Clinical Biology

Normal prostate development and growth as well as the development of prostatic neoplasia are dependent on the action of the testicular an-drogens testosterone (T) and dihydrotestos-terone (DHT).2 Testosterone, secreted by the testicular Leydig cells, is taken up by a variety of tissues, including normal prostate and prostate cancer. The type II 5a-reductase enzyme acts within the prostate to metabolize T into the more potent androgen DHT.3 Dihy-drotestosterone and T form complexes with the androgen receptor (AR), which then interact with DNA via coactivator recruitment and RNA polymerase II to induce protein synthesis and cell replication. The major mechanism for reg ulation of serum and tissue androgen concentrations is control of testicular Leydig cell T secretion via the hypothalamic-pituitary-gonadal (HPG) axis. The testes produce T in response to the serum luteinizing hormone (LH) concentration. This hormone is secreted from the anterior pituitary based on pulsatile and phasic production of LH-releasing hormone (LHRH) by the hypothalamus. In turn, and to complete the loop, LHRH secretion is suppressed by feedback at the hypothalamic level directly either by sex steroid hormones or by hormones released by their end-organ effect, such as inhibin and activin.

The testes are not the only source of andro-gens, but they are responsible for 90%-95% of the circulating T present in healthy males. Adrenal androgens [dihydro-epiandrostene-dione (DHEA) and androstenedione] may be converted to T and DHT by hydroxysteroid de-hydrogenases. Adrenal androgens may also activate mutant ARs in the absence of T or DHT.4-6 This effect may be particularly important in patients with prostate cancer treated with medical or surgical castration but who develop progressive disease despite this. However, it appears that while adrenal androgens may be important in prostate cancer progression, they do not play a critical role in prostate development or car-cinogenesis. Despite the presence of elevated serum concentrations of adrenal androgens, patients with hypogonadotrophic hypogonadism have abnormal prostate development but do not develop prostate neoplasia. Males castrated at or prior to puberty seemingly never develop prostate cancer.

The natural clinical history of prostate cancer is long, with projected transition from the first malignant cell in the prostate to distant metasta-tic disease taking more than 15 years in some cases and not occurring within the life span of a significant proportion of men.7 Important points at which the clinical course of the disease appears to accelerate include the development of metastases and the onset of resistance to primary hormone therapy. Local extension from primary prostate cancer may involve the bladder and seminal vesicles. This tumor also metastasizes through lymphatics to regional lymph nodes in the pelvis.8 Distant metastases commonly involve bone, especially the spine, but may involve distant lymph nodes and visceral organs, including the lung, liver, and adrenal glands.9

In advanced or metastatic prostate cancer, tumor response (measured by a variety of criteria) is reported in between 50% and 100% of cases with bilateral orchiectomy, exogenous estrogen therapy, or hormone therapy directed at the HPG axis and/or the intracellular AR path-way.10-14 This response is characterized by an improvement in clinical symptoms (usually bone pain) and a fall in serum prostate-specific antigen (PSA).15 Survival is better in individuals who have no bone pain, lower serum alkaline phos-phatase, better performance status, and higher serum T levels prior to medical or surgical cas-tration.16,17 Following initial treatment with castration, patients with advanced prostate cancer typically experience clinical and biochemical quiescence of their disease for an average of 18-36 months. A small number of patients survive more than 10 years following castration for advanced prostate cancer.18 However, the vast majority of patients go on to develop hormone-refractory prostate cancer characterized by worsening clinical symptoms, including bone pain, coupled with rising serum PSA. An increase in serum PSA subsequent to the hormone-induced nadir may precede clinical recurrence by several months.19 Despite significant developments in the use of chemotherapy for patients with hormone-refractory prostate cancer in recent years, the median survival from the development of hormone-refractory prostate cancer ranges 10-18 months in most patients, depending on the extent of disease present at the initiation of salvage therapy. The biological correlate of this transient response to hormonal manipulation is triphasic:20,21

• Initial androgen withdrawal results in a variable proportion of prostate cancer cells undergoing apoptosis.22 The remaining cells enter an androgen ablation-induced cell cycle arrest rather than undergoing apoptosis.

• Surviving cells undergo a variable quiescent or remission phase.

• Cell cycle induction and increased proliferation occur at the onset of hormone independence in a subset of cells, which correlates with biochemical and clinical progression.

Several key questions regarding the response of prostate cancer to hormone therapy remain to be resolved: Does combined androgen blockade provide an advantage over single therapy? Can therapy be modified to delay or alleviate the onset of hormone-refractory disease? Once prostate cancer becomes refractory to hormones, can further hormone therapy produce a meaningful disease response? Will a better understanding of the mechanisms underlying hormone resistance facilitate the development of drugs that delay or reverse it?

Was this article helpful?

0 0
10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment