Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Flutamide). A pale yellow, crystalline powder. Practically insoluble in water; freely soluble in alcohol and in acetone. Protect from light.

The United States Pharmacopeia 31, 2008 (Flutamide). A pale yellow, crystalline powder. Practically insoluble in water, in liquid paraffin, and in petroleum spirit; freely soluble in acetone, in ethyl acetate, and in methyl alcohol; soluble in chloroform and in ether. Store in airtight containers. Protect from light.

Adverse Effects and Precautions

The most frequently reported adverse effects with flutamide are hot flushes and reversible gynaecomastia or breast tenderness, sometimes accompanied by galactorrhoea. Nausea, vomiting, diarrhoea, increased appetite, anorexia, and sleep disturbances may occur. There have been reports of skin reactions, including epidermal necrolysis, and of liver damage, sometimes fatal. Other adverse effects reported in patients receiving flutamide include anaemias, haemolysis, headache, dizziness, malaise, blurred vision, anxiety, depression, decreased libido, impotence, and hypertension. Abdominal pain, chest pain, dyspnoea, and cough have been reported rarely. Discoloration of the urine to amber or yellow-green can be caused by the presence of flutamide and/or its metabolites.

Flutamide should be used with care in patients with cardiovascular disease because of the possibility of fluid retention. It should also be used with caution in patients with hepatic impairment and is contra-indicated in those with severe impairment. Regular liver function testing is recommended in all patients: therapy should be stopped or dosage reduced if there is evidence of hepatotoxicity.

Effects on the blood. A report of methaemoglobinaemia in an elderly man was attributed to flutamide. A study of 45 patients given flutamide found no cases of methaemoglobinaemia, but the authors noted a further 3 published case reports.

Effects on the liver. Hepatitis occurred in a 79-year-old man taking flutamide 750 mg daily as sole therapy after a prostatectomy, but a subsequent study in 1091 patients given flutamide 250 mg three times daily as part of a regimen for prostate cancer found marked signs of liver damage only in 4, of whom only 2 had clinical evidence of hepatotoxicity. In the USA, the FDA had 46 reports of patients with hepatotoxicity associated with flutamide up to December 1994. Of these patients, 20 died from progressive liver disease. Further cases have continued to be reported. Early tapering of the dose, stopping therapy, or switching to another anti-androgen may resolve hepatotoxic effects. Patients with chronic viral hepatitis may be at higher risk of developing hepatotoxicity with anti-androgen therapy.

Effects on the lungs. In a review of 78 cases of pneumonitis reported to the FDA between 1998 and 2000 that were associated with bicalutamide, flutamide, or nilutamide, it was found that 14 patients had died of respiratory failure. It was estimated that the incidence of pneumonitis was highest for nilutamide (0.77%), but lower for flutamide (0.04%) and brcalutamrde (0.01%).

Effects on the skin. Photosensitivity reactions have been reported in patients receiving flutamide. Some consider it to be an early manifestation of SLE.

Gynaecomastia. Gynaecomastia and breast pain are frequent adverse effects of nonsteroidal anti-androgens used to treat prostate cancer. Nearly 90% of patients treated with bicalutamide in the Early Prostate Cancer programme experienced breast pain, gynaecomastia, or both. Some patients who develop gynaecomastia will accept it as a tolerable adverse effect of therapy but others will require specifrc treatment, and a number of different measures have been tried for both prevention and treatment. The risk of breast changes can be reduced by the use of prophylactic low-dose irradiation of the breast area before nonsteroidal anti-androgen therapy is started. However, skin irritation can occur, and the long-term risk for development of breast cancer is unknown. Irradiation is unlikely to be effective once breast enlargement has occurred but it can help to reduce pain. Empirical use of oral analgesics or topical local anaesthetics may be considered for breast pain. Specifrc surgical treatment to reduce breast tissue includes liposuction and breast tissue excision.

Hormonal therapy using tamoxifen or anastrozole has been suggested, largely based on reports of benefit in various patient groups with gynaecomastia. Two randomised controlled studies of men who were treated with bicalutamide for prostate cancer found that prophylactic tamoxifen was effective for the prevention of gynaecomastia and breast pain, but that anastrozole was no better than placebo. One of these studies also assessed the use of these drugs as treatment and found that gynaecomastia and breast pain resolved in at least 65% of patients treated with tamoxifen, but only in about 18% of those treated with anastrozole. Tamoxifen is considered to be more effective than radiotherapy for prevention of gynaecomastia.

Interactions

Flutamide may increase the effect of warfarin, see Antineoplastics.

Pharmacokinetics

Flutamide is reported to be rapidly and completely absorbed from the gastrointestinal tract with peak plasma concentrations occurring 1 hour after a dose. It is rapidly and extensively metabolised; the major metabolite (2-hydroxyflutamide) possesses anti-androgenic properties. The half-life of the metabolite is about 6 hours. Both flutamide and 2-hydroxyflutamide are more than 90% bound to plasma proteins. Excretion is mainly in the urine with only minor amounts appearing in the faeces.

Uses and Administration

Flutamide is a nonsteroidal compound with anti-androgenic properties which appears to act by inhibiting the uptake and/or binding of androgens in target tissues. It is used, usually with gonadorelin analogues, in the palliative treatment of prostatic carcinoma. The usual oral dose is 250 mg three times daily. When used in combination therapy UK licensed product information recommends that flutamide treatment should be started at least 3 days before the gonadorelin analogue to suppress any ‘flare’ reaction; however, in some other countries it is recommended that treatment with both agents be begun simultaneously for optimum effect.

Congenital adrenal hyperplasia. For mention of the use of flutamide with testolactone to block androgenic effects in congenital adrenal hyperplasia.

Hirsutism. Anti-androgens (usually cyproterone or spironolac-tone) are widely used for the drug treatment of hirsutism. Flutamide has no particular advantage in this context; one study has found flutamide to be more effective than spironolactone in inhibiting hirsutism, but others found them to be of similar efficacy, and the risk of hepatotoxicity with flutamide is a problem. Nonetheless, flutamide has continued to be investigated.

Malignant neoplasms. Androgen blockade, which may include the use of flutamide, is used in the management of meta-static hormone-responsive prostate cancer; once the cancer begins to progress despite such therapy, stopping flutamide occasionally produces paradoxical disease regression. Promising preliminary results have also followed the use of flutamide in patients with adenocarcinoma of the pancreas.

Polycystic ovary syndrome. Flutamide has been used, usually with metformin, in the management of polycystic ovary syndrome; additive effects have been reported with this combination.

Preparations

The United States Pharmacopeia 31, 2008: Flutamide Capsules.

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed

Argentina: Asoflut; Dedile; Eulexin¤; Flutaplex; Flutax¤; Flutepan; Flutrax; FTDA¤; Olter¤; Australia: Eulexin; Flutamin; Fugerel; Austria: Afluta; Androbloc; Flutabene; Flutahexal; Flutastad; Fugerel; Belgium: Eulexin; Flutaplex¤; Brazil: Biomida; Eulexin; Tecnoflut; Teflut; Canada: Euflex; Chile: Androdor¤; Drogenil; Etaconil; Flulem; Czech Republic: Andraxan; Flucinom; Flutacan; Prostandril; Xadaren; Denmark: Eulexin; Fluprosin; Flutacan¤; Flutaplex¤; Profamid; Finland: Eulexin; Profamid; France: Eulexine; Prostadirex; Germany: Apimid; Flumid; Fluta; Flutamex¤; Flutexin; Fugerel; Prostica; Prostogenat¤; Testac¤; Testotard; Greece: Adiprost; Elbat; Flucinom; Flutaplex; Palistop; Prostamide; Tremexal; Hong Kong: Flutan¤; Fugerel; Hungary: Cytamid; Flutam; Fugerel; India: Cytomid; Prostamid; Ireland: Androstat; Drogenil; Israel: Eulexin; Italy: Drogenil; Eulexin; Fluprost; Virflutam¤; Malaysia: Flutan; Flutaplex; Fugerel¤; Mexico: Eulexin; Fluken; Flulem; Tafenil; Netherlands: Drogenil; Eulexin; Norway: Eulexin; New Zealand: Eulexin; Flutamin; Flutol¤; Portugal: Draxon¤; Eulexin; Russia: Flutamid (Флутамид); Flutaplex (Флутаплекс); South Africa: Eulexin; Flutahexal; Flutaplex; Singapore: Fugerel¤; Spain: Eulexin; Flutandrona; Flutaplex; Grisetin; Oncosal; Prostacur; Sweden: Eulexin; Flutacan¤; Switzerland: Flucinome; Thailand: Flutan; Fugerel; United Kingdom: Chimax; Drogenil; United States: Eulexin¤; Venezuela: Eulexin

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In China, Europe, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Aminoglutethimide). A white or slightly yellow, crystalline powder. Practically insoluble in water; freely soluble in acetone; soluble in methyl alcohol.

The United States Pharmacopeia 31, 2008 (Aminoglutethimide). A white or creamy-white, fine, crystalline powder. Very slightly soluble in water; readily soluble in most organic solvents. It forms water-soluble salts with strong acids. The pH of a 0.1% solution in dilute methyl alcohol (1 in 20) is between 6.2 and 7.3.

Adverse Effects

The most frequent adverse effects reported with aminoglutethimide include drowsiness, lethargy, and skin rashes (sometimes with fever); these generally diminish after the first 6 weeks of therapy. Dizziness and nausea occasionally occur. Leucopenia, thrombocytopenia, agranulocytosis, or severe pancytopenia have occurred rarely. Adrenal insufficiency may rarely occur, and there have been reports of other endocrine disturbances including hypothyroidism, and virilisation. Other rare effects include ataxia, headache, depression, gastrointestinal disturbances, hy-percholesterolaemia, and orthostatic hypotension. Overdosage may lead to CNS depression and impairment of consciousness, electrolyte disturbances, and respiratory depression.

Effects on the liver. Aminoglutethimide has been associated with reports of cholestatic jaundice, accompanied by rash and fever, and probably due to an idiosyncratic hypersensitivity reaction. It has been suggested that liver function tests should be carried out in patients receiving aminoglutethimide who develop fever and eruptions.

Effects on the lungs. Pulmonary infiltrates in a patient who developed progressive dyspnoea on starting therapy with aminoglutethimide were found to be due to diffuse alveolar damage and haemorrhage; thrombocytopenia was present but prothrombin and bleeding times were normal. The patient’s gas exchange and chest radiographs improved on stopping aminoglutethimide and giving corticosteroids. Blood and pulmonary eosinophilia, which resolved on stopping aminoglutethimide therapy, has also been reported.

Lupus. SLE occurred in a patient who received aminoglutethimide, and resolved when the drug was withdrawn. In another report, however, a patient with a lupus-like syndrome had a reduction in disease activity when tamoxifen therapy was changed to aminoglutethimide.

Precautions

Aminoglutethimide inhibits adrenal steroid production so supplementary glucocorticoid therapy with hydro cortisone must normally be given, although supplementation may not be necessary in patients with Cushing’s syndrome. Some patients also require a mineralocorticoid. It has been suggested that aminoglutethimide should be temporarily withdrawn in patients who undergo shock or trauma, or develop intercurrent infection. Blood pressure, blood counts, and serum electrolytes should be regularly monitored during aminoglutethimide therapy and periodic monitoring of liver and thyroid function is recommended. Aminoglutethimide should not be given during pregnancy as pseudohermaphroditism may occur in the fetus.

Aminoglutethimide frequently causes drowsiness: patients so affected should not drive or operate machinery.

Porphyria. Aminoglutethimide has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Interactions

The rate of metabolism of some drugs is increased by aminoglutethimide; patients also taking warfarin or other coumarin anticoagulants, theophylline, tamoxifen, medroxyprogesterone, or oral hypoglycaemics, may require increased dosages of these drugs. The metabolism of dexamethasone is also accelerated, which limits its value for corticosteroid supplementation in patients receiving aminoglutethimide. Use with diuretics may lead to hyponatraemia, while alcohol may potentiate the central effects of aminoglutethimide.

Pharmacokinetics

Aminoglutethimide is well absorbed after oral doses, with peak plasma concentrations occurring after 1 to 4 hours. It is metabolised in the liver, primarily to N-hydroxylaminoglutethimide and N-acetylaminoglutethimide, and appears to induce its own metabolism. The half-life, which is reported to be about 13 hours after a single dose, is decreased to around 9 hours after about 2 weeks of continuous therapy. Aminoglutethimide is excreted in urine, about half a dose being excreted unchanged and the remainder as metabolites. Only about 20 to 25% of a dose is bound to plasma protein.

Half-life. A study in 17 patients showed that the plasma half-life of aminoglutethimide had a mean value of 15.5 hours after single doses but fell to 8.9 hours during multiple-dose therapy. This marked reduction could largely be attributed to a decrease in the volume of distribution; auto-induction of metabolism might be of less importance in decreasing half-life than had been previously suggested.

Uses and Administration

Aminoglutethimide is an analogue of glutethimide and was formerly used for its weak anticonvulsant properties. Aminoglutethimide blocks the production of adrenal steroids and acts as an aromatase inhibitor to block the conversion of androgens to oestrogens (the major source of oestrogens in women without ovarian function). It was used in the treatment of meta-static breast cancer in postmenopausal or oophorect-omised women and as palliative treatment in men with advanced prostatic cancer.

Aminoglutethimide has also been used in the treatment of Cushing’s syndrome. Usual oral doses range from 1 to 2 g daily, in divided doses.

The dextroisomer of aminoglutethimide, dexaminoglutethimide has been investigated.

Preparations

British Pharmacopoeia 2008: Aminoglutethimide Tablets

The United States Pharmacopeia 31, 2008: Aminoglutethimide Tablets

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed

Argentina: Orimeten¤; Australia: Cytadren; Austria: Orimeten¤; Belgium: Orimeten¤; Brazil: Orimeten¤; Canada: Cytadren¤; Chile: Orimeten¤; Czech Republic: Orimeten¤; France: Orimetene¤; Germany: Orimeten¤; Rodazol¤; Hong Kong: Orimetene; Ireland: Orimeten¤; Israel: Orimetene¤; Italy: Orimeten¤; Malaysia: Orimetene¤; Netherlands: Orimeten¤; Norway: Orimeten¤; New Zealand: Cytadren¤; Russia: Mamomit (Мамомит); Orimeten (Ориметен)¤; South Africa: Aminoblastin¤; Orimeten¤; Spain: Orimeten¤; Sweden: Orimeten¤; Switzerland: Orimetene¤; United Kingdom: Orimeten¤; United States: Cytadren

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Nilutamide). A white or almost white powder. Very slightly soluble in water; freely soluble in acetone; soluble in anhydrous ethanol. Protect from light.

Adverse Effects and Precautions

As for Flutamide. Interstitial pneumonitis has occurred in patients receiving nilutamide, and the drug is contra-indicated in those with severe respiratory insufficiency.

Effects on the eyes. Reversible visual disturbances, particularly delayed dark adaptation, have been associated with nilutamide. Although some consider such visual disturbances to be mild and generally well tolerated, others suggest that these, together with alcohol intolerance and, more seriously, effects on the lung, mean that other nonsteroidal anti-androgens should be preferred.

Interactions

Patients receiving nilutamide may exhibit intolerance to alcohol.

Pharmacokinetics

Nilutamide is rapidly and completely absorbed from the gastrointestinal tract. It is extensively metabolised although it may inhibit its own metabolism to some extent after multiple doses. About 60% of an oral dose of nilutamide is eliminated in the urine and less than 10% in the faeces, with an elimination half-life of 41 to 49 hours.

Uses and Administration

Nilutamide is a nonsteroidal anti-androgen that is used similarly to flutamide in the treatment of prostatic carcinoma. It is given orally in a dose of 300 mg daily, usually starting on the same day that the patient undergoes orchidectomy or receives treatment with a gonadorelin analogue. Dosage may be reduced to 150 mg daily after 1 month.

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed

Argentina: Anandron; Australia: Anandron; Brazil: Anandron; Canada: Anandron; Czech Republic: Anandron; Denmark: Anandron¤; Finland: Anandron¤; France: Anandron; Greece: Anandron; Hungary: Anandron; Mexico: Anandron; Netherlands: Anandron; Norway: Anandron¤; Portugal: Anandron; Sweden: Anandron; United States: Nilandron

The four most common types of lesions associated with the prostate are acute/chronic prostatitis (bacterial/abacterial), proliferative inflammatory atrophy (PIA), benign prostatic hyperplasia (BPH), and prostate carcinoma. The types of proliferative lesions that occur in the prostate are in different regions of the prostate. Most hyperplasias are prevalent in the transitional and periurethral zones, whereas carcinomas are found mostly in the peripheral zone.

PIA, a newly recognized prostate lesion, is hypothesized to be a precursor to prostatic intraepithelial neoplasia (PIN) and to prostate cancer. Proliferative inflammatory atrophy lesions, which contain proliferating epithelial cells that fail to fully differentiate into columnar secretory cells, are typically present in the peripheral zone of the prostate, where prostate cancers arise, and are often directly juxtaposed to PIN and/or prostate cancers. PIA may link inflammation with prostatic carcinogenesis.

Inflammation

Virtually 100% of prostate specimens contain histological and immunological evidence of chronic inflammation. Inflammation is a physiological response to a variety of stimuli such as infection, tissue injury, growth factors, or chemokines. The distribution, location and histology of leukocytes determine the type of inflammation. Persistent immune activation resulting in chronic inflammation often has pathological consequences. Acute/chronic inflammation is characterized by distinct cellular changes whereas precancerous lesions are associated with the change in the balance in the angiogenic and apoptotic cell cycle process.

During the inflammation process, activated macrophages release various hydrolytic enzymes and reactive oxygen and nitrogen species that may contribute to tissue damage. Chemokines, plasma enzyme mediators (bradykinen, fibrinopeptidases), opsonins, leukotrienes, and prostaglandins are all mediators that have some role in the inflammatory process. The normal prostate is populated by αβ T-cells, B-cells and macrophages, with the T-cells being evenly distributed throughout the interstitium and between the epithelial cells. There is some indication that the number of T-cells increases with age, which correlates with the incidence of prostate inflammation during the aging process.

The proliferation and differentiation of prostate tissue are modulated by growth factors as well as hormonal androgen therapy Evidence of hormonal impact on the prostate is seen in atrophy of the prostate following castration, as well as treatment of BPH samples with a 5a-reductase inhibitor. When this inhibitor is given to patients, there is a regression of dihydrotestosterone (DHT) levels and a reduction in prostate volume.

Recent data suggests that mutations in RNase L predispose men to an increased incidence of prostate cancer, which in some cases reflect more aggressive disease and/or decreased age of onset compared with non-RNase L linked cases. It is proposed that RNase L functions in counteracting prostate cancer by virtue of its ability to degrade RNA, thus initiating a cellular stress response that leads to apoptosis. RNase L is a uniquely regulated endoribonuclease that requires 5′-triphosphorylated, 2′, 5′-linked oligoadenylates (2-5A) for its activity. The presence of both germline mutations in RNase L segregating with disease within HPC-affected families, and loss of heterozygosity (LOH) in tumor tissues suggest a novel role in the pathogenesis of prostate cancer. The association of mutations in RNase L with prostate cancer cases further suggests a relationship between innate immunity and tumor suppression.

Microbial activators may contribute to acute/chronic inflammatory processes, which could then lead to malignancy Differentiating between acute/chronic bacterial prostatitis and chronic abacterial prostatitis is done by quantification of bacterial cultures and microscopic examination of urine. Depending on the severity and duration of the inflammation, acute bacterial prostatitis displays histological evidence of stromal leukocytic infiltration accompanied by increased elaboration of prostatic secretion or leukocytic infiltration within the glandular spaces.

In contrast, bacterial/abacterial chronic prostatitis shows histological evidence of aggregation of numerous lymphocytes, plasma cells, macrophages, and neutrophils within the prostatic substance. Chemokines act as chemoattractants, which activate lymphocytes and other immune modulators into neighboring tissues via extravasation. Since antibodies penetrate the prostate with poor efficiency, this type of inflammation is difficult to treat. The normal aging process in the prostate results in aggregations of lymphocytes, which are prone to appear in the fibromuscular stroma of the gland. Frequently, this histology of the aging prostate is diagnosed as chronic prostatitis even though the macrophages and neutrophils are absent.

Stromal-epithelial interactions are crucial for normal growth and homeostasis within the prostate. These interactions are thought to influence the rate of development of benign prostatic hyperplasia and prostate carcinoma. BPH is characterized by diffuse infiltrates of activated T-lymphocytes in fibroblastic, fibromuscular, and stromal nodules. Histological evidence of nodular hyperplasia or BPH is present in 20% of men 40 years of age, 70% by age 60, and 90% in men 70 years of age. The usual benign prostatic hyperplasia nodule weighs between 60-100 grams with some nodules weighing over 200 grams. Studies indicate that BPH samples also display chronic mononuclear inflammation, which contain CD3+ T-lymphocytes and express the T-cell receptor. The epithelial cells associated with the inflammatory infiltrate were observed in the periglandular stroma and were almost exclusively activated T-cells expressing CD45RO, and producing IL-2 and IFNΎ. Expression of IFN-Ύ, IL-2, and IL-4 mRNA in benign prostatic hyperplasia suggests that the disease is associated with Th1 and Th2 response.

The Immune System

The goal for cancer immunotherapy is to induce antibody and/or T-lymphocyte immune response targeted to the cancer cells. There are several branches of the immune system that can be targets for immunotherapy. They include antibody producing B-cells, CD8+ cytotoxic T-cells, CD4+ T-helper cells, natural killer (NK) cells, natural killer T (NKT)-cells, and monocytes. B-cells produce antibodies that kill antigen presenting cells via complement, antibody dependent cellular cytotoxicity (ADCC), or apoptosis. Cell mediated response appears to play a major role in a tumor immune response. Many tumors induce a specific cytotoxic T-cell response that recognizes antigens presented by MHC-I, which can elicit a higher response.

NKT-cells share several features with NK cells, such as CD 161 and CD 122 expression. These cells display intermediate levels of T-cell receptor (TCR) and are CD4+ or CD4-/CD8-. NKT-cells produce IL-4, a pro-inflammatory cytokine, in response to engagement of the T-cell receptor. In the presence of IL-18 and IL-12, NKT-cells will produce IFN-Ύ and kill target cells in a Fas ligand (FasL) dependent manner without engagement of the TCR.

NK as well as NKT-cells recognize tumor cells through cell-cell contact and mediate killing with Fas/FasL or with the induction of cytokines or lytic enzymes. NK cells recognize target cells based on expression of activating or inhibitory receptors. Since NK cells do not recognize target cells based on MHC expression, a decrease in MHC expression does not limit their activity. Also, some Fc receptors on NK cells can bind to antibody coated tumor cells leading to ADCC.

Naїve T-cells require more than one signal for activation and subsequent proliferation into an effector cell. This activation is triggered by recognition of MHC-peptide complex and a co-stimulatory signal. Frequently, tumor cells give little or no co-stimulatory signals that can inhibit the activation of cytotoxic T-cells. The co-stimulatory signal occurs by interaction of B7 on antigen presenting cells and CD28 on the T-cells. CTLA-4 and CD28 are T-surface antigens, which bind to B7-1 or B7-2 ligands on antigen presenting cells to activate a T-cell response and control proliferation. CD28 is expressed on resting and active cells while CTLA-4 is virtually undetectable on resting cells. Their ligands, B7-1 and B7-2, are two related forms of immunoglobulin superfamily members with similar extracellular domains but with different cytosolic domains. These ligands are constitutively expressed on dendritic cells and can be induced on macrophage and B-cells. Signaling through CD28 produces a positive co-stimulatory signal and increases CTLA-4 levels on the T-cells. Although CTLA-4 and CD28 are structurally similar, they act antagonistically. Surface levels of CTLA-4 are lower than CD28, but it competes favorably for B7 binding sites due to its high avidity.

Targets of Immunotherapy

The complexity of the immune system presents many legitimate targets for the induction of an immune response. One aspect of the innate immune system present throughout the body, including the prostate epithelium and stroma, is the presence of toll-like receptors (TLR). TLRs are capable of recognizing foreign antigens and act as molecules with pattern recognition capabilities and may be soluble or cell-associated receptors. Pattern recognition receptors (PRR) are extracellular or present on cell membranes and target microbes or components in tissue fluids and blood. Typically, signals transduced through a TLR result in transcriptional activation, synthesis, and secretion of cytokines. This signaling process results in the activation of antigen presenting cells, all of which are involved in or promote inflammation. For instance, TLR-5 mRNA is found in the prostate, testis, ovaries, and leukocytes. TLR-5 interacts with microbial lipoproteins leading to nuclear factor-kappa B (NF-kB) activation, cytokine secretion, and inflammation. Other TLR activation induces secretion of cytokines, such as IFN-Ύ, MAPK pathways, or acts as a target for CpG islands (found in bacterial DNA) or double stranded (ds)RNA.

Cytokines

A second potential target for immunotherapy lies in the world of cytokines. Cytokines are low molecular weight regulatory proteins or glycoproteins that regulate the immune response, hematopoiesis, control of cellular proliferation and differentiation, and are involved in wound healing. Cytokines share many properties with hormones and growth factors in that they are secreted soluble factors that elicit biological effects. As cytokines are discovered, many can be grouped into families based on protein structural homology. Several examples of cytokine families are: interferons, tumor necrosis factors, and interleukins. These molecules are redundant and have overlapping functions. Once a cytokine encounters the appropriate receptor, it acts in an antigen non-specific manner and can induce a series of protein tyrosine phosphorylations. The two main cell types responsible for cytokine secretion are the T-helper cell and macrophage.

Interferons are one of the major groups of cytokines that have been used for clinical cancer studies. IFN-α is produced by macrophages and increases MHC-I expression, activates NK cells, induces an anti-viral state, and inhibits cell division of normal or malignant transformed cells in vitro. IFN-β, produced by fibroblasts, increases MHC-I expression and activates NK cells. IFN-Ύ is produced by CD8+ T-cells and NK cells and activates macrophages, increasing both MHC-I and MHC-II expression when foreign antigen is present. Data suggest that malignant tumors display a decrease in MHC-I expression and that the interferons may be responsible for restoring MHC-I expression, thereby increasing cytotoxic T-cell activity towards the tumor. Daily injections of recombinant INF-α have been shown to induce partial or complete regression in hematological cancers (i.e. leukemia and lymphoma), as well as some solid tumors (i.e. breast and renal cancer).

Tumor necrosis factors TNF-α and TNF-(3 have been shown to display anti-tumor activity by direct killing of the tumor cells, reducing proliferation rate (while sparing the normal cells), and inhibiting angiogenesis by damaging vascular endothelial cells. Frequently, when treated with either factor, the tumor undergoes hemorrhagic necrosis and regression. Macrophages, monocytes, and other cell types including fibroblasts and T-cells secrete TNF-α. However, TNF-β is only produced by activated T-cells and B-cells and is a mediator of immune function and involved in wound healing. Both INF-Ύ and TNF-α are associated with chronic inflammation. The complexity of cytokines and how they may potentially interact with each other has been one major obstacle of this type of therapy. Many cytokines have short half-lives and depending on the circumstances can act as either a pro-inflammatory or anti-inflammatory agent (i.e. IL-7, IL-9). Systemic administration of a large amount of cytokines has led to serious consequences and has even been fatal, therefore these immunotherapies can be limiting.

Growth Factors

Many tumors display high levels of growth factor receptors on their membranes making growth factor receptors a likely target for immunotherapy Inappropriate expression of either a growth factor or its receptor can result in uncontrolled proliferation. Vascular endothelial growth factor (VEGF) is a potent mitogen for cells and is one of the most well studied growth factors. VEGF mRNA expression is seen in breast cancer and is associated with poor prognosis of colon cancer and non-small cell lung carcinoma. VEGF can be activated by ras oncogene causing inactivation of p53 and Von Hippel Landau (VHL), as well as cause activation of PKC. VEGF is expressed in the epithelial and stromal areas of the human prostate, however, hyperplastic glands stain very poorly for the growth factor. Several studies have shown that prostate cancer specimens display 32% staining in the stroma and 56% staining in the epithelium. In contrast, staining for VEGF in benign prostatic hyperplasia displayed 73% staining of the stroma and 50% staining in the epithelium. Of note is the use of the 5α-reductase inhibitor, Finasteride®, which has been shown to decrease expression of VEGF in prostatic tissue.

Tumor Antigens

Tumor specific antigens may result from mutations that cause altered cellular proteins or may be normally expressed at certain stages of differentiation encoded by a variant form of the normal gene or may be exclusively expressed by the tumor. Tumor associated glycoprotein-72 (TAG-72) is a mucin found on many adenocarcinomas including colorectal, pancreatic, gastric, ovarian, endometrial, and mammary, as well as some prostate cancers.

Tumor antigens, while being specific for tumor tissue, can vary widely from tumor to tumor. The use of tissue specific antigens is usually undesirable, as normal tissue would also be targeted with the tumor. The case of prostate cancer is unique in that the prostate is not a vital organ and could be targeted without serious harm to the patient. This allows for the targeting of tissue specific antigens in the prostate. Several prostate specific antigens have been discovered and are targets of immunotherapy These tissue specific antigens include prostate-specific antigen, prostate alkaline phosphatase (PAP) and prostate specific membrane antigen (PSMA). Although these self-proteins are not always immunogenic they do provide a basis for further development and testing.

Monoclonal Antibody Therapy

Antigenic modulation in the treatment of many diverse cancers has been used for a number of years. In fact, the Food and Drug Administration has approved several monoclonal antibodies for treatment of various cancers and non-malignant diseases. Ideally, by treating tumor cells with an antibody, one would hope for complete destruction of the tumor without recurrences. However, tumors seem to regenerate once the antibody treatment has ceased. Passive administration of antibodies or active vaccination to induce antibodies can target cells that express antigenic proteins on their cell membranes. Monoclonal antibodies are often conjugated to chemotherapeutic agents, biological toxins, radioactive compounds, or immunotoxins. These immunoconju-gates target the neoplastic cells expressing tumor specific or tumor-associated markers. Problems with antibody specificity, delivery, and cost are often hurdles for therapy. Unlike antibodies to Her2-neu for breast cancer or antibodies to CD20 for non-Hodgkin’s lymphoma, there are limiting numbers of antibody targets for the treatment of prostate cancer.

CC49, a murine lgG1 antibody, recognizes TAG-72 and shows disease response when coupled to a radioisotope in ovarian cancer and has been shown to be expressed in prostate cancer cells. A clinical trial utilizing I-CC49 failed to show any clinically relevant data. However, when I-CC49 was used in conjunction with INF-Ύ, up-regulation of TAG-72 and enhancement of the response was seen. The trial included 16 patients with androgen independent prostate cancer (AIPC), of which 12 patients had antibody localization to the tumor. None of the patients had a >50% decline in their PSA or a radiologic response, however several had moderate pain relief from bone metastases. Rapid production of anti-mouse antibodies and development of thrombocytopenia precluded further dosing. In a subsequent clinical study, 14 patients were treated with IFN-α prior to the administration of I-CC49. Two patients had a minor radiographic response while 3 had a ≥50% reduction of their serum PSA levels. Therefore, IFN-α may be acting as an adjuvant yielding a greater response in comparison to just I-CC49 therapy.

Since prostate-specific antigen is found in the serum, many researchers have used the antigen for a potential target for immunotherapy In vitro data show that the generation of antibodies that recognize PSA and CD3 on T-cells would direct non-specific CD3+ T-cells to PSA, and in turn, this would re-direct preactivated peripheral mononuclear cells to lyse PSA expressing cells. Although demonstrated in vivo, a human trial is necessary. Since PSA is in the serum, directing antibodies to the prostate tissue would be difficult.

Prostate specific membrane antigen is an ideal target for monoclonal antibody therapy since the target cell is always internalizing the protein and its internalization is augmented by monoclonal antibody contact and is strongly expressed on nearly 100% of prostate tumors. Prostacint® (7E11 from Cytogen) is an anti-PSMA antibody used to image the prostate. Prostacint® has been found to bind an intracellular epitope of prostate specific membrane antigen and, therefore, likely binds areas of tumor necrosis. Second-generation anti-PSMA antibodies have been developed to target the extracellular domain of PSMA due to the fact that internal domain binding antibodies, such as 7E11 and PM2J0004.5 (Hybritech) do not bind viable cells.

Most antibody therapies to prostate specific membrane antigen have used J591, a mouse monoclonal antibody that is immunogenic. J591 has been genetically modified to eliminate the mouse antigens and is now fully “humanized,” allowing repeated dosing without generating anti-mouse antibodies. The unmodified antibody could focus the immune system on tumor sites to complement activation, however, dramatic responses to naked antibodies are infrequent. J591 binding to PSMA is rapidly internalized into the cell and has been quite useful for imaging of known sites of metastasis.

Antibodies to the extracellular domain of prostate specific membrane antigen and coupled to toxins or radioisotopes have been shown to have some effect in prostate cancer cell lines and murine models. In one study, J591, PEQ226.5, and PM2P079.1 were conjugated with ricin A chain (RTA), a holotoxin containing an α subunit that inactivates protein synthesis and facilitates intra-cellular trafficking of RTA. Since J591 and PEQ226.5 recognize the same epitopes that are related to PSMA, a lower cytotoxic effect was observed of the antibodies in cell mono layers in comparison to treatment with RTA alone, while the specificity of prostate specific membrane antigen expression of the tumors was increased.

A study performed by Dr. Bander and colleagues at the College of Medicine of Cornell University enrolled 53 patients into a phase-I study to assess disease staging, metastatic or recurrent disease. Twenty-nine patients received ¹¹¹In/⁹⁰Y-DOTA-J591 while 24 patients received ¹⁷⁷LU/DOTA-J591. The results indicated 98% of the patients had successful targeting of J591 to the bone and soft tissue with 87% having radiographic evidence of metastasis and 13% had zero visible lesions. Remarkably, 16 of 18 patients with no evidence of metastasis showed positive J591 staining. Other biotechnology companies have developed external domain specific anti-PSMA antibodies using mice genetically engineered to express human antibodies, resulting in the development of monoclonal antibodies that are non-immunogenic. These anti-PSMA antibodies have demonstrated significant activity in clinical trials.

Modulation of T-Cells

Modulation of the co-stimulatory signals required for T-cell activation has been shown to be an effective therapy through blocking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) with antibodies and prolonging a T-cell response. Anti-CTLA-4 blocks B7 binding to CD28, preventing stimulation and decreasing expression of T-cells. Anti-CTLA-4 antibody treatment in animal models can induce tumor rejection in immunogenic tumors. Coupled with an anti-tumor vaccination, it can induce rejection of minimally immunogenic tumors in the TRAMP animal model. In a study of CTLA-4 blockade administered immediately after primary tumor resection, a reduction of metastatic relapse from 97.4% to 44% was observed. Consistent with this, lymph nodes obtained 2 weeks after treatment reveal marked destruction or complete elimination of C2 metastases in 60% of mice receiving adjunctive anti-CTLA-4 whereas 100% of control antibody-treated mice demonstrated progressive C2 lymph node replacement.

Adjuvants are often used with various immunotherapies because they can increase B7 co-stimulation and activate macrophages. Activated macrophages can then cluster around tumors and are better T-helper activators. These increase both humoral and cell-mediated responses and correlate with tumor regression. The Fc portion of human IgG has been fused to the B7 binding domain of CTLA-4 to produce a chimeric molecule, CTLA-Ig. The human Fc portion gives the molecule a longer half-life and the B7 binding domain allows binding to CD28. A humanized antibody for CTLA-4, designated MDX-101 (Medarex, Inc.) has recently been tested in a Phase-I trial, which included 14 patients with AIPC. The study showed successful blocking of the co-stimulatory signaling with no T-cell activation occurring. The therapy was well tolerated and 2 patients had a >50% decline in prostate-specific antigen levels.

Vaccines

Tumor vaccines cause induction of a cell-mediated response to antigens and are often composed of tumor-associated proteins mixed with a nonspecific antigen. Demonstrating that antigen specific T-cells are up-regulated by a particular vaccine strategy is important for immunologic therapies. Antigen presentation is critical for any immunization technique and its enhancement can modulate tumor immunity. Anti-tumor vaccines that activate cytotoxic lymphocytes (CTLs) and human tumor infiltrating lymphocytes (HTLs) would be most desirable since HTLs induce CTLs. Human tumor infiltrating lymphocytes produce both IFN-Ύ and granulocyte macrophage colony stimulating factor (GM-CSF) and kill tumor cells. Therefore, vaccines that induce anti-tumor CTLs include MHC-II restricted epitopes, which would trigger a HTL response to tumor-associated antigens. A method of activating these T-cells may be to use the antigen presenting dendritic cells to initiate the immune response.

Dendritic cells are the most potent antigen-presenting cells, capable of presenting antigen to CD8+ (MHC-I restricted) and CD4+ (MHC-II restricted) T-cells. Dendritic cell-based vaccines use a patient’s bone marrow derived antigen presenting cells that are able to sensitize naive T-cells to new antigens. By combining dendritic cells with tumor antigens, the therapy supposes that the dendritic cells will then activate T-cells with tumor antigen.

Mouse dendritic cells, pulsed with tumor fragments and incubated with GM-CSF, were re-infused into the mice to activate the TH and CTL response to the tumor antigen. Mouse tumor cells are immunogenic, therefore animals injected with killed tumor cells do not grow tumors when challenged with live tissue, a term designated protective immunity. The same is true for humans. When tumor cells were transfected with GM-CSF and given back to the patient, they were able to secrete more GM-CSF and enhance the differentiation and activation of the host antigen presenting cells. As the dendritic cells surround the tumor cells, GM-CSF is secreted by the tumor and enhances presentation of antigen to the TH and CTL cells.

Denedron Corporation has developed Provenge®, a recombinant fusion protein with GM-CSF fused to prostate acid phosphatase (PAP), a prostate specific isozyme of acid phosphatase that is secreted by prostate cells. This strategy uses autologous dendritic cells combined with human GM-CSF. Thirty-one patients with prostate cancer were enrolled in the clinical study and received three monthly infusions and one final boost at 24 months if the disease had not progressed. Results showed 38% of the patients had a T-cell response against native prostate acid phosphatase while some had a decline in their PSA levels. T-cells collected after the treatment revealed the presence of IFN-Ύ, a reflection of successful activation.

The use of prostate acid phosphatase as a vaccine has also been studied, since serum prostate alkaline phosphatase levels increase with prostate cancer progression, from 33% up to 92%, making it a more important marker for advanced disease. One study used a xenogenic homologue of PAP (mPAP), which was given to patients with metastatic prostate cancer. The homologous mPAP possessed sufficient differences from self-antigen to render it immunogenic, but similar enough that they would cross-react with human prostate acid phosphatase. Seven out of 21 patients had stable disease following the vaccination beyond one year while three patients had stable disease beyond three years. All of the patients had T-cell immunity to mPAP and 11 out of 21 had induced immunity to human prostate acid phosphatase.

A PAP peptide (termed PAP-5) capable of binding the HLA-A2 molecule was used to pulse an antigen presenting cell fraction containing dendritic cells isolated from a healthy HLA-A2 donor. The cells were expanded and employed to elicit a CD8+ CTL response. The peptide lysed prostate tumors in an antigen specific manner. CTLs were evaluated for peptide specific activity and potency in an in vitro chromium release assay. The assay revealed that the CTLs generated after stimulation of PAP-5 peptide loaded dendritic cells were able to endogenously process the PAP-5 antigen.

Human prostate cancer cells were removed at the time of surgery and expanded in culture. They were transfected to secrete a high amount of GM-CSF via ex vivo retroviral transduction with GM-CSF cDNA. Eight of 11 patients were then irradiated and given a subcutaneous injection of their corresponding vaccine every 21 days (3-6 doses). Biopsies showed the presence of macrophages, dendritic cells, T-cells, and eosinophils. Delayed type hypersensitivity (DTH) vs. irradiated, unmodified, autolo-gous tumor cells and recall antigen were tested pre/post treatment to assess specific tumor cells and recall antigens to determine if a tumor specific response was achieved. Two of eight patients had a DTH response prior to the vaccination while seven out of eight patients had a DTH response post vaccination. Biopsies of the DTH sites showed that 80% of the T-cells expressed CD45RO with the presence of Th1 and Th2 cells. Expression of CD45RO indicates that the T-cell has switched isoforms and is now acting as an effector cell.

A vaccine study targeting prostate specific membrane antigen (PSMA) enrolled twenty-six patients with various stages of prostate cancer. Patients were given either a cDNA plasmid encoding the extracellular domain of PSMA (with or without CD86), an adenoviral vector expressing prostate specific membrane antigen, or both in a prime-and-boost strategy trial. Some of the patients received GM-CSF in addition to their treatment. A DTH response to the PSMA expressing plasmid was seen in some of the patients including all 10 patients receiving the adenoviral vector. PSA decline was seen in some patients receiving vaccination only. Due to the various stages of disease and GM-CSF combination treatments, the results of this study are difficult to interpret.

T-Bodies

A T-cell receptor that has been modified so the intra/extracellular part of the domain is the same but the most distal part of the receptor is replaced with a single chain antibody, is known as a T-body. The distal portion of the receptor being modified is the portion that would normally recognize the peptide antigen complex in the MHC cleft. A T-cell could then be activated to attach to a tumor using a specific antibody to a tumor specific antigen. Sadelain et al. have created an artificial T-cell receptor (Pz-1) that is composed of an external PSMA-specific single chain antibody, linked to the CD 8 hinge and transmembrane domain, followed by the cytoplasmic T-cell receptor signal transduction domain. The receptor is capable of redirecting the specificity of the T-cell to target PSMA expressing cells, independent of MHC. In vitro data shows successful lysis of PSMA expressing prostate cancer cells lines and no effect on the non-PSMA expressing cells. These results indicate proliferation of modified T-cells in response to the presence of PSMA expression.

Summary

More than 80% of prostate carcinoma tissue consists of tumor cells at advanced stages, with minor infiltration of inflammatory cells. This indicates that the immune system is not involved. As a result, researchers have the opportunity to tap into a powerful natural defense system that can be augmented to involve prostate cancers. Immunotherapy can focus the immune system on a particular cancer with a wide range of alternatives that can be used singly or in concert to provide a tremendous benefit to the patient. By combining therapies involving biological response modifiers (i.e. cytokines and growth factors), conjugated monoclonal antibodies (including toxins and radiolabels), and cancer vaccines (tumor marker proteins with or without dendritic cell augmentation), the future of immunotherapeutic treatment of prostate cancer looks very promising.

Drug Nomenclature

Histrelin Acetate

Adverse Effects and Precautions

As for Gonadorelin.

Uses and Administration

Histrelin is an analogue of gonadorelin with similar properties. A subcutaneous implant containing histrelin acetate 50 mg, and designed to release histrelin acetate 50 to 60 micrograms daily for 12 months, is used in the palliative treatment of advanced prostate cancer. Histrelin is used in the treatment of precocious puberty in children. It has also been investigated in disorders related to the menstrual cycle, and in the treatment of acute porphyr-ias.

Administration in children. For the suppression of gonadal sex hormone production in children with central precocious puberty, histrelin acetate has been given by subcutaneous inj ection in usual doses equivalent to histrelin 10 micrograms/kg daily. Alternatively, a subcutaneous implant containing histrelin acetate 50 mg and designed to release histrelin acetate 65 micrograms daily for 12 months may be used. The implant is not recommended for children under 2 years of age. References.

Proprietary Preparations

Malaysia: Vantas

USA: Supprelin; Vantas

(British Approved Name, US Adopted Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):

Triptorelin Acetate

Drug Approvals

(British Approved Name Modified, rINNM)

Triptorelin Diacetate

Drug Approvals

(British Approved Name Modified, rINNM)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):

Triptorelin Embonate

Drug Approvals

(British Approved Name Modified, rINNM)

Adverse Effects and Precautions

As for Gonadorelin.

Local reactions. For reference to local reactions occurring following injection of gonadorelin analogues, including triptorelin, see Leuprorelin Acetate.

Sepsis. A report of 2 patients in whom triptorelin therapy led to sepsis caused by expulsion of necrotic fibroids through the cervix.

Interactions

As for Gonadorelin.

Pharmacokinetics

Triptorelin is rapidly absorbed after subcutaneous injection, with peak plasma concentrations achieved about 40 minutes after a dose. The biological half-life has been stated to be about 7.5 hours, although longer half-lives have been reported in patients with prostate cancer, and shorter half-lives in some groups of healthy subjects.

Uses and Administration

Triptorelin is an analogue of gonadorelin with similar properties. It is used for the suppression of go-nadal sex hormone production in the treatment of malignant neoplasms of the prostate, deviant sexual behaviour in men, precocious puberty, and in the management of endometriosis, female infertility, and uterine fibroids. Triptorelin may be given as the base, acetate, diacetate, or embonate, although for some preparations stated to contain the acetate or diacetate it is not always clear which has actually been used. Doses are usually given in terms of the base, and the following are each equivalent to about 1 mg of triptorelin:

• triptorelin acetate, 1.05 mg

• triptorelin diacetate, 1.09 mg

• triptorelin embonate, 1.30 mg

Triptorelin is given as a daily subcutaneous injection, or as an intramuscular or subcutaneous depot preparation lasting a month or longer.

In the palliative treatment of advanced prostate cancer, a dose equivalent to triptorelin 3 or 3.75 mg is given intramuscularly as a depot preparation every 4 weeks the first dose may be preceded by 100 micrograms daily for 7 days by subcutaneous injection. In some countries, depot preparations containing 3.75 mg may be given subcutaneously instead. A longer-acting depot preparation that contains the equivalent of triptorelin 11.25 mg is given once every 12 to 13 weeks. In some countries, depot doses of 3 mg once every 4 weeks or 11.25 mg once every 12 to 13 weeks may also be used for medical therapy in locally advanced disease. An anti-androgen such as cyproterone acetate may be given for several days before beginning therapy with triptorelin and continued for about 3 weeks to avoid the risk of a disease flare.

An 11.25-mg intramuscular depot preparation, given every 12 weeks, may be used in the management of deviant sexual behaviour in men. The addition of an anti-androgen should be considered when starting therapy, to counteract the initial rise in serum-testosterone concentrations.

Similar doses of the 3- or 3.75-mg depot preparations may be given for up to 6 months in the management of endometriosis or uterine fibroids, with treatment begun during the first 5 days of the menstrual cycle. The 11.25-mg depot may be used as an alternative for endometriosis. In the management of female infertility doses of 100 micrograms subcutaneously daily, with gonadotrophins, have been recommended from the second day of the menstrual cycle for about 10 to 12 days.

In children with precocious puberty a dose equivalent to triptorelin 50 micrograms/kg from the 3-mg depot preparation may be given intramuscularly every 4 weeks. Alternatively, using the 3.75-mg preparation, doses of 1.875 mg for children weighing less than 20 kg, 2.5 mg for children of 20 to 30 kg, or 3.75 mg for children of more than 30 kg may be given intramuscularly or subcutaneously the first 3 doses should be given at 14-day intervals, with further doses given every 4 weeks. The longer acting 11.25-mg depot preparation, given intramuscularly once every 3 months, is another alternative.

Delayed and precocious puberty. Gonadorelin analogues such as triptorelin are used in the management of central precocious puberty. They may also be effective in delayed puberty although they are most likely to be helpful where this is due to hypogonadism. Triptorelin has been used to differentiate gonadotrophin deficiency from constitutional delayed puberty, although one study found it to be less accurate than a test using human chorionic gonadotrophin.

Disturbed behaviour. Combined therapy with triptorelin, which suppressed testosterone secretion by inhibiting the pituitary-gonadal axis, and supportive psychotherapy, has been tried in the treatment of men with paraphilias: a reduction in abnormal sexual thoughts and behaviours has been reported, although the study was uncontrolled.

Endometriosis. Gonadorelin analogues are effective in the management of endometriosis, but the need for long-term therapy to prevent recurrence limits their value because of the risk of osteoporosis ‘add-back’ therapy (hormone replacement) can be used to prevent this. References.

Fibroids. Gonadorelin analogues have been used as an alternative to surgery in the treatment of uterine fibroids, despite some concern that this may complicate the diagnosis of malignancy. References to the use of triptorelin.

Growth retardation. As discussed gonadorelin analogues have been given with growth hormone to short girls without growth hormone deficiency, in an attempt to delay puberty and bone maturation and thus maximise the final height achieved. Use in growth hormone-deficient children has also been investigated. However, there is some doubt about the extent of benefit, and in any case the concept of such treatment in children who are not clinically deficient in growth hormone is controversial, and some authorities do not consider it appropriate. References to the use of triptorelin.

Infertility. Gonadorelin analogues are used in the management of infertility related to hypogonadotrophic hypogonadism in both men and women. For a discussion of infertility and its management, including the role of gonadorelin analogues.

Malignant neoplasms. Triptorelin, like other gonadorelin analogues, may be used in the production of androgen blockade in patients with prostate cancer.

Porphyria. Triptorelin has been used successfully to suppress premenstrual exacerbations of acute intermittent porphyria, in doses of 3.75 mg by intramuscular depot injection given monthly.^lt To reduce the risk of osteoporosis, ‘add-back’ therapy with topical oestrogen and oral calcium was used in one case, and tibolone in another.

Proprietary Preparations

Argentina: Decapeptyl Gonapeptyl

Austria: Decapeptyl Pamorelin

Belgium: Decapeptyl

Brazil: Neo Decapeptyl

Chile: Decapeptyl

Czech Republic: Decapeptyl Diphereline

Denmark: Decapeptyl Pamorelin

Finland: Decapeptyl

France: Decapeptyl Gonapeptyl

Germany: Decapeptyl Pamorelin

Greece: Arvekap Gonapeptyl

Hong Kong: Decapeptyl Diphereline

Hungary: Decapeptyl Diphereline

India: Decapeptyl

Ireland: Decapeptyl Gonapeptyl

Israel: Decapeptyl Diphereline

Italy: Decapeptyl Gonapeptyl

Malaysia: Decapeptyl

Mexico: Trelstar †

The Netherlands: Decapeptyl Gonapeptyl Pamorelin

Poland: Decapeptyl Diphereline

Portugal: Decapeptyl

Russia: Decapeptyl Diphereline

South Africa: Decapeptyl

Singapore Decapeptyl

Spain: Decapeptyl Gonapeptyl

Sweden: Decapeptyl Moapar

Switzerland: Decapeptyl

Thailand: Decapeptyl Diphereline

Turkey: Decapeptyl

UK: Decapeptyl Gonapeptyl

USA: Trelstar

Venezuela: Decapeptyl

More recent studies of PSA response to ADT have confirmed and amplified those observations. The odds ratio for progression to androgen-refractory disease within 24 months of starting androgen deprivation therapy was almost 15 times higher for patients who did not achieve undetectable PSA. For each unit increase in Gleason score, the cumulative hazard of androgen-refractory progression was nearly 70%. In one cohort of Asian men, nadir prostate specific antigen was the most accurate predictor of disease progression and was independently prognostic of survival; achieving a PSA level of 1.1 ng/mL or less at 6 months after initiation of ADT was the most sensitive and specific predictor of progression at 2 years. Considering the kinetics of PSA rise before ADT compared with the rate of prostate specific antigen decline after ADT also predicted outcome, specifically prostate cancer–specific mortality. If the pre-ADT rise in PSA level was rapid and the decline after ADT was slow, the cancerspecific mortality was significantly worse than for those with slow rises of PSA level before ADT and rapid declines after androgen deprivation therapy.

Almost without exception, those no longer responding to ADT (androgen refractory) remain on ADT. Therefore, factors influencing survival in that disease state should be considered in this discussion. In most cases, available data are based on pretreatment or post-treatment responses to other systemic treatments. Consistently predictive variables (by both univariate and multivariate analysis) of survival in this state include performance status, serum lactate dehydrogenase concentration, serum alkaline phosphatase concentration, hemoglobin level, and prostate specific antigen response to secondary therapy. The survival of men treated on seven sequential chemotherapy protocols at one institution provided an early experience in developing predictive measures. A 50% decline in PSA level in response to chemotherapy was one of the most significant variables predicting survival. A nomogram based on a larger group of patients found the presence of visceral disease, Gleason score, performance status, baseline PSA level, serum lactate dehydrogenase and alkaline phosphatase concentrations, and hemoglobin level useful in modeling prognosis.

Response to androgen blockade

The magnitude and rapidity of the initial response to ADT are strong predictors of the durability of that response.

Table: Therapeutic Approaches to Androgen Deprivation Therapy[*]

DES, diethylstilbestrol; LH, luteinizing hormone; LHRH, luteinizing hormone–releasing hormone.

* Several agents have multiple mechanisms of action.

Ablation of Androgen Sources

Bilateral orchiectomy quickly reduces circulating testosterone levels to less than 50 ng/dL, which, on the basis of this procedure, is considered the castrate range. Within 24 hours of surgical castration, testosterone levels are reduced by more than 90%. The Veterans Administration Cooperative Urological Research Group (VACURG) conducted a series of large clinical trials, demonstrating the clinical effectiveness of surgical castration in reducing pain and performance status in men with advanced disease.

Scrotal (Simple) Orchiectomy

A straightforward outpatient procedure, the simple scrotal orchiectomy can be performed under local anesthesia. At the level of the external ring, each spermatic cord is grasped and infiltrated with 10 mL of 1% lidocaine without epinephrine. This cord block can be performed before the formal skin preparation and draping. After infiltration of the skin overlying the median raphe with 1% lidocaine, a 6- to 8-cm incision is made directly over the median raphe. After the skin incision, electrocautery is used exclusively to transect the other tissue layers, reducing the risk of scrotal hematoma formation. The incision is directed into one hemiscrotum, where the tunica vaginalis is divided and the testicle delivered through the wound. The cord is mobilized above the testicle but below the level of the external ring. The cord structures are divided into two or three equal components, and the cord is ligated with nonabsorbable sutures. I favor double ligation of the proximal cord with two sutures, one of which is a suture ligature. The cord is transected relatively close to the ligatures to limit the amount of nonviable tissue distal to the ligature. Care is taken to examine for any bleeding as a scrotal hematoma after scrotal orchiectomy can be dramatically large. The identical procedure is performed on the contralateral side. The dartos is then reapproximated in the midline, closing each semiscrotal incision at the same time in one layer. The skin is closed with interrupted absorbable sutures. Drains are not used for clean scrotal wounds. Scrotal supports are used for the first several days after surgery, and ice is applied for symptomatic relief.

Subcapsular orchiectomy has been advocated as a technique of androgen deprivation therapy (ADT) that avoids the psychological consequences of an empty scrotum. Because this approach relies on the complete removal of all intratesticular tissue and Leydig cells, it is more dependent on technique to achieve ADT than a simple orchiectomy is. In a properly performed operation, however, the hormonal and cancer responses are indistinguishable from those of a simple, complete orchiectomy.

Antiandrogens

Cyproterone Acetate

The classic steroidal antiandrogen with direct androgen receptor–blocking effects, cyproterone acetate also rapidly lowers testosterone levels to 70% to 80% through its progestational central inhibition. An oral agent, the recommended dose is 100 mg, two to three times per day. Side effects are consistent with the hypogonadal state and include loss of libido, erectile dysfunction, and lassitude. Severe cardiovascular complications can occur in up to 10% of patients, limiting the use of cyproterone acetate. Gynecomastia occurs in less than 20% of men. Rare cases of fulminant hepatotoxicity have been reported. It has been used at doses of 50 to 100 mg/day for the treatment of hot flashes.

Nonsteroidal Antiandrogens

By blocking the testosterone feedback centrally, the nonsteroidal antiandrogens cause LH and testosterone levels to increase. Testosterone levels reach about 1.5 times the normal levels of hormonally intact men. This allows antiandrogen activity without inducing hypogonadism; potency, therefore, can be preserved. However, in clinical trials specifically examining erectile functioning and sexual activity in men receiving flutamide monotherapy, long-term preservation of those domains was only 20%, not much different from men undergoing surgical castration. The peripheral aromatization of increased testosterone to estradiol has been demonstrated after antiandrogen administration, leading to the widely recognized gynecomastia and mastodynia associated with these agents. Gastrointestinal toxicity, most notably diarrhea, is more common with flutamide than with the other nonsteroidal antiandrogens. Liver toxicity, ranging from reversible hepatitis to fulminant hepatic failure, is associated with all nonsteroidal antiandrogens, and periodic monitoring of liver function is required.

Antiandrogen Withdrawal Phenomenon

Patients treated with a combination of an antiandrogen and an luteinizing hormone–releasing hormone agonist can experience a decline in prostate specific antigen (PSA) level and even objective responses with the withdrawal of the antiandrogen from the combination. On the basis of this response, it appears that the antiandrogen is actually exerting agonistic activity on prostate cancer cells. This phenomenon, first described with flutamide has now been demonstrated with all antiandrogens, including cyproterone acetate as well as DES and progestational agents. Declines in prostate specific antigen level are seen within 4 weeks with flutamide withdrawal and within 6 weeks with bicalutamide and nilutamide withdrawal. Between 15% and 30% of patients may have declines in PSA level of more than 50% after antiandrogen withdrawal and have a median duration of 3.5 to 5 months. Objective, measurable tumor responses are observed less commonly. Overall survival has not been shown to be increased in those demonstrating the antiandrogen withdrawal phenomenon compared with those who have not. Clinical trial designs of novel agents must take this phenomenon into consideration, given the possible confounding effects. Prospective criteria to predict who will demonstrate this response have not been established, but it has been recognized that those with rapid PSA responses after androgen ablation have higher rates of antiandrogen withdrawal phenomenon.

It has been postulated that mutations in the androgen receptor may underlie this phenomenon, allowing the antiandrogen to behave like an activator of the androgen receptor. The widely used prostate cancer cell line LNCaP expresses an androgen receptor with a specific point mutation that causes cell proliferation in the presence of hydroxyflutamide; the identical mutation was found in human tumor samples from patients who had remarkable declines in prostate specific antigen level after antiandrogen withdrawal. Similar point mutations in the androgen receptor have been described for bicalutamide to act as an agonist; the structural basis of this mutation, resolved by x-ray crystallography, demonstrates the ability of bicalutamide to bind to the mutant androgen receptor in a fashion similar to dihydrotestosterone (DHT) to the wild-type androgen receptor.

Flutamide

A nonsteroidal antiandrogen, flutamide was the first “pure” antiandrogen. Because of the short half-life (6 hours) of the active metabolite, 2-hydroxyflutamide, this oral agent requires a three-times-a-day dosing schedule, 250 mg per dose. Elimination of hydroxyflutamide is by renal excretion. Unlike with the steroidal antiandrogens, there are no associated side effects of fluid retention or thromboembolism. In a randomized, double-blind study comparing flutamide with DES (3 mg/day) in metastatic prostate cancer, overall survival was significantly shorter with flutamide (28.5 months) than with DES (43.2 months).

Bicalutamide

A nonsteroidal antiandrogen with a long serum half-life (6 days), bicalutamide has a once-per-day dosing schedule and therefore is likely to have better compliance. It is the most potent of the nonsteroidal antiandrogens and the best tolerated. The pharmacokinetics of bicalutamide are not affected by age, renal insufficiency, or moderate hepatic impairment. The R isomer of bicalutamide has about a 30-fold higher binding affinity to the androgen receptor compared with the S isomer and functionally processes the antiandrogen activity. Like the other antiandrogens, bicalutamide is associated with maintenance of serum testosterone levels; in the majority of patients, these remain within the normal range.

Bicalutamide as monotherapy has been most extensively studied, and like the inferiority of flutamide monotherapy to DES, bicalutamide monotherapy at a dose of 50 mg/day was inferior to castration in survival of men with metastatic disease. At higher dose of 150 mg/day, however, bicalutamide monotherapy appears to have efficacy equivalent to that of medical or surgical castration in men with metastatic or locally advanced disease. In these large phase III studies, bicalutamide monotherapy (150 mg/day) had significantly better quality of life in the domains of sexual interest and physical capacity. There was, however, a high rate of gynecomastia (66.2%) and breast pain (72.8%). Of more concern, in men with low-risk, localized prostate cancer, bicalutamide was associated with significantly worse overall survival compared with those on watchful waiting.

Nilutamide

The plasma half-life of nilutamide is 56 hours, and elimination is by hepatic clearance employing the cytochrome P-450 system. Because steady-state plasma levels are achieved in 14 days on once-per-day dosing, dosing recommendations are a single 300-mg daily dose for the first month of treatment followed by a single 150-mg daily dose. About one quarter of men receiving nilutamide therapy will note a delayed adaptation to darkness after exposure to bright illumination. In approximately 1% of patients, nilutamide is also associated with interstitial pneumonitis, which can progress to pulmonary fibrosis. The early effects are usually reversible with cessation of nilutamide. In a small study, there was a suggestion of a role for nilutamide as an effective secondary hormonal agent.

Inhibition of LHRH

LHRH Agonists

The LHRH agonists exploit the desensitization of luteinizing hormone–releasing hormone receptors in the anterior pituitary after chronic exposure to LHRH, thereby shutting down the production of LH and, ultimately, testosterone. The clinical utility of the current LHRH agonists is based on the creation of analogs of native LHRH by amino acid substitutions, particularly position 6 in the peptide, increasing their potency and half-lives ( Table: Structure of LHRH and Therapeutic Analogs ). Pharmacologic depot preparations and osmotic pump devices allow dosing to extend from 28 days to 1 year, respectively ( Table: LHRH Agonists Approved for the Treatment of Prostate Cancer ). In a review of 24 trials involving more than 6600 patients, survival after therapy with an LHRH agonist was equivalent to that of orchiectomy.

Table: Structure of LHRH and Therapeutic Analogs

LHRH, luteinizing hormone–releasing hormone.

Table: LHRH Agonists Approved for the Treatment of Prostate Cancer

LHRH, luteinizing hormone–releasing hormone.

The initial exposure to more potent agonists of LHRH results in a flare of LH and testosterone levels. This phenomenon is seen with all available LHRH preparations and can result in a severe, life-threatening exacerbation of symptoms. The flare, associated with up to a 10-fold increase in luteinizing hormone, may last 10 to 20 days. Fortunately, the co-administration of an antiandrogen functionally blocks the increased levels of testosterone. Although it had been argued that the administration of the antiandrogen should precede the administration of the LHRH agonist by a week, others have found no differences in prostate specific antigen levels with the simultaneous administration of both agents. Given the predictable length of the flare phenomenon, co-administration of antiandrogens is required for only 21 to 28 days.

LHRH Antagonists

The LHRH antagonists bind immediately and competitively to the LHRH receptors in the pituitary, reducing LH concentrations by 84% within 24 hours of administration. The direct antagonistic activity eliminates the LH and testosterone flare, which is a major therapeutic advantage of these agents; there is no need for antiandrogen co-administration. Hormonally naive patients with impending spinal cord compression or severe bone pain for whom surgical castration is not appropriate may uniquely benefit from this class of agents; clinical response has been observed with the LHRH antagonist cetrorelix.

In clinical trials of the luteinizing hormone–releasing hormone antagonist abarelix, testosterone levels dropped quickly, with 34.5%, 60.5%, and 98.1% of men chemically castrate at 2, 4, and 28 days, respectively. Compared with an LHRH agonist and an antiandrogen, abarelix monotherapy was equally effective in achieving castrate levels of testosterone. Ninety percent of men with symptomatic prostate cancer treated in an open-label fashion had improvements in pain or disease-related problems.

Many of the first- and second-generation antagonists induced significant histamine-mediated side effects, complications not as often observed in third- and fourth-generation agents. Nevertheless, severe allergic reactions can occur, even after previously uneventful treatment. Abarelix is approved in the United States for the treatment of advanced prostate cancer in patients who cannot take other hormonal therapies and have refused surgical castration. Given the rare but serious allergic reactions, patients must be monitored for at least 30 minutes after administration.

FSH levels are only partially suppressed by LHRH agonists, and FSH levels are significantly elevated after surgical castration, given the loss of inhibitory feedback. LHRH antagonists reduce both LH and FSH levels. In an androgen-insensitive prostate cancer xenograft model, cetrorelix significantly reduced tumor growth, suggesting that other factors stimulate tumor growth. In men with disease progression after surgical castration, treatment with abarelix reduced FSH levels by nearly 90% but did not meet criteria for PSA response.

Inhibition of Androgen Synthesis

Aminoglutethimide

Aminoglutethimide inhibits the conversion of cholesterol to pregnenolone, an early step in steroidogenesis. Given its inhibition of a very proximal step in adrenal function, aminoglutethimide blocks production of aldosterone and cortisol. As the medical version of a total adrenalectomy, the use of this agent requires replacement of cortisone and fludrocortisone. Side effects include anorexia, nausea, rash, lethargy, vertigo, hypothyroidism, and nystagmus. Clinical responses have been observed in a subset of patients with androgen-refractory prostate cancer treated with aminoglutethimide plus cortisone. In the PSA era, 37% of patients had more than a 50% decline in PSA level with treatment by aminoglutethimide (1000 mg/day) and hydrocortisone acetate (40 mg/day), with median response times lasting 9 months.

Ketoconazole

An orally active, broad-spectrum azole antifungal agent, ketoconazole interferes with two cytochrome P-450–dependent pathways: inhibition of 14-methylation in the conversion of lanosterol to cholesterol and blockade of 17,20-desmolase, affecting the conversion of C21 to C19 steroids. On the basis of the observation that some patients taking the drug developed gynecomastia, investigations of its effects on steroid synthesis demonstrated loss of adrenal steroid synthesis and testosterone synthesis by Leydig cells. The effects were rapid, with testosterone levels dropping to the castrate level within 4 hours of administration in some cases; the effects were also immediately reversible, indicating that dosing must be continuous to maintain low testosterone levels (400 mg every 8 hours).

Early experience with ketoconazole in the treatment of prostate cancer showed this agent to be tolerable, durable, and effective and palliative for those whose first-line androgen ablation therapy had failed. Although it is effective in rapidly bringing testosterone levels into the castrate range, with continuous treatment with ketoconazole in the otherwise hormonally intact individual (no other surgical or chemical ADT), testosterone levels begin to rise and can reach low-normal ranges within 5 months of therapy. Therefore, ketoconazole is currently used for men with androgen-refractory prostate cancer, often as the first or second agent in so-called secondary hormonal manipulation. In addition to gynecomastia (caused by alterations in testosterone-to-estradiol ratios), ketoconazole is associated with lethargy, weakness, hepatic dysfunction, visual disturbance, and nausea. Because of the adrenal suppression, ketoconazole is usually given with hydrocortisone (20 mg, twice per day).

Mechanisms of androgen axis blockade

There are four general forms of androgen deprivation therapy: ablation of androgen sources, inhibition of androgen synthesis, antiandrogens, and inhibition of LHRH or LH.

Bilateral orchiectomy reduces testosterone by 90% within 24 hours of surgery.

Nonsteroidal antiandrogens cause LH and testosterone levels to increase.

Serious liver toxicity is a possible side effect of all antiandrogens.

Antiandrogens can act agonistic on some tumors; antiandrogen withdrawal results in decline of PSA level in 15% to 30% of patients.

Bicalutamide 150-mg monotherapy appears to have efficacy equivalent to that of medical or surgical castration for locally advanced or metastatic prostate cancer.

All LHRH agonists induce a testosterone increase on initial exposure. Co-administration of an antiandrogen functionally blocks the effects of testosterone.

Molecular biology of androgen axis

Androgen deprivation is one of the most effective therapies against any solid tumor; unfortunately, with time, almost all prostate cancers will become androgen refractory.

All current forms of ADT function by either lowering levels of circulating androgens or blocking the binding of androgen to the androgen receptor.

Almost all androgen-refractory prostate cancer remains sensitive to androgen; therefore, ADT should continue in hormone-refractory disease.

Androgens produced by the adrenal gland, androstenedione and dehydroepiandrosterone, are stimulated by adrenocorticotropic hormone (ACTH) released by the pituitary gland in response to corticotropin-releasing factor. Adrenal androgens do negatively feed back on ACTH secretion; cortisol acts as the feedback signal. Adrenal androgens are relatively weak compared with testosterone and DHT and are almost entirely bound to albumin ( Table: Major Circulating Androgens ). Adrenal androgens remain normal in men who have undergone orchiectomy, and adrenal androgens are insufficient to maintain prostatic epithelium in such men.

Table: Major Circulating Androgens

It had been known for at least a century that prostatic epithelium undergoes atrophy after castration (Hunter, 1840). The breakthrough in Huggins’ hypothesis was the recognition that benign prostatic epithelium and prostate carcinoma are biochemically analogous and respond in a similar fashion to androgen ablation. With emphasis on the importance of basic observations — “The evidence for the facts which represent the premises was obtained entirely in the laboratory” (Huggins, 1944) — studies on acid phosphatase provided the crucial link between benign and malignant prostate cells. Large amounts of acid phosphatase were found in the prostate glands of men and monkeys (Kutscher and Benjamin, 1935), in primary and metastatic prostate cancer (Gutman et al, 1936), and the levels increased with androgen administration (Gutman and Gutman, 1938). Serum levels of acid phosphatase were increased in men with disseminated prostate cancer (Gutman and Gutman, 1938; Barringer and Woodard, 1938). With localization of the enzyme to prostatic epithelial cells and primary and metastatic prostatic cancer cells (Gomori, 1939), the stage was set for Charles Huggins, R. E. Stevens, and Clarence V. Hodges to test the hypothesis in men with prostate cancer.

Despite negative results of castration in two men with prostate cancer reported by Young (1936), a series of 21 consecutive patients with locally advanced or metastatic prostate cancer underwent surgical castration at the University of Chicago. “A noticeable improvement occurred in the clinical status of all but three patients,” with weight gain, resolution of anemia, and improvement in pain (Huggins et al, 1941). Other reported consequences of castration, a large appetite for food, loss of sexual desire and penile erections, and hot flashes, remain the common side effect profile of androgen ablation therapy today. Although this report was the first to describe the benefits of androgen ablation in the treatment of prostate cancer, it also created a new disease state, androgen-refractory prostate cancer.

In considering these “failure cases” (Huggins, 1942), it was found that those with small testes at time of castration had a poor prognosis, the first description of a more ominous prostate cancer arising in the hypogonadal man. After castration, rises in the levels of urinary 17-ketosteroids, a major metabolite of the adrenal gland, led to the hypothesis that adrenal androgens contributed to subsequent disease progression. The first reports of bilateral adrenalectomies for the treatment of hormone-refractory disease (Huggins and Scott, 1945) are described later in a somewhat defensive manner (Scott, 1954), perhaps because of the lack of response and high perioperative mortality. Hypophysectomy and pituitary irradiation (Murphy and Schwippert, 1951) were also investigated. Unfortunately, the benefits of surgical castration were soon equaled by the tenacity and inevitable progression of androgen independence, a state still synonymous with the lethal form of the disease. Even in accepting the Nobel Prize (1966) for this work, Charles Huggins admitted, “Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease.”

Direct ablation of the source of androgen, like surgical castration, is only one of the perturbations of the hypothalamic-pituitary-gonadal axis developed to treat prostate cancer. The first central inhibition of the axis exploited the potent negative feedback of estrogen on luteinizing hormone (LH) secretion. It is now known that estradiol is a thousand-fold more potent at suppressing LH and follicle-stimulating hormone (FSH) secretion by the pituitary compared with testosterone (Swerdloff and Walsh, 1973). The effects of estrogen on the male phenotype, namely, regression of androgen-sensitive tissues, have been exploited, historically, to produce the effects of castration without surgical removal of the testes. For example, capons (neutered roosters) were produced by placement of estrogen pellets in the neck of the bird rather than by castration (Scott, 1954). Among the various estrogenic compounds, diethylstilbestrol (DES) has been most widely studied and used. Early studies indicating improved survival in men treated with both surgical castration and continuous DES (Nesbit and Baum, 1951) have not held up under further scrutiny, but the equivalence of DES compared with castration has. Indeed, given the effectiveness of the considerably less expensive estrogenic compounds, it is unfortunate that the associated cardiovascular toxicity has limited their widespread use.

The first isolation of luteinizing hormone–releasing hormone (LHRH) by Andrew Schally and colleagues (1971) required the hypothalami of 165,000 pigs to obtain 800 μg of the 10–amino acid peptide. This Nobel Prize (1977) – winning work led to the development of synthetic LHRH analogs, peptides generated by substituting d–amino acid residues at certain locations in the natural compound, creating both LHRH agonists and LHRH antagonists. After an initial surge in LH release (and testosterone levels) in response to LHRH agonists, the loss of phasic pituitary stimulation results in plummeting LH levels. In the absence of LH, Leydig cell production of testosterone drops to castrate levels. Initially, the clinical utility of these agents was hampered by their short half-life, requiring daily injections to maintain suppression of the hypothalamic-pituitary axis. The generation of long-acting depot preparations, lasting several months, has established LHRH agonists as the dominant treatment in hormone therapy for prostate cancer. Recently, direct LHRH antagonists have been developed for clinical use. Lacking agonist action, these agents do not produce the surge in LH and testosterone. It is interesting that both classes of compounds were developed within a few years of the discovery of LHRH, and yet it took decades to develop clinically useful agents.

Moving beyond strategies targeting the hypothalamicpituitary axis, interruption of ligand-receptor interaction with antiandrogenic compounds is another way to reduce androgen action in prostate cancer. All antiandrogens inhibit androgen action by binding to the androgen receptor in a competitive fashion and are classified as steroidal or nonsteroidal. The steroidal antiandrogen cyproterone acetate is a derivative of 17-hydroxyprogesterone and suppresses LH release (and testosterone production) through its central progestational inhibitory effects. Therefore, steroidal antiandrogens block androgen action at the cellular level and also reduce circulating testosterone levels, leading to the classic side effects of hypogonadal state, such as loss of libido and erectile dysfunction. On the other hand, the nonsteroidal antiandrogens have no antigonadotropic effects and simply block androgen receptors, including those in the hypothalamic-pituitary axis. By blocking the normal inhibiting feedback of testosterone, the antiandrogens produce a paradoxical increase in LH and testosterone. Although this maintenance of testosterone can preserve potency, the peripheral conversion of this excessive testosterone to estrogen can lead to painful gynecomastia.