Subtypes Of Alpha1-Adrenoceptors In BPH: Future Prospects For Personalized Medicine

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology
Article Date: 16 Mar 2009 - 3:00 PDT

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UroToday.com - We have recently reviewed the current molecular and physiological findings of alpha(1)-adrenoceptor (alpha(1)-AR) subtypes, and discussed a potential new strategy, "personalized medicine", for the treatment of benign prostatic hyperplasia (BPH).

BPH has been demonstrated to be a common problem presenting with lower urinary tract symptoms (LUTS) in elderly men. It has been estimated that BPH affects over 50% of men aged 60 years, and this ratio goes up to 80% by the age of 80, most of whom have LUTS1. The incidence of LUTS related to BPH (LUTS/BPH) appears to be higher due to the increased longevity of men. Since LUTS/BPH greatly affect the patient's quality of life (QOL), not only symptom severity but also the impact of LUTS on QOL are the usual reasons why patients with BPH seek medical care. In other words, the goals of LUTS/BPH treatment should include symptom reduction with fewer adverse effects and preservation of QOL. Therefore, management of LUTS/BPH requires careful thought so that the most appropriate treatment can be targeted to each "individual" patient.

Alpha(1)-AR plays a major role in the regulation of smooth muscle contraction in most organs of the human body. Three subtypes, alpha(1a)-, alpha(1b)- and alpha(1d)-AR, have been characterized pharmacologically and in molecular terms. The expressions of these subtypes were reported to be observed in the prostate, urinary bladder and central nervous systems2, and they are considered to be critical mediators of LUTS/BPH3. The role of alpha(1)-AR blockade in the treatment of elderly men with LUTS/BPH is well defined, and alpha(1)-AR antagonists have emerged as an effective and non-invasive treatment option for men with LUTS/BPH. A number of alpha(1)-AR antagonists are currently approved in the United States, Europe and Asia for the treatment of LUTS/BPH. They are generally well tolerated; however, there are differences in the efficacy and adverse effect profiles among the various alpha(1)-AR antagonists, because they have specific characteristics, such as alpha(1)-AR subtype selectivity.

On the other hand, recent molecular approaches, including gene targeting approaches in mice4,5, single nucleotide polymorphism (SNP) genotyping6,7, real-time RT-PCR8-10, and microarray-based expression profiling11, have provided not only new knowledge about alpha(1)-AR subtypes but also new strategies to improve the efficacy and reduce the adverse effects of LUTS/BPH medical therapy. Previously, we demonstrated in our real-time RT-PCR study that patients with LUTS/BPH were divided into those who showed the predominance of alpha(1a)-AR mRNA expression levels (49%) and those who showed the predominance of alpha(1d)-AR mRNA expression levels (51%)8. We succeeded in showing that the genetic background differed among patients using a molecular approach.

In general, a drug may exhibit varying effects depending on the patient, even among patients with the same disease. This inter-patient variability of drug response is a major problem in clinical practice and drug development. Pharmacogenomics deal with genetically determined variations in how individuals respond to drugs12,13. Tamuslosin hydrochloride, a relative alpha(1a)-AR-selective antagonist, is more effective for patients showing a dominant expression of the alpha(1a)-AR subtype10. On the other hand, naftopidil, a relative alpha(1d)-AR-selective antagonist, is more effective for patients showing a dominant expression of the alpha(1d)-AR subtype. This is the first clinical study to clarify the correlation between the genomics of alpha(1)-AR subtypes in the prostate and the efficacy of subtype-selective alpha(1)-AR antagonists in LUTS/BPH patients.

Various genomics-based techniques have been applied with increasing success to the molecular characterization of several diseases, which has resulted in a more detailed classification scheme and has produced clinical diagnostic tests, which have been applied to both the prognosis and the prediction of outcome with medical treatment. As described above, pharmacogenetics has been aimed at identifying genetic components of inter-individual variability in patient response to medical treatment. This will establish an individually based treatment (personalized medicine) and elucidate the molecular basis of the treatment regimen for further improvements. Although our previous study implies that differences in genetic background are responsible for the diverse responses to subtype-selective alpha(1)-AR antagonists10, it may be difficult to immediately put this theory to practical clinical use, because routine prostate biopsy is invasive for patients with LUTS/BPH to measure the expression level of each alpha(1)-AR subtype mRNA. Recently, a genomic approach, including single nucleotide polymorphism (SNP) study, has played a main role in pharmacogenetics and personalized medicine. Other possible molecular approaches, such as transcriptomic, proteomics and metabolomics approaches, may enable the discovery of biomarkers implicated in the drug response and contribute to understanding inter-individual variations in the pharmacokinetics and pharmacodynamics of alpha(1)-AR antagonists. In addition, a novel class of functional polymorphisms, termed miRSNPs/polymorphisms, was reported, and is defined as a polymorphism present at or near microRNA binding sites of functional genes that can affect gene expression by interfering with microRNA function14. With further advances in molecular biology, we believe that "personalized medicine" based on genetically determined variations for BPH medical therapy will be realized in the future.

References:

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10. Kojima Y, Sasaki S, Kubota Y, Hayase M, Hayashi Y, Shinoura H, Tsujimoto G, Kohri K. Expression of alpha1-adrenoceptor subtype mRNA as a predictor of the efficacy of subtype selective alpha1-adrenoceptor antagonists in the management of benign prostatic hyperplasia. J Urol. 2008; 179:1040-1046.
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Written by Yoshiyuki Kojima1, Shoichi Sasaki1, Yasuhiro Shibata1, Makoto Imura1, Masa Hayase1, Shinsuke Okada1, Yasue Kubota1, Yutaro Hayashi1,
Gozoh Tsujimoto2 and Kenjiro Kohri1 as part of Beyond the Abstract on UroToday.com
1Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
2Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutial Sciences, Kyoto University Faculty of Pharmaceutial Sciences, Kyoto University, Kyoto, Japan

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