Does doxazosin affect prostatic growth?
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LETTER TO THE EDITOR Does Doxazosin Affect Prostatic Growth? A recent editorial raises the issue of the precise mechanism whereby a 1 -adrenoceptor antagonists (blockers) in general, and doxazosin in particular, pro- vide acute and chronic relief of lower urinary tract symptoms (LUTS) [1]. The conventional wisdom is that the predominant acute action is via relaxation of the periurethral stromal smooth muscle, subsequent reduction in urethral resistance, and corresponding in- crease in uroflow [2–4]. It is assumed that a compo- nent of the improvement in detrusor instability is sec- ondary to the a-blocker-induced reduction in outflow obstruction [5]. However, there is little evidence of a correlation between the degree or time scale of flow change and symptom improvement induced by either a-blockers or 5-a-reductase inhibitors [6–8]. Consistent with this discrepancy, it has been suggested that additional spi- nal and supraspinal actions make an important con- tribution to the a-blocker-induced symptom improve- ment [9–12]. The complex symptomatology of LUTS would certainly indicate a multifactorial etiology and the potential for several loci where a-blockers could act [13]. The data cited in the editorial [14] raise the possi- bility that doxazosin (and other a-blockers) may also affect prostatic growth. Long-term studies certainly indicate a durability of clinical response to doxazosin, in the face of a presumed ongoing hyperplasia, be- yond that expected from acute adrenoceptor blockade [15]. Subsequent to acceptance of the article, addi- tional information, discussed below, has been pub- lished, which may help to put the findings from the mouse [14] into clinical context. In the mouse prostatic reconstitution model, dox- azosin was found to have a proapoptotic action and to reduce oncogene-induced growth without affecting normal cellular growth patterns [14]. This proapop- totic effect does not appear to be restricted to the mouse; at least in vitro, a similar profile of activity is observed in cancer cell lines [16,17] and in primary vascular cultures [18,19], at concentrations similar to those found at therapeutic doses of the drug [17]. As in the case of the mouse, there was little effect of dox- azosin on normal cell function. This effect on vascular proliferation may not be unique to doxazosin; a quali- tatively similar profile has been described for carve- dilol [20]. Intriguingly, however, the effect could not be reproduced by doses of other a-blockers, including prazosin, phenoxybenzamine, and terazosin, even at supraoptimal receptor blocking doses [19]. Even un- der conditions where chlorethylclonidine was used to alkylate cell surface receptors, doxazosin was still ac- tive [19], raising the possibility of an intracellular site of action. A key issue is the relevance of these in vitro and in vivo findings to the clinical profile of the drug. In a small clinical study involving tissue biopsies, doxazo- sin was found to induce apoptosis at doses (2–8 mg) routinely used in BPH patients [21]. In this clinical study a good correlation (r = 0.79) was noted between doxazosin-induced apoptosis in biopsies and symp- tom improvement [17,21]. Although it is likely that the correlation could merely reflect the small sample size (n = 24), it is pertinent to note that similar correlations have not been observed between symptoms and uro- dynamic parameters. Larger and longer ongoing stud- ies will determine the clinical significance of doxazo- sin-induced apoptosis and the contribution from a1- dependent and independent actions of the drug. Michael G. Wyllie Director of Urology Medical Department Pfizer, Inc. New York, New York REFERENCES 1. Buttyan R: The mouse prostate reconstitution model of prostate diseases [editorial]. Prostate 1997;33:164–165. 2. Caine M, Pfau A, Perlberg S: The use of alpha-adrenergic block- ers in benign prostatic obstruction. Br J Urol 1976;48:255–263. 3. Caine M, Perlberg S, Mereetyk S: A placebo controlled, double- blind study of the effect of phenoxybenzamine in benign pros- tatic obstruction. Br J Urol 1978;50:551–556. 4. Furuya S, Kumamoto Y, Yokoyama E, Tsukamoto T, Izumi T, Abiko Y: Alpha-adrenergic activity and urethral pressure in prostatic zone in benign prostatic hypertrophy. J Urol 1982;128: 836–839. 5. Susset JG: Effects of aging and prostatic obstruction on detrusor morphology and function. In Hinman C (ed): ‘‘Benign Prostatic Hypertrophy,’’ New York: Springer-Verlag, 1985:653–665. 6. Barry MJ, Cockett ATK, Holtgrewe HL, McConnell JD, Sihelnik SA, Winfield HN: Relationship of symptoms of prostatism to commonly used physiological and anatomical measures of the severity of benign prostatic hyperplasia. J Urol 1993;150:351– 358. 7. McConnell JD: Finasteride therapy for benign prostatic hyper- plasia. In Kirby RS, McConnell JD, Fitzpatrick JM, Roehrborn CG, Boyle P (eds): ‘‘Textbook of Benign Prostatic Hyperplasia,’’ ISIS Medical Media, 1996:259–265. 8. Gerber GS, Contreas BA, Zagaja GP, Kim JH, Steinberg GD, Rukstalis DB: Doxazosin in men with lower urinary tract symp- toms: Urodynamic evaluation at 15 months. Urology 1997;50: 229–233. The Prostate 35:152–153 (1998) © 1998 Wiley-Liss, Inc.
Transcript of Does doxazosin affect prostatic growth?
LETTER TO THE EDITORDoes Doxazosin Affect Prostatic Growth?
A recent editorial raises the issue of the precisemechanism whereby a1-adrenoceptor antagonists(blockers) in general, and doxazosin in particular, pro-vide acute and chronic relief of lower urinary tractsymptoms (LUTS) [1]. The conventional wisdom isthat the predominant acute action is via relaxation ofthe periurethral stromal smooth muscle, subsequentreduction in urethral resistance, and corresponding in-crease in uroflow [2–4]. It is assumed that a compo-nent of the improvement in detrusor instability is sec-ondary to the a-blocker-induced reduction in outflowobstruction [5].
However, there is little evidence of a correlationbetween the degree or time scale of flow change andsymptom improvement induced by either a-blockersor 5-a-reductase inhibitors [6–8]. Consistent with thisdiscrepancy, it has been suggested that additional spi-nal and supraspinal actions make an important con-tribution to the a-blocker-induced symptom improve-ment [9–12]. The complex symptomatology of LUTSwould certainly indicate a multifactorial etiology andthe potential for several loci where a-blockers couldact [13].
The data cited in the editorial [14] raise the possi-bility that doxazosin (and other a-blockers) may alsoaffect prostatic growth. Long-term studies certainlyindicate a durability of clinical response to doxazosin,in the face of a presumed ongoing hyperplasia, be-yond that expected from acute adrenoceptor blockade[15]. Subsequent to acceptance of the article, addi-tional information, discussed below, has been pub-lished, which may help to put the findings from themouse [14] into clinical context.
In the mouse prostatic reconstitution model, dox-azosin was found to have a proapoptotic action and toreduce oncogene-induced growth without affectingnormal cellular growth patterns [14]. This proapop-totic effect does not appear to be restricted to themouse; at least in vitro, a similar profile of activity isobserved in cancer cell lines [16,17] and in primaryvascular cultures [18,19], at concentrations similar tothose found at therapeutic doses of the drug [17]. As inthe case of the mouse, there was little effect of dox-azosin on normal cell function. This effect on vascularproliferation may not be unique to doxazosin; a quali-tatively similar profile has been described for carve-dilol [20]. Intriguingly, however, the effect could notbe reproduced by doses of other a-blockers, includingprazosin, phenoxybenzamine, and terazosin, even atsupraoptimal receptor blocking doses [19]. Even un-
der conditions where chlorethylclonidine was used toalkylate cell surface receptors, doxazosin was still ac-tive [19], raising the possibility of an intracellular siteof action.
A key issue is the relevance of these in vitro and invivo findings to the clinical profile of the drug. In asmall clinical study involving tissue biopsies, doxazo-sin was found to induce apoptosis at doses (2–8 mg)routinely used in BPH patients [21]. In this clinicalstudy a good correlation (r = 0.79) was noted betweendoxazosin-induced apoptosis in biopsies and symp-tom improvement [17,21]. Although it is likely that thecorrelation could merely reflect the small sample size(n = 24), it is pertinent to note that similar correlationshave not been observed between symptoms and uro-dynamic parameters. Larger and longer ongoing stud-ies will determine the clinical significance of doxazo-sin-induced apoptosis and the contribution from a1-dependent and independent actions of the drug.
Michael G. WyllieDirector of Urology
Medical DepartmentPfizer, Inc.
New York, New York
REFERENCES
1. Buttyan R: The mouse prostate reconstitution model of prostatediseases [editorial]. Prostate 1997;33:164–165.
2. Caine M, Pfau A, Perlberg S: The use of alpha-adrenergic block-ers in benign prostatic obstruction. Br J Urol 1976;48:255–263.
3. Caine M, Perlberg S, Mereetyk S: A placebo controlled, double-blind study of the effect of phenoxybenzamine in benign pros-tatic obstruction. Br J Urol 1978;50:551–556.
4. Furuya S, Kumamoto Y, Yokoyama E, Tsukamoto T, Izumi T,Abiko Y: Alpha-adrenergic activity and urethral pressure inprostatic zone in benign prostatic hypertrophy. J Urol 1982;128:836–839.
5. Susset JG: Effects of aging and prostatic obstruction on detrusormorphology and function. In Hinman C (ed): ‘‘Benign ProstaticHypertrophy,’’ New York: Springer-Verlag, 1985:653–665.
6. Barry MJ, Cockett ATK, Holtgrewe HL, McConnell JD, SihelnikSA, Winfield HN: Relationship of symptoms of prostatism tocommonly used physiological and anatomical measures of theseverity of benign prostatic hyperplasia. J Urol 1993;150:351–358.
7. McConnell JD: Finasteride therapy for benign prostatic hyper-plasia. In Kirby RS, McConnell JD, Fitzpatrick JM, RoehrbornCG, Boyle P (eds): ‘‘Textbook of Benign Prostatic Hyperplasia,’’ISIS Medical Media, 1996:259–265.
8. Gerber GS, Contreas BA, Zagaja GP, Kim JH, Steinberg GD,Rukstalis DB: Doxazosin in men with lower urinary tract symp-toms: Urodynamic evaluation at 15 months. Urology 1997;50:229–233.
The Prostate 35:152–153 (1998)
© 1998 Wiley-Liss, Inc.
9. Yoshimura N, Sasa M, Yoshida O, Takaori S: Alpha1-adrenergicreceptor-mediated excitation from the locus ceruleus of the sa-cral parasympathetic preganglionic neuron. Life Sci 1990;47:789–797.
10. Ramage AG, Wyllie MG: A comparison of the effects of dox-azosin and terazosin on the spontaneous sympathetic drive tothe bladder and related organs in the anesthetized cat. Eur JPharmacol 1995;294:645–650.
11. Danuser H, Thor K: Inhibition of central sympathetic and so-matic outflow to the lower urinary tract of the cat by the alpha-adrenergic antagonist, prazosin. J Urol 1995;153:1308–1312.
12. Ishizuka O, Persson K, Mattiason A, Naylor AM, Wyllie MG,Andersson K-E: Micturition in conscious rats with and withoutoutlet obstruction: Role of spinal alpha1-adrenoceptors. Br JPharmacol 1996;117:962–966.
13. Andersson K-E, Lepor H, Wyllie MG: Prostatic alpha1-adreno-ceptors and uroselectivity [review]. Prostate 1997;30:202–215.
14. Yang G, Timme TL, Park SH, Wu X, Wyllie MG, Thompson TC:Transforming growth factor (B1)- transduced mouse prostaticreconstitutions: II. Induction of apoptosis by doxazosin. Prostate1997;33:157–163.
15. Kirby RS: Doxazosin in the treatment of obstruction of the lowerurinary tract. In Kirby RS, McConnell JD, Fitzpatrick JM, Roe-hrborn CG, Boyle P (eds): ‘‘Textbook of Benign Prostatic Hy-perplasia,’’ ISIS Medical Media, 1996:287–293.
16. Allen LF, Ferguson SB, Moore ME: Prostate cell growth inhibi-tion by doxazosin. Eur Urol 1996;30:74.
17. Kyprianou N, Allen LF, Wyllie MG: Induction of prostate ap-optosis by doxazosin; alpha1-adrenoceptor-dependent and -in-dependent actions? Br J Pharmacol 1998; in press.
18. Tsai TJ, Lin RH, Chang CC, Chen YM, Chen CF, Ko FN, TengCM: Vasodilator agents modulate rat glomerular mesangialgrowth and collagen synthesis. Nephron 1995;70:91–99.
19. Hu Z-W, Shi X-Y, Hoffman BB: Doxazosin inhibits proliferationand migration of human vascular smooth muscle. J CardiovascPharmacol 1998; in press.
20. Sung C-P, Arleth AJ, Ohlstein EH: Carvedilol inhibits vascularsmooth muscle cell proliferation. J Cardiovasc Pharmacol 1993;21:221–227.
21. Litvak JP, Borkwoski A, Jacobs SC, Kyprianou N: Induction ofprostate apoptosis by doxazosin: Targeting alpha1 blockade inbenign prostatic hyperplasia. J Urol 1997;157:1083.
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