Effect of terazosin on tissue vascularity and apoptosis in transitional cell carcinoma of bladder

Abstract

Objectives-To present a pilot study to determine whether the alpha 1 -adrenoceptor antagonist terazosin can induce apoptosis in transitional cell carcinoma (TCC) of the bladder, similar to the effect seen with prostate cancer. The alpha 1 -adrenoceptor antagonist terazosin has recently been shown to induce apoptosis in prostate cancer cells both in vitro and in vivo and to reduce prostatic tissue vascularity by potentially affecting endothelial cell adhesion.Methods-The records of 24 men who underwent radical cystectomy for TCC of the bladder at the Lexington Veterans Affairs Medical Center were reviewed. The control group consisted of 15 men who were never exposed to terazosin. The study group consisted of 9 men who were treated with terazosin before cystectomy. Sections of the bladder tumor and normal trigone were subjected to immunohistochemical analysis for microvessel density, endothelial cell CD31 expression, and apoptosis detection (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling), as well as high-molecular-weight cytokeratin staining.

Antitumor Action of a1-Adrenoceptor Blockers on Human Bladder, Prostate and Renal Cancer Cells

“…A variety of the mechanisms for antitumor actions of α 1 -adrenoceptor blockers have been proposed: mitochondria-mediated activation of caspase-3/-9 and cjun N-terminal kinase 1/2, recruitment of Fas-associated death domain and the ensuing activation of caspase-8, activation of transforming growth factor-β 1 signaling pathway and IκBα induction, or an antagonistic effect of Bcl-2. α 1 -Adrenoceptor blockers, alternatively, exhibit antiangiogenic effects, thereby suppressing cell growth in human prostate cancer [25][26][27][28] or human bladder cancer [29]. α 1 -Adrenoceptor blockers also modulate differentiation and cell death of human erythroleukemia cells by a mechanism independent of α 1 -adrenergic blocking [30].…”

The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

“…Importantly, the cytotoxic and anti-proliferative effects are supported by several in vivo mice studies [48,66], suggesting ubiquitous anticancer actions of these drugs. In support of in vitro findings a retrospective study in 24 patients with bladder cancer, 15 of which had been treated with terazosin over a 3–6 month period, had a reduction in incidence, tissue MVD and increase in apoptotic index [83]. The only trials with doses that are of clinical relevance are with bladder, pituitary and ovarian cancer, all of which are within the standard dosage ranges of the respective medications [48,50,66].…”

Recent advances in the design and synthesis of prazosin derivatives

“…In 2005, it was found that compound 2 gives rise to an apoptotic/anti-angiogenic effect in transitional cell carcinoma of the bladder, similar to the effect seen in prostate cancer [48].…”

“…The starting material was represented by polymer bound amines (48) which reacted with 6,7-dimethoxy-2,4-dichloroquinazoline followed by an aromatic nucleophilic substitution with the appropriate amine and subsequent cleavage to give the desired quinazoline (51) (Figure 8) A modified synthesis of the antihypertensive agent iodoazidoarylprazosin (52) [44] (Figure 1) has been published recently. Compound 52 is a prazosin derivative shown to function as a multi-drug-resistance reversal agent and used as a standard photo-affinity label for competition assays on P-glycoprotein.…”