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The Impact of Alpha1-Adrenoceptors on Prostate Cancer Growth

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The Impact of Alpha1-Adrenoceptors on Prostate Cancer Growth
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  Letters to the Editor Re: Al Mosawi AJ: Identification of Nonneurogenic Neurogenic Bladder inInfants (Urology 70: 335–356, 2007) We read the article by Al Mosawi 1 with great interest. Asthe author mentioned in his report, the main focus of thephysician when treating patients with nonneurogenicneurogenic bladder must be to preserve upper urinary tractfunction. However, some of the patients might be refractiveto all known conservative therapies, including chronic in-termittent catheterization, anticholinergic therapy, and sa-cral nerve stimulation, with an ultimate result of end-stage renal failure. The author also indicates that bycorrecting the high-storage pressure by performing vesi-cotomy in 1 patient, he achieved success with renalfunction preservation during 6 years of follow-up. Wealso believe that conservative therapy must be the firstchoice in patients diagnosed with Hinman-Allen syn-drome; however, in some special cases, refractory to theconservative therapies, with worsening clinical featuresduring follow-up, surgical therapy (eg, auto-augmenta-tion, augmentation cystoplasty with Mitrofanoff proce-dure) could be an alternative choice to preserve renalfunction. We have experience with augmentation cysto-plasty with the Mitrofanoff procedure in 8 patients diag-nosed with Hinman-Allen syndrome. At a mean fol-low-up of 54.78  18.52 months, the renal function hasbeen well preserved and no patient has progressed toend-stage renal disease. Kaya Horasanli, M.D.Mesrur Selcuk Silay, M.D.Cengiz Miroglu, M.D. Department of 2nd UrologySisli Etfal Training and Research HospitalIstanbul, Turkey Reference 1. Al Mosawi AJ: Identification of nonneurogenic neurogenic bladderin infants. Urology  70:  355–356, 2007. The Impact of Alpha1-Adrenoceptorson Prostate Cancer Growth DEAR EDITOR: Alpha-adrenergic blockers (alpha-1 adrenoreceptor an-tagonists/alpha-1AA) for the treatment of BPH-relatedsymptoms remain the most common medical therapy inEurope being used also in the treatment of many otherurologic diseases such as prostatitis, urinary stones etc.These drugs have been demonstrated to improve bladderoutlet obstruction caused by the enlarged prostatethrough relaxing the smooth muscle of prostatic urethra;however, evidence support a potential impact of alpha-1AA on the overall function of the prostate gland otherthan obstructive BPH.Previous studies have demonstrated that 3 subtypes of alpha1-adrenergic receptor are present in the prostaticgland (alpha1 A , alpha1 B , and alpha1 D ), among whichonly the alpha 1A  receptors function has been partiallyexplained appearing to be linked to contraction.Our collective anecdotal experience suggests that tam-sulosin, a selective alpha-1 adrenoreceptor antagonist,lowers serum PSA values in certain patients indicating apossible interaction between alpha-1AA and epithelialcells. Furthermore, it could be assumed that anejacula-tion and reduction of ejaculated sperm volume inducedby tamsulosin is probably caused by a reduction of spermliquefaction thanks to a possible influence of alpha-1AAon prostatic epithelial cells. 1 Interestingly, although Collins  et al . 2 demonstratedthat adrenergic receptors activity is regulated by andro-gens in the rat ventral prostate, other experimental stud-ies failed to determine whether androgen ablation affectsexpression of alpha1A-adrenergic receptors in the humanprostate. 3 On the other hand, Chon  et al . 4 over the pastdecade, showed that 2 alpha-1AA, terazosin and doxazo-sin, are able to induce apoptosis of both epithelial andstromal prostatic cells.There are no published studies outlining a possible roleof alpha-1-adrenergic receptors on prostate cancer devel-opment; however, several experimental studies investi-gated the impact of alpha-1AA on the prostatic epithe-lial malignant cells. Siddiqui  et al ., 5 Garrison  et al ., 6 andIlio  et al ., 7 demonstrated that doxazosin a quinazoline-based alpha-adrenergic blocker inhibit growth and in-duce apoptosis in malignant epithelial prostatic cells.Although the apoptotic effect of doxazosin on humanprostatic stromal cells has been demonstrated to be me-diated through an autocrine production of TGF-beta1, 6 the mechanism of apoptotic action on epithelial cellsremains undefined. Recently, Garrison and Kyprianou 7 proposed a death receptor-mediated mechanism with apotential integrin contribution toward cell survival out-comes to explain apoptotic effects of alpha1-adrenocep-tor antagonists against malignant epithelial prostate cells.Although Tahmatzopoulos and Kyprianou 8 supportedthat antitumor efficacy of alpha-1AA is independent of  E-mail: stamatiouk@gmail.com, sofras@uoc.gr 756  © 2008 Elsevier Inc. UROLOGY 71: 756–759, 2008 • 0090-4295/08/$34.00All Rights Reserved  an alpha1-adrenoceptor mechanism, there is enough ev-idence that alpha-1AA are able to induce apoptosis andprevent cell invasion and migration of prostate tumorepithelial cells. Even if only the quinazoline-based al-pha1-adrenoceptor antagonists such as doxazosin andterazosin obtain all the abovementioned characteristics 8 it is imperative those properties to be confirmed by fur-ther studies. Retrospective studies for example, couldpossibly assess the impact of alpha-1AA on prostatecancer epidemiology.Although the use of alpha-1AA for the treatment of lower urinary tract symptoms (LUTS) associated withbenign prostatic hyperplasia (BPH) has been establishedin Europe for more than 20 years, it is still not verypopular in the United States. It was not until recentlythat it has been approved by the U.S. Food and DrugAdministration (FDA). This is probably the reason ex-plaining the low number of relative studies in the liter-ature.The only published study examining the prostate can-cer risk among users of alpha-blockers failed to demon-strate any association 9 ; however, the study was hazardedby the enhanced diagnostics of prostate cancer amongmen treated medically for BPH related symptoms. Large,epidemiologic studies are required to identify the impactof alpha1-adrenoceptor antagonists’ usage on prostatecancer incidence and further investigation is needed toexamine a preventive potential of these drugs and afuture usage as chemoprevention agents against prostatecancer.To our knowledge, prostate cancer is a slowly progres-sive disease whose frequency increases with ageing andbecause these drugs have been in use for over the past 2decades, perhaps it is the high time for the frequency of prostate cancer on users of alpha-1AA to be studied. Konstantinos StamatiouAndreas Skolarikos Frank Sofras Department of Urology, University of CreteHeracleion, Greece References 1. Hisasue S, Furuya R, Itoh N,  et al : Ejaculatory disorder caused byalpha-1 adrenoceptor antagonists is not retrograde ejaculation but aloss of seminal emission. Int J Urol  13:  1311–1316, 2006.2. Collins S, Quarmby VE, French F,  et al : Regulation of the adrenergicreceptor and its m-RNA in the rat ventral prostate by testosterone.FEBS Lett  233:  173–176, 1988.3. Benaim EA, Karam JA, Soboorian MH,  et al : The effect of combinedandrogen ablation on the expression of alpha1A-adrenergic receptorin the human prostate. Prostate  60:  310–316, 2004.4. Chon JK, Borkowski A, Partin AW,  et al : Alpha 1-adrenoceptorantagonists terazosin and doxazosin induce prostate apoptosis with-out affecting cell proliferation in patients with benign prostatichyperplasia. Urol  161:  2002–2008, 1999.5. Siddiqui EJ, Shabbir M, Thompson,  et al : Growth inhibitory effect of doxazosin on prostate and bladder cancer cells: is the serotoninreceptor pathway involved? Anticancer Res  25:  4281–4286, 2005.6. Ilio KY, Park II, Pins MR,  et al : Apoptotic activity of doxazosin onprostate stroma in vitro is mediated through an autocrine expressionof TGF-beta1. Prostate  48:  131–135, 2006.7. Garrison JB, and Kyprianou N: Doxazosin induces apoptosis of benign and malignant prostate cells via a death receptor-mediatedpathway K. Cancer Res  66:  464–472, 2006.8. Tahmatzopoulos A, and Kyprianou N: Apoptotic impact of alpha1-blockers on prostate cancer growth: a myth or an inviting reality?Prostate  59:  91–100, 2004.9. Murtola TJ, Tammela TL, Maattanen L,  et al : Prostate cancer riskamong users of finasteride and alpha-blockers—a population basedcase-control study. Eur J Cancer  43:  775–781, 2007. Re: Duchene DA, Winfield HN, CadedduJA,  et al. : Is Laparoscopic Ureterolysis aPanacea for Idiopathic RetroperitonealFibrosis? (Urology 69: 1017–1021, 2007) I read with interest the article written by Duchene et al. 1 First, I appreciate the efforts taken by the authors tocollect information from various institutions on this par-ticular rare disease. Second, this article is one of thelargest series of laparoscopic ureterolysis ever published.This article, in my opinion, could have been moreinformative if it were a prospective and a randomizedtrial, as pointed out by the authors themselves. It wouldhave been much more informative if the authors hadprovided us with the valuable data on how many pa-tients, who were given only medical treatment, reallybenefited from conservative approach.As the authors had rightly admitted, since this is aretrospective survey, with inputs from various centers,there is no uniformity in the protocol followed.I am not also fully convinced about one of the con-clusions drawn, which states that most institutions rec-ommended an attempt at steroids followed by laparo-scopic ureterolysis. Steroids still remain one of themainstays in medical management and there is enoughevidence nowadays to suggest that conservative treat-ment involving steroids with or without other immuno-suppressive drugs is curative in a good number of pa-tients. 2 I do agree that laparoscopic ureterolysis is now evolv-ing as a primary form of   surgicaltreatment  in centers of laparoscopic excellence. This article appears to be con-veying a wrong message that every retroperitoneal fibro-sis, after a course of immunosuppressive agents, shouldideally be subjected for a laparoscopic ureterolysis, if yourcenter is one of laparoscopic expertise.The references quoted in the article (references 7through 9), the publications of Kavoussi  et al. , 3 Fugita  etal. , 4 and Elashry  et al. , 5 respectively, in fact underline thescope of laparoscopy in ureterolysis and compare theirresults with the more traditional open ureterolysis withomental wrapping. It may be inappropriate to come tothe conclusion that laparoscopic ureterolysis is the pan-acea for retroperitoneal fibrosis. This point is furtherreinforced by Vaglio et al. 6 It is high time that we frame UROLOGY 71 (4), 2008  757
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