Androgen ablation therapy of prostate cancer

Androgen withdrawal induces programmed cell death (apoptosis) in prostate cells resulting in prostate tissue involution and, after some time, only a rudimentary prostate is left that is composed mainly of stromal cells (Kyprianou and Isaacs 1988; English et al. 1989). This process is reversible. Re-stimulation with androgens results in rapid proliferation and growth of the gland to its adult size. When rats are castrated one can observe massive induction of programmed cell death starting about 24-48 hours later and continuing 7-10 days (Denmeade etal. 1996). Associated with androgen withdrawal is a rapid increase in expression of transforming growth factor-S (TGF-S), an inhibitor of prostate cell proliferation, and of testosterone-repressed message-2 (Kyprianou and Isaacs 1989). The latter encodes a glycoprotein also known as clusterin or sulphated glycoprotein-2 (SGP-2) that acts as a chaperone and has antiapoptotic properties in prostate tumor cells (Sensibar et al. 1995; Humphreys et al. 1999). Recent fine dissection of the events occurring after androgen withdrawal in a mouse model revealed that a hypoxia response seems to be induced and several cell types are involved (Shabsigh et al. 2001). Apoptosis is first induced in the endothelial cells of the blood vessels in the prostate, followed by the epithelial cells and finally the stromal cells (Buttyan etal. 2000).

Induction of programmed cell death in prostate cells by withdrawal of androgenic stimulation is the basis for the treatment of non-organ-confined prostate cancer. Although the methods of androgen withdrawal have changed over the years, the basic principle has remained the same since introduction of androgen ablation by Charles Huggins, who received the Nobel Prize for his pioneering work on prostate cancer treatment (Huggins and Hodges 1941; Huggins and Stevens, 1940). In the past, surgical castration (orchiectomy) or chemical castration by high-dose estrogen treatment were used, whereas nowadays the preferred choice of androgen ablation is treatment with gonadotropin-releasing hormone (Gn-RH) agonists that block LH production and testicular testosterone biosynthesis (Afrin and Ergul 2000; Auclerc etal. 2000; DiPaola etal. 2001). Sometimes GnRH analogs are combined with antiandrogens that block the androgen receptor (Kuil and Mulder 1994) to achieve complete androgen blockade (Crawford etal. 1999; Geller 1991; Labrie 1995; 1998). This combination eliminates testicular androgens and, in addition, inhibits activation of the androgen receptor by adrenal androgens (mainly dihy-droepiandrosterone, its sulphate and androstenedione) that contribute about 10% of total androgen activity (Leewansangtong and Crawford 1998). Commonly used antiandrogens are the steroid derivative cyproterone acetate, and the nonsteroidal antiandrogens flutamide, nilutamide, and bicalutamide.

The major problem in treating advanced prostate cancer is that all these treatment methods are only effective as long as the tumors grow androgen-dependently or are at least androgen sensitive. Almost all tumors will progress to an androgen-independent, hormone-refractory state during treatment, thus rendering all common therapies ineffective. Treatment-resistance develops after about two years in the mean. However, there are significant individual differences depending on the biological nature of the tumors. It was postulated that androgen ablation would provide a selective pressure for androgen-independently growing cells that will survive androgen withdrawal by adaptation to the condition of androgen shortage. These cells are those responsible for tumor recurrence and formation of distant metastasis. In the last few years increasing experimental evidence has accumulated showing that changes in androgen receptor signaling are crucial in this process (Culig etal. 2002; Eder etal. 2001).

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