8.1

Introduction

In the clinical setting, benign prostatic hyperplasia (BPH), a common prostatic

disease in elderly men (Kawabe 2006), is generally treated using α1-adrenoceptor

(AR) antagonists. Indeed, in patients with BPH, α1-AR antagonists have been shown

to decrease prostatic smooth muscle tone and rapidly affect urinary flow.

Based on the selectivity for α1-AR, α1-AR antagonists can be classified as

subtype-nonselective α1-AR antagonists or subtype-selective α1-AR antagonists.

Importantly, research has demonstrated that cardiovascular side effects are less

frequent in patients administered with subtype-selective α1-AR antagonists than in

those

patients

administered

with

subtype-nonselective

α1-AR

antagonists

(Roehrborn and Schwinn 2004). In Japan, only subtype-selective α1-AR antagonists,

which were developed in Japan, are prescribed for patients with BPH because these

drugs exhibit high tolerability with fewer side effects (Yokoyama et al. 2006;

Tsuritani et al. 2010).

α1-ARs are divided into α1A, α1B, and α1D subtypes (Bylund et al. 1994). α1A-AR

is the most abundant subtype in the prostate gland, followed by α1D-AR (Walden

et al. 1999). Tamsulosin is an α1A-AR- and α1D-AR-selective antagonist, and

silodosin is a highly selective α1A-AR antagonist. Naftopidil is also an α1A-AR-

and α1D-AR-selective antagonist but has a comparatively higher selectivity for α1D-

AR than tamsulosin. Notably, naftopidil has been shown to enhance bladder capac-

ity, promote voiding by blocking the activity of afferent nerves (Yokoyama et al.

2006), and clinically alleviate obstructive voiding and storage symptoms associated

with BPH (Nishino et al. 2006; Takahashi et al. 2006).

8.2

History of a1-AR Antagonists

The global incidence of prostate cancer (PCa) in men is increasing continuously

(Gronberg 2003). The majority of PCa cases arise in the prostate, concomitant with

BPH (Bostwick et al. 1992). The incidence of BPH has been shown to increase with

age, to a greater extent than that of PCa (Alcaraz et al. 2009). Thus, generally, α1-AR

antagonists are often administered for the treatment of BPH before the diagnosis

of PCa.

In two observational cohort epidemiological studies, a low prevalence of PCa has

been reported in patients with BPH administered with α1-AR antagonists. Indeed,

the quinazoline-based, subtype-nonselective α1-AR antagonists doxazosin and

terazosin were shown to decrease PCa incidence (Harris et al. 2007). Additionally,

alfuzosin, a subtype-nonselective α1-AR antagonist, and tamsulosin, a subtype-

selective α1-AR antagonist, reduce the incidence of high-grade PCa in a manner

related to the cumulative duration of α1-AR antagonist administration (Murtola et al.

2009). These data strongly suggested that α1-AR antagonists may have anticancer

effects.

Drug repositioning (DR) is a strategy used to develop new applications for

existing approved drugs by discovering novel therapeutic effects or drug targets

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