Alternate Hormonal Treatment Approaches to Metastasis Prostate Cancer - Dissertation Example

? Alternate Hormonal Treatment Approaches to Metastasis Prostrate Cancer Introduction: The fundamental unit of life is cell. The human body is made up of numerous cells and these cells carry out various functions all throughout the body. Generally growth occurs in the body when the cells divide to form new cells in an orderly way. They perform their functions and ultimately they die. This phenomenon helps the body to stay healthy and functional. However in some cases the cells do not die and instead they keep dividing abnormally creating new cells that is not essential to the body. They are in the form of mass of tissue called as the growth of tumor. And the group of many related diseases is termed as Cancer. The tumors can be benign or malignant. Mostly the benign tumors are not cancerous. The benign tumors can be easily removed from the body and their growths are restricted and they never come back and hence it is considered to cause less or no harm to the body. On the other hand malignant tumors are cancerous. And the cells in these tumors are generally abnormal. These abnormal cells grow without any control or order and they never get destructed or they never die. Ultimately they invade the near by tissues or organs causing severe damages. These abnormal cancer cells can always break from the malignant tumors and they can enter the blood stream and the lymphatic nodes. This is the way the cancer cells spreads from the place of origin (Primary) or the epicenter to the form new sites (secondary) tumors in other parts of the body. Thus the process of cancer spreading all throughout the body is called as Metastasis or the advanced stage of cancer which is lethal. While there are tremendous advances in the field of cancer research and treatment, the increase in the mortality rate is still a menace in the medical field. Cancer is the second leading cause of death in the U.S and nearly 90 percentage of the cancer deaths are due to metastasis. (Khusial 2008). This paper will deal with the alternate hormonal treatments for the metastasis prostate cancer. Thus prostate is the gland in a man’s reproductive system. It secretes the seminal fluid and nourishes the sperm. “The prostate is about the size of the walnut. It is located below the urinary bladder and in the front of the rectum.”(Nixon and Gomez 2004). For the normal functioning of the prostate the male hormones called as androgens are needed. The male sex characteristics are mainly determined by the male hormones which includes testosterone produced by the testicles. Thus if cancer cells attacks prostate it is termed as the prostate cancer. As discussed the prostate cancer can be of two major types namely the benign Prostrate Hyperplasia which is the abnormal growth of the benign prostate cells, this can be removed and it causes less or nor harm to the human body. On the other hand the malignant tumor in prostate are lethal where the cancer cells spread to the adjacent tissues and other parts of the body especially the lymph nodes, blood stream, bladder, rectum etc. Thus the abnormal cancer cells spreading rapidly causing lethal effect to the other organs is called as the stage of metastasis. “Prostrate cancer develops as a result of a series of faults occurring in the genes that control cell growth in the prostate.” (Chinegwundoh 2011). These faults can be inherited from one generation to the other or can be developed as a result of damage of the DNA. The damage to the Deoxy Ribo Nucleic can be in turn caused by the erratic food habits, cancer-inducing chemicals and radiations. The other risk factor for the occurrence of the prostate cancer encompasses the following elements such as increased age, genetic inheritance and family history of breast cancer, ethnicity, and mainly personal hygiene and dietary components. “In 2007 ,approximately 219,000 new cases of PC were diagnosed.”(Shahani, Braga-Basaria, and Basaria 2008). Prostrate Cancer Staging: “Staging is a system used to describe the size, aggressiveness, and spread of a cancer.” (Dawson 2011). Thus the concept of staging in cancer assists in guiding the treatment and can help to predict the percentage of curing the cancer. There are four stages in the abnormal growth of the cancer cells. Stage I or Stage A is the period when the occurrence and development of the tumor is not known and cannot be identified. Stage II or Stage B, is the stage where the tumor cells multiply within the prostate and it can be felt during the rectal examination or through biopsy. Stage III or Stage C is the time period where the cancer cells spread outside the prostate and start their attack on the nearby tissues. Stage IV or Stage D is the last stage where the cancer cells spread to the lymph nodes and other parts of the body it also enters the blood stream. The Stage IV can also be called as the metastasis stage. During this stage the treatment given to the patients mainly through the hormonal therapy such as the gonadotrophin releasing hormone agonist to effect the suppression of the androgen function and thereby suppress the growth of the cancer cells, is been resisted by the cancer cells itself and that ultimately lead to the development of the other alternate pharmacological treatment approaches. Some of the Hormonal treatment approaches for the Stage IV (Metastasis) Prostrate cancer includes the following; Androgen Deprivation Therapy, Antiandrogen Monotherapy, Complete androgen blockade, intermittent androgen suppression etc. The secondary Hormonal therapy includes antiandrogen withdrawal, Antiandrogens, cytochrome P450 inhibition, usage of gulcocorticoids and CYP-17 inhibition. The above mentioned were some of the hormonal treatment approaches for the prostate cancer in the metastasis stage. This paper will mainly focus on the specific molecular target of the alternate hormonal treatment, their mechanism of action and efficacy in clinical trails of the drugs. Initially the Androgen deprivation therapy is the highly recommended as the first treatment for men with the metastasis prostate cancer. The ADT deals with the decreasing the levels of the androgen hormones predominately the testosterone which is the vital fueling agent for the cancer cells. Consecutive decrease in the level of the androgens ultimately shrinks the size of the prostate cancer and keeps the growth under control. Mechanism of Action of ADT: Testosterone and the dihydrotestosterone (DTH) are the two main androgens in males. The testosterone is mainly present in the circulation and the DHT is the primary androgen present in the prostatic tissues. The Androgen deprivation therapy mainly focuses on the functions of the androgens where through the action of the androgen receptor (AR), a member of the steroid hormone receptor family of ligand –activated nuclear transcription factors. “Androgens such as testosterone and dihyrotestosterone mediate their biological effects through the androgen receptor.” (Sadar 2011). Thus when compared to the testosterone the, dihydrotestosterone binds with the Androgen receptor in a much more stable manner ultimately leading to the increased transcriptional activation, mainly at the tissue level. Moreover the Androgen receptor which exists in the cytoplasm is bound to heat shock proteins, which stabilizes the AR and allow the androgen binding. “Upon the ligand interaction the, the AR homodimerizers, undergoing phosphorylation and translocation to the nucleus, where it binds androgen response elements and induces the transcription of the target genes.” (Harris et al. 2009). This ultimately involved in the cell-cycle regulation and proliferation. Thus the androgens have said to play a critical role in strongly controlling the metastasis prostate growth. Hence through the usage of the dihydrotestosterone, the testicular androgen synthesis and the levels of the circulating androgens are reduced to great extent. Thereby minimizing AR ligand availability and subsequent AR-mediated proliferate effect on prostate. Thus the proliferation of the androgens is reduced through the androgen deprivation therapy. Moreover the circulating testosterone levels can be used to assess the efficacy of the androgen depletion, where the total testosterone level to be below 50 ng/dl. This level of the testosterone can be considered as the basic level of suppression and it remains benchmark for the evaluating the efficacy of the other anti androgenic drugs such as Fltuamide, nilutamide etc. The efficacy of the Androgen deprivation therapy can be estimated in the form of the androgen suppression and the capability to consistently achieve the serum levels of total testosterone below 50 ng/dl. Thus the drugs mentioned above are able to suppress the androgens in the prostate and in spite of maintenance of the anorchid serum androgen levels if the disease spread then it can be called as the androgen-independent stage and under such conditions the castration-resistant is preferred. Androgen deprivation therapy‘s efficacy and its clinical trails: “A clinical trial is one of the final stages of a long and careful cancer research process.”(National Cancer Institute). Thus Clinical trails reveal the fact that analysis of tissues from men undergoing a short-term ADT were found to have the testosterone level and the dihydro testosterone levels reduced to nearly 70-80 percentage. Although very limited suppression of transcripts for androgen –regulated genes was observed. On the other hand in patients with castration-resistant prostate cancer the testosterone levels were high and it was equivalent to the untreated men. Thus the ADT can be considered as the therapeutic target for the metastasis prostate cancer. “Thus experimental and clinical evidences suggests that enzymes of tumoral steroid metabolism can support castration-resistant prostate cancer and might provide multiple new targets for therapeutic intervention.” (Harris et al. 2009). Moreover the side effects of the ADT can be categorized under sexual, Physical, metabolic and systemic after effects. Like any other treatment, the treatment for the metastasis prostate cancer definitely has multiple side effects which also cause depression and emotional liability among the patients. Fatigue, lack of energy, anemia, weight loss, genital shrinkage are some the after effects of ADT. Intermittent Androgen Suppression Therapy: “Intermittent androgen deprivation therapy (IADT) has been proposed as an alternative approach to not only minimizes long term side effects but also to delay development of the androgen independent state.” (Kabir 2008). Thus the Intermittent androgen suppression therapy is a kind of the Androgen deprivation therapy and it is considered to be the feasible alternative for the treatment of metastasis prostate cancer. The mechanism of Action of IADT: “The functional unit of the prostate is the glandular acinus that consists of both epithelial and stromal elements.” (Evens, Timothy and Bitran 1998). These epithelial components encompasses the secretory epithelial, basal epithelial cells, neuroendocrine cells also macrophages and lymphocytes. Thus the secretory epithelial cells are androgen-dependent and they have the androgen receptors on their surface. At the time of the withdrawal of the androgens, these cells involutes through the activation of a cell death phenomenon called as the apoptosis. This apoptotic regression in an androgen –dependent tumor can be induced by a procedure which reduces the intracellular concentration of the dihyrotestosterone in the prostate gland which extends more than eighty percentages. (Evens, Timothy and Bitran 1998). Thus the androgen levels of the DHT are reduced considerably within the prostate cells and thereby reducing the growth rate of the metastasis prostate cancer. But the concept underlying the progression and the proliferation of the prostate cancer, although with the occurrence of complete withdrawal of androgen relates to the clonal evolution of cells within the tumor that are mainly androgen – independent. Hence it is possible that in spite of the permanent androgen withdrawal or deprivation might even cause the growth of the androgen –independent cells and progress considerably. Thus the recent medical reports reveal the fact that transformation of the surviving clonogenic tumor cells called as the stem cells from an androgenic – dependent phenotype into an androgen – independent phenotype induces the cessation of the androgen- dependent cell growth in the prostate cancer. “Although effective in lowering the PSA levels and potentially improving prostate cancer control, ADT is associated with the significant side effects.”(Shore and Freeland 2009). The efficacy and clinical trails: The concept of the intermittent androgen suppression for the treatment of metastatic prostate cancer has only recently begun with its clinical trails. They found to decrease the toxicity and improve the quality of life when compared to the continuous treatment of the androgen deprived therapy. Also based on the additional preclinical models, the intermittent androgen suppression lead to an overall positive effect on the metastatic prostate cancer and a better survival. Thus for the concept of IAS to be implemented in the prostate cancer, there must be availability of the reversible agents for the androgen deprivation and also the tumor markers. Recently nineteen patients with the advanced or the metastasis prostate cancer were treated with the diethylstilbestrol (DES) which is an intermittent endocrine therapy schedule. (Evens, Timothy and Bitran 1998). Almost all the patients revealed a sign of relief from the toxicity of the prostate cancer. Another largest clinical experience, which involved 47 patients for testing the efficacy of IAS, were administered with the PSA which means the prostate specific antigen which was utilized as a marker just to monitor the disease progression and regression. (Buchan and Goldenberg 2011). According to that the combined androgen suppression consisting of cyproterone acetate and low doses of DES along with the antiandrogen was administered and continued for six months. (Buchan and Goldenberg 2011). The results indicated that with the usage of the intermittent androgen suppression therapy the quality of the life of the patients were improved considerably. Moreover the patients were able to regain their sexual activity considerably. (Buchan and Goldenberg 2011). Thus the overall clinical trail denotes the point that though during the initial stages of the IAS therapy the levels of the testosterone were high, but was reduced as the treatment progressed. Thus the above description briefly describes the effect of the hormonal treatments on the Metastasis prostate cancer. The forthcoming part of the paper will discuss on the exclusive drugs which are designed to treat the advanced or the Stage D prostate cancer. Abiraterone is the name of the drug which is used in the castration- resistant prostate cancer. This is the drug which is used in the prostate cancer in the advanced stage and which does not respond to the androgen deprivation treatments or with the antiandrogens. The U.S Food and Drug Administration had approved Zytiga (abiraterone acetate) in combination with the prednisone which is a steroid to treat the patients who are in the late stage of the prostate cancer. Thus this drug is produced mainly to have a control over the secretion of the testosterone and block the testosterone effects considerably. But in some cases even if the testosterone levels are low the cancer continues to grow and those types of cancers are called as the castration-resistant prostate cancer as discussed earlier. Thus zytiga (Commercial name of abiraterone) is a pill that targets the specific protein in the cells of the prostate tissues called as the cytochrome P450 17A1 (CYP 17A1). (Edlin 2012). This particular protein plays a vital role in the production of testosterone. This drug directly hinders the function of the cyctochrome P450 17A1 and thereby decreases the production of testosterone that would stimulate the cancer cells to continue growing. Zytiga’s safety and effectiveness were established in a clinical study of 1195 patients with the last-stage castration-resistant prostate cancer who had received prior treatment with the docetaxel chemotherapy. (Edlin 2012). Patients received the drug daily along with the steroid and they indicated the increase in the life span when compared to the patients who were not treated with the drug. “Patients who received Zytiga and prednisone combination had a median overall survival of 14.8 months compared to 10.9 months for the patients receiving the placebo and prednisone.”(FDA). Apart from the clinical trails the patients also reported some of the side effects with the intake of Zytiga, which included swelling in the joints accompanied with the discomfort, low levels of potassium in the blood, fluid retention in the legs and feet, hot flashes, diarrhea, cough, high blood pressure, urinary frequency and urinary tract infection, etc. Mechanism of Action of Abiraterone: “It could temporarily slow down the normal processes by which CYP 17 can convert the secondary androgens like the dehydroepiandrosterone(DHEA) which are made in the adrenal glands into testosterone and dihydrotestosterone.”(Prostate Cancer Info Link 2011). Thus the basic mechanism of action of the abiraterone is that it inhibits the CYP 17A1 which is an enzyme mainly prevalent in the testicular, adrenal and the prostratic tumor tissues. As the name implies the CYP17 catalyzes two major sequential reactions namely the following a) the conversion of the pregnenolone and progesterone to their 17-?-hydroxy derivatives. (Goldenberg 2011). The above conversion process is mainly assisted by its hydroxylase activity. And the other conversion would be the subsequent formation of the dehydroepiandrosterone (DHEA) and androstenedione products which are formed through its lyase activity. The dehydroepiandrosterone (DHEA) and androstenedione are androgens and they are the precursors of the testosterone which ultimately assist in the growth of the cancer cells in prostate. (Goldenberg 2011). Thus the drug inhibits the catalytic activities of the enzyme CYP17 and ultimately reducing the level of the circulating testosterone level. “It is within this context that some skepticism has agreed recent second-line hormone therapies, including the novel CYP17 inhibitor abiraterone or the novel androgen receptor inhibitor MDV3100.” (Tolcher and Cooper 2011). Also the Abiraterone should be administered with the low dose of gulcocorticoid namely the prednisone so as to suppress and keep the side effects under control. Incase if the drug is given to the patients without the prednisone, it may result in the build in the concentration of another hormone called as the adrenocorticotrophic hormone which also causes lethal effects in the body. Administration of abiraterone has caused in the positive clinical trails as discussed earlier. ”Abiraterone acetate, a prodrug has undergone phase I assessment, and is rapidly progressing from phase II to phase III trials, in the view of its high level antitumor activity.”(Reid et al. 2008). Maximum Androgen Blockage: “LHRH agonists reduce the testosterone to castrate levels by suppressing only androgens produced by testes.”(Perlmutter and Lepor 2007). Thus the impact of the adrenal androgens on the prostate cancer in the human body with LHRH agonist is highly controversial. The maximum androgen blockage had been achieved pharmacologically through the process of combining the LHRH agonist with an antiandrogen. Thus along with the androgen deprivation therapy the maximum androgen blockage can effectively increase the life span of the advanced prostate cancer patients. This means that the overall survival attributable to the maximum androgen blockage was increase approximately to seven to eight months respectively. Thus the effective mechanism of the Maximum androgen blockage can be clearly defined. Estrogen Therapy: “Estrogen regulates the development and function of prostate at several stages of a man’s life by indirect and direct mechanisms.”(Harkonem and Makela 2004). Thus the results on the estrogen stimulation of the prostatic proliferation, induction of prostatic dysplastic changes by neonatal estrogenisation or by a long period estrogen in combination with the androgen deprivation had caused in the decrease growth and inhibiting development of the advanced or the stage IV prostate cancer. Thus the role of the estrogens in the suppression of the proliferation of the cancer cells in prostate organ of the human body includes an array of activities. “Direct cytotoxicity to the prostatic epithelium, androgen inactivation, suppression of the anterior pituitary and the direct suppression of the Leydig cell function in the testis.”(Scherr and Pitts 2003). Thus the mechanism of action of the estrogens on the cancer cells would be through the primary steroidal effect through the negative feedback on the hypothalamus and anterior pituitary gland, and resulting in the down-regulation of the luteinizing hormone and thereby causing decrease in the level of the testosterone to castrate levels. The above mechanism is well known and it hinders the secretion of the testosterone. On the other hand the nonsteroidal nonhormonal mechanism is that the estrogens can increase the levels of the sex hormones binding globulin, increase pituitary prolactin production and thereby directly inhibiting the gonadal production of the testosterone. However a recent study reveals the fact that antiestrogens may effectively inhibit the development and the growth of the prostate cancer in human body. “Androgens decline in response to estrogen therapy. A decline in the DHEA and a rise in the DHT are both associated with the decline in PSA while patients receive estrogen therapy.”(Aggarwal et al. 2009). Thus with the detailed discussion about the alternate hormonal treatments for the metastasis prostate cancer and their mechanism of action along with the efficacy of clinical trails the paper will next focus on a brief note on Secondary hormone therapy. Secondary Hormone Therapy: Most of the patients who are in the advanced stage or the metastasis stage of the prostate cancer initially respond well to the Androgen deprivation therapy and the cancer cells can be completely washed out. But in some cases within two years or so the growth of the cancer cells can be seen again. This type of prostate cancer occurring again can be termed as the castrate resistant. As discussed above the castrate- resistant means the androgen deprivation therapy is no longer effective and they does not have any impact on the cancer cells. In such cases the secondary hormone therapy can be considered and the patients can be treated with the second-line hormone therapy which includes the treatments such as the orchiectomy, and complete blockage of the androgen. Also trying different types of antiandrogen can also be considered. Thus the cancer cells which are resistant to one antiandrogen treatment may not be resistant to another and hence different kinds of antiandrogen can be used for the patients who develop the prostate cancer even after treating them. Also as mentioned trying out the other medicines such as the steroids, estrogens and the antifungal medication Ketoconazole can bring about positive effects in controlling the androgen level and blocking the levels of the circulating testosterone. Thus the overall androgen activity should be blocked completely. Also stopping the antiandrogen in the patients who were already treated with the complete androgen blockage. Thus the above were some of the secondary level hormonal treatments for the advanced level prostate cancer. Conclusion: Cancer in general can be considered as one of the most dreadful diseases in the world for which proper completely curable medicines are yet to be structured by the physicians. Even though HIV is considered to be more dreadful than cancer, people affected by the HIV virus can prolong their life span by taking proper medication. But in the case of cancer if a person gets affected by the cancer cells it causes lethal effects within a short period of time. One of the reasons that cancer is horrifying is that most of the cancers cannot be detected at an early stage and people are devoid of occurrence of cancer. Though few types of cancers can be diagnosed at an early stage most of them are not curable and it ultimately leads to death. Some of the vital reasons that can be considered to enhance the occurrence of the cancers would be the life style of the people, age factor, diet habits and exposure to carcinogenic agents like radiation and other chemicals. Thus among the above citied reasons the food habits of the people and the exposure to the carcinogenic pollutants in the atmosphere can be considered as the highlighted ones. Hence in today’s world people are more towards sophistication and better life style and just to fulfill their luxury needs they exploit nature and the atmosphere. Thus atmosphere is getting polluted day by day with the carcinogenic pollutant which in turn affects the human beings causing dreadful diseases like cancer. To sum up, the future generation should be well aware of the negative effects caused by cancer and they should involve themselves in taking proper food habits and preserving mother nature so that to prevent the dreadful diseases like cancer and so on. References: Aggarwal, R, Weinberg, V, Small, EJ, Oh, W, Rushakoff, R and Ryan, CJ., 2009. The Mechanism of action of estrogen in castration-resistant prostate cancer: clues from hormone levels, Clinical Genitourin Cancer, vol. 7, no. 3, pp. 71- 76. Buchan, N and Goldenberg, SL., 2011. 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