- Hormonal regulation of [beta]2-adrenergic receptor level in prostate cancer
Androgen deprivation is the only effective systemic therapy available for patients with prostatic carcinoma, but is associated with a gradual transition to a hormone-refractory prostate cancer (HRCAP) in which ligand-independent activation of the androgen receptor has been implicated. The [beta]2-adrenergic receptor ([beta]2-AR) is a well-known activator of the androgen receptor.Prostatic cell lines were analyzed using cDNA micro-array, real time RT-PCR, radioligand binding assay, cAMP measurements, transfection and thymidine incorporation assay. Clinical specimens were studied by immunohistochemistry and Affymetrix microarrays.Here, we show that [beta]2-AR was transiently down-regulated both at mRNA- and protein levels when hormone-sensitive prostate cancer cells, LNCaP, were cultured in steroid stripped medium (charcoal-stripped fetal calf serum) or when the cells were treated with the anti-androgen, bicalutamide (Casodex). The number of [beta]-adrenergic receptors was modestly up-regulated in androgen independent cell lines (LNCaP-C4, LNCaP-C4-2 and DU145) compared to LNCaP. Triiodothyronine (T3) increased the level of [beta]2-AR and the effect of T3 was inhibited by bicalutamide. Immunohistochemical staining of human prostate specimens showed high expression of [beta]2-AR in glandular, epithelial cells and increased expression in malignant cells compared to benign hyperplasia and normal tissue. Interestingly, [beta]2-AR mRNA was strongly down-regulated by androgen ablation therapy of prostate cancer patients.The level of [beta]2-AR was increased by T3 in prostatic adenocarcinoma cells and reduced in prostate cancer patients who had received androgen ablation therapy for 3 months. Prostate © 2008 Wiley-Liss, Inc. (Source: The Prostate)
- Seven az products to enter discount not deducted list
The Department of Health have confirmed that the following products will be added to the 'List of Drugs for which Discount is not Deducted' (Part II of the Drug Tariff) with effect 1st March 2008: - Arimidex 1mg tablets - Casodex 50mg tablets - Casodex 150mg tablets - Seroquel 100mg Tab (Source: Health News from Medical News Today)
- Seven astra zeneca products added to part ii of the drug tariff
The PSNC reports that the following products from Astra Zeneca have been added to the 'List of Drugs for which Discount is not Deducted' (Part II of the Drug Tariff) with effect from the 1st March 2008:
• Arimidex 1mg tablets
• Casodex 50mg tablets
• Casodex 150mg tablets
• Seroquel 100mg Tablets
• Seroquel 150mg Tablets
• Seroquel 200mg Tablets
• Seroquel 300mg Tablets
Following a decision by AstraZeneca to adjust the basis of calculation of their pharmacy rebates, these seven products now meet the criterion for high cost, low volume items where no discount is available. To ensure the change in their rebate scheme is cost neutral to pharmacy, AstraZeneca will also be making a corresponding downward adjustment to the levels of purchases required to qualify for a monthly rebate. Please see the link above for further details. (Source: NeLM Headline News)
- 1[alpha],25-dihydroxyvitamin d3 down-regulates expression of prostate specific membrane antigen in prostate cancer cells
Prostate specific membrane antigen (PSMA) expression correlates with prostate cancer grade and is increased in hormone-refractory prostate cancer. The increased expression of PSMA following androgen deprivation therapy may be a consequence of the down-regulation of PSMA expression by androgen. Moreover, 1[alpha],25-dihydroxyvitamin D3 (1,25-VD) has been shown to suppress prostate cancer progression as well as cell motility and invasion. Since PSMA is positively correlated with both of these characteristics, we hypothesized that 1,25-VD would regulate PSMA expression.LNCaP prostate cancer cells were treated with 1,25-VD, followed by analysis of cell surface PSMA expression. The PSMA enhancer, located within the third intron of the PSMA gene, was cloned into a reporter vector and regulation by 1,25-VD was investigated. The role of the androgen receptor (AR) in 1,25-VD mediated suppression of PSMA expression was examined using Casodex and AR specific siRNA.Surface expression of PSMA was significantly decreased in a dose-dependent manner by 10 nM 1,25-VD or greater. Regulation by 1,25-VD occurred at the level of the PSMA enhancer. Over-expression of the vitamin D receptor (VDR) also decreased expression of PSMA. Additionally, suppression of AR translation using siRNA technology blocked the suppressive effect of 1,25-VD on PSMA expression, however inhibition of PSMA expression by 1,25-VD occurred in the absence of androgens.Suppression of PSMA by 1,25-VD occurs at the level of the PSMA enhancer and is elevated by over-expression of the VDR. This regulation involves the AR, but is not dependent on the presence of androgens. Prostate © 2008 Wiley-Liss, Inc. (Source: The Prostate)
- Expression of bnip3 correlates with hypoxia-inducible factor (hif)-1[alpha], hif-2[alpha] and the androgen receptor in prostate cancer and is regulated directly by hypoxia but not androgens in cell lines
BNIP3 is a hypoxia-induced protein involved in cell death and survival but its role in human tumors is unclear. This study investigated the role of BNIP3 in prostate cancer.The expression of BNIP3, the androgen receptor (AR), hypoxia inducible factor (HIF)-1[alpha], HIF-2[alpha] and the hypoxia regulated gene GLUT1 were assessed in tissue microarrays constructed from 149 radical prostatectomy specimens. Statistics compared expression of these factors between each other, conventional clinicopathological parameters and PSA recurrence. Since an association between BNIP3 and AR and the HIFs was observed, the influence of hypoxia, dihydrotestosterone and the AR blocker, Casodex, was also investigated in prostate cell lines.BNIP3 was expressed in the nucleus and cytoplasm. Eight of 149 (5.5%) tumors showed no expression, 44/149 (29.5%) cases showed exclusively cytoplasmic expression, 17/149 (11.5%) cases showed exclusively nuclear expression and 80/149 (53.5%) cases showed both cytoplasmic and nuclear expression. There was a significant correlation between cytoplasmic BNIP3 expression and Gleason score (P = 0.005), age (P = 0.02), AR (P = 0.001), and GLUT1 (P = 0.006). There was a significant correlation between nuclear BNIP3 expression and HIF-1[alpha] expression (P = 0.006) and HIF-2[alpha] expression (P = 0.013) but no correlation between BNIP3 and pre-operative PSA, tumor volume, margin positivity or capsular invasion (all P > 0.05). There was an increase in BNIP3 expression under conditions of hypoxia (0.1% 02) but not with dihydrotestosterone stimulation or with Casodex treatment.These findings suggest that BNIP3 is directly regulated by hypoxia but that there may be a hormonal independent mechanism coordinating the expression of BNIP3 in prostate tumors. Prostate © Wiley-Liss, Inc. (Source: The Prostate)
- Amendment to bicalutamide (casodex) uk licence
The Committee for Medicinal Products for Human Use (CHMP) of the EMEA has issued a positive opinion confirming that bicalutamide (Casodex®) 150mg offers benefits to men with locally advanced prostate cancer at high risk of disease progression, either as monotherapy or adjuvant to treatment with radiotherapy or radical prostatectomy. The Opinion has been ratified in the UK and the licence amended.
The amended wording of the bicalutamide 150mg licence is as follows:
“Casodex 150mg is indicated either alone or as adjuvant to radical prostatectomy or radiotherapy in patients with locally advanced prostate cancer at high risk of disease progression”.
In the UK bicalutamide 150mg has been licensed for patients with locally advanced prostate cancer since 2000; therefore this amendment is not expected to impact on clinical practice. It will only help clinicians to categorise the type of patients who are eligible to receive bicalutamide 150mg. According to the press release, high risk of disease progression technically means that all patients with locally advanced prostate cancer with a Gleason score of 8-10 and a serum PSA greater than 20ng/ml are eligible for bicalutamide 150mg. (Source: NeLM news - Cancer)
- Human sperm express a functional androgen receptor: effects on pi3k/akt pathway
BACKGROUND
Results from mice lacking the androgen receptor (AR) showed that it is critical for the proper development and function of the testes. The aim of this study was to investigate whether a functional AR is present in human sperm.
METHODS
The expression of AR and its effects on sperm were evaluated by RT-PCR, Western Blot, Immunocytochemistry, PI3Kinase and DNA laddering assays.
RESULTS
We showed in human sperm that AR is located at the head region. Dihydrotestosterone (DHT), in a dose-dependent manner, leads to the rapid phosphorylation of the AR on tyrosine, serine and threonine residues and this effect was reduced by the AR antagonist hydroxyflutamide (OH-Flut). The effects of AR were evaluated on the phosphoinositide-3 kinase/protein kinase B (PI3K/AKT) pathway. Specifically, 0.1 and 1 nM DHT stimulated PI3K activity, whereas 10 nM DHT decreased PI3K activity and levels of p-AKT S473 and p-AKT T308, p-BCL2, and enhanced phosphatase and tensin homologue (PTEN) phosphorylation. In addition, 10 nM DHT was able to induce the cleavage of caspases 8, 9 and 3 and cause DNA laddering, and these effects were reversed either by casodex or OHFlut. By using wortmannin, a specific PI3K inhibitor, the cleavage of caspase 3 was reproduced, confirming that in sperm the PI3K/AKT pathway is involved in caspase activation.
CONCLUSIONS
Human sperm express a functional AR that have the ability to modulate the PI3K/AKT pathway, on the basis of androgen concentration. (Source: Human Reproduction)
- Pc-1/prlz contributes to malignant progression in prostate cancer
PC-1/PrLZ gene overexpression has been identified to be associated with prostate cancer progression. Previous studies have revealed that PC-1 possesses transforming activity and confers malignant phenotypes to mouse NIH3T3 cells. However, the functional relevance of PC-1 expression changes during prostate cancer development and progression remains to be evaluated. In this study, gain-of-function and loss-of-function analyses in LNCaP and C4-2 cells, respectively, were implemented. Experimental data showed that PC-1 expression was in positive correlation with prostate cancer cell growth and anchor-independent colony formation in vitro, as well as tumorigenicity in athymic BALB/c mice. Moreover, PC-1 expression was also found to promote androgen-independent progression and androgen antagonist Casodex resistance in prostate cancer cells. These results indicate that PC-1 contributes to androgen-independent progression and malignant phenotypes in prostate cancer cells. Furthermore, molecular evidence revealed that PC-1 expression stimulated Akt/protein kinase B signaling pathway, which has been implicated to play important roles in promoting androgen refractory progression in prostate cancer. Increased PC-1 levels in C4-2 cells may represent an adaptive response in prostate cancer, mediating androgen-independent growth and malignant progression. Inhibiting PC-1 expression may represent a novel therapeutic strategy to delay prostate cancer progression. [Cancer Res 2007;67(18):8906–13] (Source: Cancer Research)
- Casodex(bicalutamide) tablet [astrazeneca pharnaceuticals lp]
Updated Date: Aug 6, 2007 EST (Source: DailyMed Drug Label Updates for the last seven days (since May 20, 2007 EST))
- Recall of counterfeit casodex batch, uk
The MHRA has been alerted to a counterfeit batch of Casodex (Bicalutamide) 50mg tablets (batch number 65520). This drug is used in the treatment of patients with prostate cancer. The MHRA has issued a drug alert to recall this product from the market, to minimise the risk to patients. The MHRA was contacted by a wholesaler, who was offered a suspicious batch of Casodex by another wholesaler. This is now subject of a Class 1 medicines recall, today, 01 June 2007. [click link for full article] (Source: Prostate News From Medical News Today)
|
