Endocrine treatment in prostate cancer

Abstract

Over its natural course, prostate cancer is a heterogeneous tumour with a generally slow but constant rate of growth. The androgen dependence of the prostate gland was demonstrated more than half a century ago by the landmark studies of Professor C. Huggins and colleagues. They established that androgens are implicated not only in growth regulation of the normal gland but also in the pathogenesis of prostate cancer, and that this malignant tissue retains some degree of androgen dependence. This concept was supported by studies of symptomatic clinical cancer, with androgen ablative therapy bringing relief to the patient in more than 80% of the cases. The classical treatment consisted of either bilateral orchiectomy, or administration of diethylstilbestrol (DES). Other forms of therapy followed, involving successive waves of new compounds that either withdrew androgen support from the cancer or blocked the androgens from their receptors in the prostate cancer cells. Chronologically, the progestagens can be well recognised, with one in particular: The successful derivative, cyproterone acetate (CPA). There also have been a number of oral vs. parenteral estrogens, the development of the luteinizing hormone‐releasing hormone agonists (LH‐RHA), the introduction of the non‐steroidal anti‐androgens characterised by flutamide and casodex, and more recently, the introduction of the LH‐RHA. Moreover, there have been multiple possible forms of combination treatment to obtain maximal androgen blockade (MAB). However, no major differences in treatment outcome have been reported during the last 5 decades and most treatment choices have been based on tradition, associated side effects, the preferences of a particular doctor and patient, together with economic considerations. Furthermore, endocrine treatment has never been shown to cure clinical prostate cancer, which consequently has led to initiatives to defer endocrine treatment or to use it intermittently or use it as a form of neo‐adjuvant or adjuvant treatment with surgery or radiotherapy. The history of endocrine therapy is replete with clinical trials that do not represent the patient population in general, and these trials share the clinical fact that they ignore the 20% to 30% of all patients who lack an initial response to a given endocrine treatment. Thus, it is no wonder that prognostic factors determine the outcome more than the treatment itself. Important to current endocrine treatment, however, is the shift to earlier stages of prostate cancer at initial diagnosis. Integration of endocrine treatment at this earlier phase in the pathogenesis of prostate cancer will substantially alter the treatment strategy in relation to long‐term benefit with regard to survival, associated side effects, and costs. This complex adjustment is enhanced by recent discoveries in the molecular biology of the prostate which show, on the one hand, that the dihydrotestosterone‐androgen receptor (DHT‐AR) complex is important in the regulation of gene expression, but also that a nu...

Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor

“…Both androgen and androgen receptor (AR) are recognized risk factors in the development of prostate cancer [17][18][19][20]. These observations are further corroborated by genetic evidence from transgenic mouse models, suggesting that increased AR signaling in the prostate is linked to an increase in precancerous lesions [21].…”

Suppressive effects of antiandrogens, finasteride and flutamide on development of prostatic lesions in a transgenic rat model

“…It has been shown that LH-releasing hormone (LHRH) agonists can transitionally stimulate serum testosterone release, and then reduce the level through blocking LH. 5 Treatment with the two antiandrogens here resulted in decreased expression of SV40 Tag via inhibition of AR function. The SV40 Tag acts as an oncoprotein through interaction with both retinoblastoma (Rb) 28 and p53 tumor-suppressor gene products.…”

“…4,5 Although androgen ablation at this hormone refractory stage is ineffective, androgen deprivation strategy as an early intervention may delay the promotion and/or progression of prostate cancer, resulting in reduced morbidity and mortality.…”

“…7 Another potential suppressive agent is the nonsteroidal antiandrogen flutamide, which exerts effects by interfering with the binding of DHT or testosterone to the AR. 5 The study of prostate cancer chemoprevention and treatment has been hindered by the lack of appropriate animal models. Recently, we have established transgenic (TG) rats, designated TRAP (Transgenic Rat for Adenocarcinoma of the Prostate), bearing a probasin promoter/ simian virus 40 T antigen (SV40 Tag) construct in which androgen-dependent prostate cancers develop rapidly.…”

Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

“…Approximately 80-90% of prostate cancers are dependent on androgens at initial diagnosis. Since the discovery by Huggins and Hodges (1941) that prostate cancer progression is influenced by androgen actions, androgen-deprivation therapy (ADT) to suppress androgens binding to androgen receptor (AR) remains the major treatment regimen for the disease (Denis and Griffiths, 2000). However, ADT ultimately fails, and prostate cancer progresses to a hormonerefractory (androgen-independent) state with advanced metastasis and high morbidity and mortality.…”