[4-[(benzyl)(4-nitrophenyl)amino]-1-methylpyrrole-2-carbonyl]pyrrolidine (22) is as potent an AR antagonist as the typical anilide-type AR antagonists hydroxyflutamide and bicalutamide. Further, compound 22 had potent binding affinity for T877A mutated AR, and dose-dependently inhibited the testosterone-induced production of prostate-specific antigen in LNCaP cells bearing T877A AR.
BJU Int. 2008 Jun 19;
Burich RA, Holland WS, Vinall RL, Tepper C, Devere White RW, Mack PC
OBJECTIVE To determine the benefit of genistein combined polysaccharide (GCP) in combination with the androgen receptor antagonist bicalutamide, the antimicrotubule taxane docetaxel, and the Src kinase inhibitor pp2 as part of a treatment regimen for advanced prostate cancer (CaP). MATERIALS AND METHODS The growth inhibitory and apoptotic effects of GCP in combination with bicalutamide, docetaxel and pp2 were evaluated in both the androgen-dependent LNCaP line, and three androgen-independent lines: CWR22Rv1, PC-3, and LNCaP-R273H. The LNCaP-R273H model is an LNCaP variant expressing a p53(GOF) allele; like CWR22Rv1 and PC-3, it is able to grow in a minimal androgen environment. The effects of GCP treatment in combination with the aforementioned drugs were measured using an MTT assay, Western blotting, flow cytometric analysis, and caspase activation assay. Altered schedules of drug administration were explored using combinations of GCP and docetaxel. RESULTS GCP potentiated the activity of docetaxel in all four cell lines, resulting in growth inhibition and increased apoptosis. The combination of GCP and bicalutamide had enhanced activity in both the LNCaP and LNCaP-R273H lines, which may better represent patient tumour cells after progression to androgen independence. Administration of docetaxel followed by GCP resulted in a synergistic interaction in LNCaP cells, with increased apoptosis. By contrast, GCP administered first showed subadditivity, probably resulting from GCP-mediated induction of G1 arrest interfering with docetaxel activity. CONCLUSION These data suggest that GCP, an isoflavone-enriched compound with minimal side-effects and far superior intestinal absorption rate of genistein, has significant clinical potential in combination with docetaxel, bicalutamide or targeted agents for the treatment of advanced CaP.
Nucleation and crystal growth in supersaturated solutions of a model drug.
J Colloid Interface Sci. 2008 May 27;
Lindfors L, Forssén S, Westergren J, Olsson U
The crystallization process in aqueous solutions of the drug bicalutamide and the effect of the polymer polyvinylpyrrolidone (PVP) have been studied. Results showed that PVP decreased the crystallization rate significantly in a system with PVP concentrations as low as 0.01% (w/w), without changing the polymorph formed. The crystal habit was altered already at PVP concentrations as low as 0.001% (w/w). Measurements made with self-diffusion NMR indicated that the decrease in crystallization rate was not because of a reduced supersaturation due to bicalutamide binding to PVP in solution. Furthermore, in experiments designed to specifically study crystal nucleation, the same nucleation rate was found in the absence and presence of PVP. Instead, PVP adsorbs to the crystals formed in solution and by doing so, the crystal growth rate is reduced. This was confirmed in separate experiments using bicalutamide nanocrystals. By combining theories describing classical nucleation and crystal growth, with some modifications, a consistent description of several independent experiments performed in polymer-free systems was obtained. From these experiments a crystal-water interfacial tension of 22.1 mN/m was extracted. We also analyze the interfacial tension of other crystalline organic solids and find that it varies approximately as the logarithm of the solubility. This finding is discussed within the framework of the Bragg-Williams regular solution theory where we also compare with the tension of liquid alkanes.
Cancer Res. 2008 Jun 15; 68(12): 4709-18
Placencio VR, Sharif-Afshar AR, Li X, Huang H, Uwamariya C, Neilson EG, Shen MM, Matusik RJ, Hayward SW, Bhowmick NA
Mechanisms of androgen dependence of the prostate are critical to understanding prostate cancer progression to androgen independence associated with disease mortality. Transient elevation of transforming growth factor-beta (TGF-beta) occurs after androgen ablation. To determine the role of TGF-beta on prostate response to androgen ablation, conditional TGF-beta type II receptor knockout mouse models of the epithelia (Tgfbr2(NKX3.1KO)) and stromal fibroblasts (Tgfbr2(fspKO)) were used. After castration, the prostates of Tgfbr2(NKX3.1KO) mice had apoptosis levels similar to those expected for control Tgfbr2(floxE2/floxE2) mice. Prostates of Tgfbr2(fspKO) mice, however, had reduced regression and high levels of proliferation associated with canonical Wnt activity throughout the glandular epithelia regardless of androgen status. In contrast, Tgfbr2(floxE2/floxE2) prostates had epithelial canonical Wnt activity only in the surviving proximal ducts after castration. In vitro studies showed that androgen antagonist, bicalutamide, transiently elevated both Tgfbr2(floxE2/floxE2) and Tgfbr2(fspKO) stromal expression of Wnt-2, Wnt-3a, and Wnt-5a. The neutralization of Wnt signaling by the expression of secreted frizzled related protein-2 (SFRP-2) resulted in decreased LNCaP prostate epithelial cell proliferation in stromal conditioned media transfer experiments. In vivo tissue recombination studies using Tgfbr2(fspKO) prostatic stromal cells in combination with wild-type or SV40 large T antigen expressing epithelia resulted in prostates that were refractile to androgen ablation. The expression of SFRP-2 restored the Tgfbr2(fspKO)-associated prostate responsiveness to androgen ablation. These studies reveal a novel TGF-beta, androgen, and Wnt paracrine signaling axis that enables prostatic regression of the distal ducts after androgen ablation while supporting proximal duct survival.
Adjuvant hormonal treatment - the bicalutamide early prostate cancer program.
Front Radiat Ther Oncol. 2008; 41: 39-48
Wirth MP, Hakenberg OW, Froehner M
Several randomized trials have demonstrated that adjuvant medical or surgical castration may improve overall survival in patients with locally advanced prostate cancer undergoing external beam radiotherapy. After radical prostatectomy, patients with positive lymph nodes seem to benefit from adjuvant hormonal treatment rather than from treatment at the time of clinical progression in terms of overall survival. In patients with locally advanced, lymph node-negative prostate cancer, adjuvant hormonal treatment after radical prostatectomy has been demonstrated to delay progression without impact on survival. The Bicalutamide Early Prostate Cancer Program, the largest ongoing prostate cancer trial in the world, investigates the effect of early treatment with 150 mg bicalutamide compared with placebo as monotherapy or adjuvant treatment after radical prostatectomy or external beam radiotherapy. It demonstrated that early treatment with bicalutamide may delay objective progression of prostate cancer irrespective of primary treatment. Considering overall survival, however, there was an advantage only in the setting of external beam radiotherapy for locally advanced prostate cancer. In patients with localized disease who initially underwent watchful waiting, there was a trend to decreased survival in the arm immediately treated with bicalutamide. Altogether, there is no indication for treatment with bicalutamide in patients with localized disease.
J Cancer Res Clin Oncol. 2008 May 20;
Arai Y, Akaza H, Deguchi T, Fujisawa M, Hayashi M, Hirao Y, Kanetake H, Naito S, Namiki M, Tachibana M, Usami M, Ohashi Y
PURPOSE: To assess quality of life (QOL) data from a double-blind Phase III study evaluating bicalutamide (Casodextrade mark) 80 mg as part of maximum androgen blockade (MAB) in patients with previously untreated advanced prostate cancer. METHODS: Patients with untreated stage C/D prostate cancer were randomized to MAB with bicalutamide plus a luteinizing hormone-releasing hormone agonist (LHRHa) or LHRHa monotherapy. QOL was evaluated at baseline and at weeks 1, 5, and 24 using the Japanese version of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. RESULTS: A total of 203 patients were assessed for QOL. The MAB group had more rapid and greater improvements in "emotional well-being" and "prostate cancer-specific issues" domain scores than the monotherapy group. Further analysis of "prostate cancer-specific issues" revealed that, compared with monotherapy, MAB provided a greater improvement in "micturition disorder"-related QOL. Complete improvement rates for items related to "pain and micturition disorder" were also higher with MAB. Item scores of "pain and micturition disorder" did not correlate strongly with prostate-specific antigen levels or tumor size. Fewer patients who had deterioration in their "pain and micturition disorder" item scores at week 1 in the MAB group than the monotherapy group. CONCLUSIONS: Maximum androgen blockade with bicalutamide plus LHRHa did not reduce the overall QOL of patients with previously untreated advanced prostate cancer. MAB was superior to monotherapy in achieving early improvement of QOL related to micturition disorder and pain.
Carcinogenesis. 2008 May 16;
Seaton A, Scullin P, Maxwell PJ, Wilson C, Pettigrew J, Gallagher R, O'Sullivan JM, Johnston PG, Waugh DJ
The aim of our study was to assess the importance of the CXC chemokine, interleukin-8 (IL-8) in promoting the transition of prostate cancer (CaP) to the androgen- independent state. Stimulation of the androgen-dependent cell lines, LNCaP and 22Rv1, with exogenous recombinant-human IL-8 (rh-IL-8) increased androgen receptor (AR) gene expression at the mRNA and protein level, assessed by quantitative PCR and immunoblotting, respectively. Using an ARE-luciferase construct we demonstrated that rh-IL-8 treatment also resulted in increased AR transcriptional activity in both these cell lines, and a subsequent up-regulation of PSA and Cdk2 mRNA transcript levels in LNCaP cells. Blockade of CXC-chemokine receptor-2 (CXCR2) signaling using a small molecule antagonist (AZ10397767) attenuated the IL-8 induced increases in AR expression and transcriptional activity. Furthermore, in MTT assays, co-administration of AZ10397767 reduced the viability of LNCaP and 22Rv1 cells exposed to bicalutamide. Our data shows that IL-8 signaling increases AR expression and promotes ligand-independent activation of this receptor in two androgen dependent cell lines, describing two mechanisms by which this chemokine may assist in promoting the transition of CaP to the androgen-independent state. In addition, our data shows that IL-8 promoted regulation of the AR attenuates the effectiveness of the AR antagonist bicalutamide in reducing CaP cell viability.
Differential mechanisms of bicalutamide-induced apoptosis in prostate cell lines.
Prostate Cancer Prostatic Dis. 2008 May 13;
Floyd MS, Teahan SJ, Fitzpatrick JM, Watson RW
Bicalutamide is a non-steroidal antiandrogen used in the treatment of prostate cancer. Although widely accepted as an androgen receptor antagonist, the mechanism by which it induces apoptosis remains unclear. Defining exact pathways by which bicalutamide induces its apoptotic effects would help to advance its clinical applications. We aimed to (a) examine the apoptotic effects of bicalutamide at 24 h and (b) comment on the role of the caspases and calpains in mediating bicalutamide-induced apoptosis in androgen-dependent and androgen-independent cells. PWR-1E, PC-3 and DU-145 cells were treated with bicalutamide and assessed for apoptosis by flow cytometry at 24 h. DU-145 cells were used to compare differences between two different metastatic receptor-negative cells and to verify apoptotic induction at 48 h. To delineate a specific pathway of action for bicalutamide, PC-3 and PWR-1E cells were pretreated with specific inhibitors of caspase-dependent (zVAD-FMK) and caspase-independent pathways (calpain 2 inhibitor). Bicalutamide induced apoptosis in androgen-dependent PWR-1E cells via a caspase-dependent and calpain-independent mechanism. In androgen-independent PC-3 cells, bicalutamide also induced apoptosis by mechanisms that were partially inhibited by pan-caspase inhibition but were partially calpain dependent. Understanding into how bicalutamide exerts its effects in androgen-independent cells will yield further insights into the treatment of hormone-refractory disease.Prostate Cancer and Prostatic Diseases advance online publication, 13 May 2008; doi:10.1038/pcan.2008.23.
Neoplasia. 2008 May; 10(5): 418-28
Lorenzo PI, Saatcioglu F
Androgen deprivation induces the regression of prostate tumors mainly due to an increase in the apoptosis rate; however, the molecular mechanisms underlying the antiapoptotic actions of androgens are not completely understood. We have studied the antiapoptotic effects of androgens in prostate cancer cells exposed to different proapoptotic stimuli. Terminal deoxynucleotidyl transferase-mediated nick-end labeling and nuclear fragmentation analyses demonstrated that androgens protect LNCaP prostate cancer cells from apoptosis induced by thapsigargin, the phorbol ester 12-O-tetradecanoyl-13-phorbol-acetate, or UV irradiation. These three stimuli require the activation of the c-Jun N-terminal kinase (JNK) pathway to induce apoptosis and in all three cases, androgen treatment blocks JNK activation. Interestingly, okadaic acid, a phosphatase inhibitor that causes apoptosis in LNCaP cells, induces JNK activation that is also inhibited by androgens. Actinomycin D, the antiandrogen bicalutamide or specific androgen receptor (AR) knockdown by small interfering RNA all blocked the inhibition of JNK activation mediated by androgens indicating that this activity requires AR-dependent transcriptional activation. These data suggest that the crosstalk between AR and JNK pathways may have important implications in prostate cancer progression and may provide targets for the development of new therapies.