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PubMed1999

Inhibitors of 17alpha-hydroxylase/17,20-lyase (CYP17): potential agents for the treatment of prostate cancer.

Prostate cancer (PCa) is now the most prevalent cancer in men in the U.S.A. and Europe. At present the major treatment options include surgical or medical castration. These strategies depend on the abolition of the production of testosterone by the testes. However, as these procedures do not affect adrenal androgen production, they are frequently combined with androgen receptor antagonist to block their action. Inhibition of the key enzyme which catalyzes the biosynthesis of androgens from pregnane precursors, 17alpha-hydroxylase/17,20-lyase (hereafter referred to as CYP17 ) could prevent androgen biosynthesis from both sources. Thus total blockade of androgen production by CYP17 inhibitors may provide effective treatment of prostate cancer patients. Indeed, this strategy is now an area of intense interest within research institutions and the pharmaceutical industry. This review highlights development in the design and evaluation of both steroidal and non-steroidal CYP17 inhibitors since 1965. Major emphasis is given to the potent CYP17 inhibitors and those which may show clinical promise. The review could function as a comprehensive working reference of research accomplishment in the field and what problems remain to be tackled in the future.

Affinity Labels↗
PubMed2003

Bisphosphonates in the management of metastatic prostate cancer.

Prostate cancer (PCA) frequently metastasizes to the bones, and skeletal metastases represent the most common cause of morbidity in advanced PCA. Besides the development of skeletal events due to metastases, patients with PCA are at higher risk for benign osseous complications, such as osteoporosis and fractures. Bisphosphonates (BPs) have emerged as an integral part of the management of skeletal disease related to PCA. Currently available data support their routine use to prevent androgen-deprivation-induced osteoporosis and its secondary complications. Dosing at 3-month intervals is appropriate; further studies will have to demonstrate the efficacy of annual dosing. In men with already established bone metastases, BPs might be helpful in preventing skeletal-related events in patients who do not respond to alternative therapies and are at high risk for bone fractures or spinal cord compression. In patients with hormone-refractory prostate cancer, BPs might be administered for analgesic purposes. Prospective randomized trials will have to explore the clinical role of BPs in the prevention of bone metastases following local therapy with curative intent in men at high risk for PCA recurrences.

Antineoplastic Agents↗
PubMed1990

[Changes in prostatic acid phosphatase, gamma-seminoprotein and prostate specific antigen after endocrine therapy for stage D2 prostate cancer].

Prostatic acid phosphatase (PAP), gamma-seminoprotein (gamma-Sm) and prostate specific antigen (PSA) were examined on 120 cases of stage D2 prostate cancer between 1979 and 1989. All patients received endocrine therapy as the first treatment; castration and immediate administration of estrogen or antiandrogen (101), LH-RH analogs (13), estrogen (3) and antiandrogen (3). The actuarial survival rates were calculated by the cause-specific survival method. Pretreatment levels of PAP, gamma-Sm and PSA did not influence prognosis. After start of treatment, the relationship between the changes of the markers and prognosis were examined. At 1 month after the start of the treatment, normalization of PAP or gamma-Sm was not reflected in the following course. On the contrary, at 3 and 6 months, groups with normalization of PAP or gamma-Sm showed better prognosis than those with elevated levels. The same tendency of PSA was obtained at 6 months after start of treatment. In patients with normalized PAP at 3 months, abnormal gamma-Sm showed worse prognosis than normalized gamma-Sm. Therefore, the significance of determination on the two markers was manifested. As histological grade influenced the following course, poorly differentiated adenocarcinoma with normalized PAP at 3 months showed better prognosis than those with elevated levels. In conclusion, it is worthwhile to measure multiple markers for predicting the prognosis of stage D2 prostate cancer treated with endocrine therapy.

Acid Phosphatase↗
PubMed2005

[Usefulness and positioning of MAB therapy for prostate cancer].

Prostate cancer is a relatively slow-growing disease compared to other cancers, and the patients tend to be older. Taking into consideration therefore life expectancy of the patients and risks of recurrence and progression, conservative treatments (mainly hormonal therapy) are often applied for early cases, as well as radical treatments (total prostatectomy and radiotherapy). Particularly in Japan, many patients start treatment with hormonal therapy alone, in both early and advanced cases. Hence, Maximal Androgen Blockade (MAB) therapy, in which surgical or medical castration (such as LH-RH agonist treatment) and anti-androgen treatment are combined, is widely exercised with the hope to enhance treatment effects. The usefulness of MAB therapy has been assessed in a number of randomized comparative studies, covering mainly metastatic cases. The efficacy of the therapy with the use of flutamide as non-steroidal anti-androgen has been confirmed in some of the studies, although the magnitude of the efficacy cannot be said major. In Phase III clinical studies of MAB therapy with bicalutamide being conducted in Japan for patients in Stages C and D, however, the patient group treated with MAB therapy demonstrated more favorable results compared to the group treated with LH-RH agonist alone, particularly in terms of time to progression (TTP) of the patients in Stage C. These are relatively new findings on the usefulness and adaptability of MAB therapy. In this Panel Discussion, views and experiences are exchanged on a wide variety of topics covering the real usefulness of MAB therapy, its adaptability, possible outcomes of hormonal therapy in early cases, and the future of MAB therapy, taking into account the prevailing opinions and current practices on prostate cancer in both the United States and Japan.

Androgen Antagonists↗
PubMed1994

Frequency and distribution of numerical chromosomal aberrations in prostatic cancer.

Prostatic cancer frequently shows striking morphological heterogeneity and multifocal growth. To better understand the relationship between chromosomal changes and pathological characteristics, 31 routinely processed radical prostatectomy specimens were studied for the presence of numerical chromosomal aberrations by in situ hybridization with centromeric nucleic acid probes specific for chromosomes 7, 10, 17, X, and Y. In 24 of the cases preoperative core biopsy specimens were available and were examined with the probe for the X chromosome. In eight of the prostatectomy specimens chromosome numbers consistent with a normal male karyotype were found. Three cases, besides diploid chromosome numbers, showed a focal doubling of hybridization signals, consistent with tetraploidy. The other 20 cases displayed numerical chromosomal aberrations to a various degree. In this group the appearance of numerical chromosomal aberrations often showed considerable local heterogeneity, generally coinciding with morphological dedifferentiation, and was significantly correlated with tumor stage (P = .0004) as well as primary (P = .0068), worst (P = .0002), and combined (P < .0001) Gleason grades, total tumor volume (P = .0448), and the volume of tumor with Gleason grades 4 or 5 (P < .0001). In four of the 24 core biopsy specimens no residual tumor tissue was left for cytogenetic examination. In the remaining 20 biopsy specimens the presence or absence of numerical changes matched the result obtained on the corresponding prostatectomy specimen. We conclude that in prostatic cancer the presence of numerical chromosomal aberrations is associated with advanced disease. Especially in low differentiated tumors local heterogeneity in 2 chromosome numbers can be very marked. It is possible to forecast the presence or absence of numerical chromosomal changes on preoperative core biopsy specimens.

Adenocarcinoma↗
PubMed2001

The androgen receptor gene and its influence on the development and progression of prostate cancer.

Prostate adenocarcinoma has the highest incidence of any malignancy and is the second leading cause of cancer-related deaths in men in industrialized countries. The development and progression of prostate cancer are dependent on testosterone and dihydrotestosterone; the androgen receptor is the vehicle through which these androgens exert their regulation on prostate cellular proliferation and differentiation. As a result, much effort has been devoted to elucidating the role of the androgen receptor in prostate cancer. The CAG and GGN trinucleotide repeats in exon 1 of the androgen receptor gene have been linked to prostate cancer risk and progression in some studies. Also, androgen receptor gene amplification may be a mechanism of prostate cancer cell adaptation to hormonal therapy. In addition, androgen receptor somatic mutations can result in receptors that have altered binding specificity when compared with wild-type receptors and heightened affinity for hormones other than testosterone and dihydrotestosterone. Gene amplification and somatic mutations, coupled with the fact that various growth factors have been shown to stimulate androgen receptor activity independently of androgens, may enable prostate cancer cells to grow despite testicular-androgen ablation. Unfortunately, current medical therapy for metastatic prostate cancer is deficient, hormone-refractory prostate cancer is a major obstacle in treatment, and, as a result, prostate cancer mortality is still significant. Further study of the function of the androgen receptor will offer a better understanding of prostate cancer pathogenesis and progression, aiding the development of more effective treatments for this disease.

Adenocarcinoma↗
PubMed1992

Early detection of prostate cancer.

Prostate cancer is unique among the potentially lethal human malignancies in the wide discrepancy between the high prevalence of histologic changes recognizable as cancer and the much lower prevalence of the clinical disease. Despite the availability of effective tests for early detection and of effective treatment for cancers so detected, the diagnosis usually is not established until the tumor is locally advanced or metastatic. Yet, physicians hesitate to use these tests for fear that many cancers found would be latent, of little threat to the life or health of the host, and treatment could introduce inappropriate morbidity. Latent or "clinically unimportant" cancers can be distinguished from those that are clinically important by the larger volume, higher grade, and greater invasiveness of the latter. The available tests can detect only those cancers large enough to be palpable, visible on ultrasound, or capable of elevating the serum level of prostate-specific antigen. Such cancers are clinically important and should be treated for cure if the life expectancy of the patient is sufficiently long and the morbidity rate of therapy is low. Early detection of prostate cancer using the tests that are available today may widen the window of opportunity so that treatment indeed becomes possible in those for whom it is necessary.

Antigens, Neoplasm↗
PubMed1991

The American Cancer Society National Prostate Cancer Detection Project. Findings on the detection of early prostate cancer in 2425 men.

The American Cancer Society National Prostate Cancer Detection Project (ACS-NPCDP) is a multidisciplinary, multicenter effort to assess the feasibility of early prostate cancer detection by digital rectal examination (DRE), transrectal ultrasound (TRUS), and prostate specific antigen (PSA) assay. By June 1990, 2425 men not previously suspected of having prostate cancer had been examined in ten participating clinical centers according to the project protocol. Three hundred ninety-six men (16.3%) were recommended for biopsy on the basis of TRUS or DRE. An analysis of the results of 330 completed biopsies showed 52 cancers detected by DRE and/or TRUS. Forty-four (84.6%) of the men with cancer had positive TRUS examination results compared with 33 (63.5%) with positive DRE. Five additional cancers were discovered as a result of elevated PSA levels. The overall detection rate was 2.4% and this rate varied by age. The detection rate in men 55 to 60 years of age was 1.3% and this rose to 3.3% in men older than 65 years of age. The estimated sensitivity was significantly greater for TRUS compared with DRE (77.2% versus 57.9%; P less than 0.05). The estimated specificity of DRE was greater than that of TRUS (96.3% versus 89.4%; P less than 0.01). The positive predictive value (PPV) for the tests varied as a function of patient and disease characteristics. The overall PPV was 28.0% for DRE and 15.2% for TRUS. The occurrence of elevated PSA levels significantly increased the PPV of both TRUS and DRE. The majority of cancers detected were at early stages. These preliminary data suggest the feasibility of using these techniques to promote cancer control, but additional data and follow-up are needed to assess the significance of the results.

Age Factors↗
PubMed1996

The results of a five-year early prostate cancer detection intervention. Investigators of the American Cancer Society National Prostate Cancer Detection Project.

BACKGROUND: The American Cancer Society-National Prostate Cancer Detection Project (ACS-NPCDP) is a multidisciplinary evaluation of early prostate cancer detection interventions. This report summarizes the experience of the investigators to date and describes the overall and relative performance of the different detection modalities studied in this project. METHODS: Two thousand nine hundred ninety-nine men aged 55 to 70 years at entry who were not already under evaluation for prostate cancer were recruited to participate in up to 5 annual examinations by prostate specific antigen (PSA), digital rectal examination (DRE), and transrectal ultrasound (TRUS). In the course of 5 years of intervention, ACS-NPCDP investigators have completed 9937 examinations, recommended 1215 biopsies, and detected 203 cancers. RESULTS: Loss to cohort follow-up was greatest in the first year. Overall, TRUS led to twice the number of recommendations for biopsy compared with DRE (8.9% versus 4.4%). Elevated PSA was observed in 13.0% of 9535 measurements performed. The overall cancer detection rate declined significantly during the five years of intervention. Detection was significantly associated with age and symptom status at entry. DRE had lower sensitivity compared with TRUS or PSA, particularly in later years of follow-up. The specificity of TRUS was lower than that for DRE. PSA was elevated in 69.2% of examinations that led to cancer detection, compared with only 10.9% when cancer was not found. PSA level, PSA density, and PSA change were all related to the presence of cancer. Less than 6% of the cancers detected in this study were clinically advanced at the time of diagnosis. CONCLUSIONS: These data quantify the yield of early cancer detection that may be expected when PSA, DRE, and TRUS are used in populations comparable to the men participating in the ACS-NPCDP. Continued follow-up and further research is needed to assess whether men receiving early prostate cancer interventions benefit as a result.

Aged↗
PubMed2002

A standard definition of disease freedom is needed for prostate cancer: undetectable prostate specific antigen compared with the American Society of Therapeutic Radiology and Oncology consensus definition.

PURPOSE: Freedom from prostate cancer is defined by undetectable prostate specific antigen (PSA) after surgery and the American Society of Therapeutic Radiology and Oncology (ASTRO) criteria are recommended for irradiation. Whether these definitions of disease freedom are comparable was evaluated in this study. MATERIALS AND METHODS: From August 1992 to August 1996 simultaneous irradiation with prostate 125iodine implantation followed by external beam irradiation was performed in 591 consecutive men with stage T1T2NX prostate cancer. All patients had a transperineal implant and none received neoadjuvant hormones. Disease freedom was defined by a PSA cutoff of 0.2 ng./ml. and the ASTRO consensus definition. Median followup was 6 years (range 5 to 8). RESULTS: Of the 591 men in this study 65 had recurrence by ASTRO criteria and 93 had recurrence by a PSA cutoff of 0.2 ng./ml., which was a significant difference (p = 0.001). On multivariate analysis of the factors related to disease-free status the definition of disease freedom, pretreatment PSA and Gleason score were highly significant. Of the 528 men with a minimum 5-year PSA followup the 8-year disease-free survival rate by ASTRO criteria was 99% in those who achieved a PSA nadir of 0.2 ng./ml. and 16% in those with a nadir of 0.3 to 1 ng./ml. Of the 469 disease-free patients by ASTRO criteria with a minimum 5-year followup 455 (97%) achieved a PSA nadir of 0.2 ng./ml. or less. CONCLUSIONS: The definition of freedom from prostate cancer significantly affects treatment results. A standard definition is needed and a PSA cutoff of 0.2 ng./ml. is suggested as the standard for all curative treatments for localized prostate cancer.

Brachytherapy↗
PubMed2004

D-GPCR: a novel putative G protein-coupled receptor overexpressed in prostate cancer and prostate.

The use of molecular targets in novel strategies of tumor treatment largely depends on the identification of proteins with a tumor- or tissue-restricted expression. We identified the novel protein D-GPCR that is selectively overexpressed in human prostate cancer and prostate and belongs to the subfamily of odorant-like orphan G protein-coupled receptors. Quantification of D-GPCR transcripts in different human tissues by real-time PCR demonstrated 27-fold overexpression in prostate compared to skeletal muscle, the organ with second highest transcript numbers in males. Investigation of tumor/normal cDNA pairs obtained from 241 cancer patients including four prostate tumors confirmed the preferential expression in prostate. When comparing the mean transcript level of 15 prostate cancer tissues to their non-tumorous counterparts, D-GPCR was almost 6-fold upregulated. Coupled in vitro transcription and translation of D-GPCR cDNA produced a protein band of approximately 28 kDa. Recombinant, His-tagged protein was expressed in transfected HEK293 cells and gave rise to a 30 kDa band specifically detected by anti-His antibody. These data provide the basis for future studies evaluating the diagnostic potential of D-GPCR and its utility as a novel target in immunotherapy of prostate cancer.

Aged↗
PubMed2001

Induction of tumor specific cytotoxic T lymphocytes in prostate cancer using prostatic acid phosphatase derived HLA-A2402 binding peptide.

PURPOSE: Human prostatic acid phosphatase is a prostate specific differentiation antigen. Prostatic acid phosphatase levels increase in the serum of patients with prostate cancer and its peptide from positions 299 to 307 (PAP 299-307) is recognized by HLA-A2 restricted cytotoxic T lymphocytes. We investigated whether HLA-A2402 binding prostatic acid phosphatase derived peptides induce HLA-A2402 restricted, tumor specific cytotoxic T lymphocytes from the peripheral blood mononuclear cells of patients with prostate cancer. MATERIALS AND METHODS: Peptide binding activity was measured with RMA-S-A*A2402 cell lines and flow cytometry. Cytotoxic T-lymphocyte activity of the peripheral blood mononuclear cells of patients with prostate cancer and healthy donors was measured by interferon-gamma and (51)creatinine release assays. Prostatic acid phosphatase expression in the tumor cell lines at the messenger RNA and protein levels was investigated by reverse transcriptase-polymerase chain reaction and immunohistochemical analysis, respectively. RESULTS: An HLA-A2402 binding, prostatic acid phosphatase derived peptide consisting of the prostatic acid phosphatase amino acid sequence from positions 213 to 221 (PAP 213-221, LYCESVHNF) showed the ability to induce HLA-A2402 restricted and tumor specific cytotoxic T lymphocytes, which are cytoxic to prostatic acid phosphatase positive tumor cells from the peripheral blood mononuclear cells of patients with prostate cancer. CONCLUSIONS: PAP 213-221 may be appropriate as a cancer vaccine for specific immunotherapy in patients with HLA-A2402 positive prostate cancer.

Acid Phosphatase↗
PubMed2001

Identification of potential diagnostic markers of prostate cancer and prostatic intraepithelial neoplasia using cDNA microarray.

The identification of novel genes or groups of genes expressed in prostate cancer may allow earlier diagnosis or more accurate staging of the disease. We describe the assembly and use of a 1877-member microarray representing cDNA clones from a range of prostate cancer stages and grades, precursor lesions and normal tissue. Using labelled cDNA from tumour samples obtained from TURP or radical prostatectomy, analysis of expression patterns identified many up-regulated transcripts. Cell lines were found to over-express fewer genes than diseased tissue samples. 17 known genes were found to over-express more than 4-fold in 4 or more cancers out of 15 cancers. Only 2 genes were over-expressed in 6 out of 15 cancers or more, whilst no genes were consistently found to be over-expressed in all cancer samples. Novel prostate cancer associations for several well characterized genes or full length cDNAs were identified, including PLRP1, JM27, human UbcM2, dynein light intermediate chain 2 and human homologue of rat sec61. Novel associations with high-grade PIN include: breast carcinoma fatty acid synthase and cDNA DKFZp434B0335. We shortlist and discuss the most significant over-expressed genes in prostate cancer and PIN, and highlight expression differences between malignant and benign samples.

Aged↗
PubMed1998

Allelic imbalance in familial and sporadic prostate cancer at the putative human prostate cancer susceptibility locus, HPC1. CRC/BPG UK Familial Prostate Cancer Study Collaborators. Cancer Research Campaign/British Prostate Group.

A recent report has provided strong evidence for a major prostate cancer susceptibility locus (HPC1) on chromosome 1q24-25 (Smith et al, 1996). Most inherited cancer susceptibility genes function as tumour-suppressor genes (TSGs). Allelic loss or imbalance in tumour tissue is often the hallmark of a TSG. Studies of allelic loss have not previously implicated the chromosomal region 1q24-25 in prostate cancer. However, analysis of tumour DNA from cases in prostate cancer families has not been reported. In this study, we have evaluated DNA from tissue obtained from small families [3-5 affected members (n = 17)], sibling pairs (n = 15) and sporadic (n = 40) prostate tumours using the three markers from Smith et al (1996) that defined the maximum multipoint linkage lod score. Although widely spaced (12-50 cM), each marker showed evidence of allelic imbalance in only approximately 7.5% of informative tumours. There was no difference between the familial and sporadic cases. We conclude that the incidence of allelic imbalance at HPC1 is low in both sporadic tumours and small prostate cancer families. In this group of patients, HPC1 is unlikely to be acting as a TSG in the development of prostate cancer.

Aged↗
PubMed1982

Response to luteinizing releasing hormone, thyrotrophic releasing hormone, and human chorionic gonadotropin administration in healthy men at different risks for prostatic cancer and in prostatic cancer patients.

A comparative study of the pituitary and testicular response to luteinizing releasing hormone (LHRH), thyrotrophic releasing hormone (TRH), and human chorionic gonadotrophin (HCG) administration was carried out in (a) low-risk young South African black men and high-risk North American black men for prostatic cancer and (b) healthy elderly South African men and South African black men with prostatic cancer. A comparable HCG response occurred in young South African and North American black men, while a greater release of prolactin, but a lesser release of luteinizing hormone in response to LHRH:TRH occurred in South African black men. The response to HCG was comparable in elderly and young South African black men, although the prolactin release in response to TRH was greater in elderly men. A more prolonged release of luteinizing hormone was evident in men with prostatic cancer. Higher estradiol and estrone but lower androstenedione levels occurred in men with prostatic cancer. Data suggest that, in the elderly South African black men with prostatic cancer, estrogen metabolism is modified and that either the estrogen level or the higher estrogen:androgen levels modify the pituitary response to LHRH:TRH. A Western diet enhanced the changes in hormone profiles evident in black South African men with prostatic cancer.

Adult↗
PubMed1996

[Intermittent intra-arterial chemotherapy for the treatment of patients with bladder cancer or prostate cancer using implantable injection pump].

BACKGROUND: The objective of this study is to evaluate the usefulness of intra-arterial chemotherapy using an implantable injection system for the treatment of bladder or prostate cancer. METHODS: Twenty-four patients with bladder cancer and 13 with prostate cancer were treated with intermittent intra-arterial chemotherapy using a totally implantable injection pump. A heparinized catheter was percutaneously fixed through the femoral artery with the tip 2 or 3 cm above the bifurcation of the common iliac artery, and the pump was placed in a subcutaneous pocket. RESULTS: The total number of infusion sessions for bladder cancer ranged from 4 to 38 times (mean 20.8), and 15 of the 24 patients were injected from 2 to 19 sessions (mean 8.5) as outpatients. The tumor response for 15 patients with newly diagnosis muscle-invasive bladder cancer were 12 patients in CR, 1 in PR, and 2 in NC, and 9 patients with recurrent bladder cancer were 6 patients in CR, 1 in PR, and 2 in NC. The total number of infusions for prostate cancer ranged from 6 to 35 times (mean 20.2), and 10 of the 13 patients were injected from 1 to 11 times (mean 6.3) as outpatients. All 13 patients with prostate cancer were treated with hormone therapy and irradiation, and achieved PR. Complications of this drug delivery system were obstruction of the catheter or pump observed in 7 patients, dislocation of the catheter in 2, and obstruction of right external iliac artery in 1. CONCLUSION: These findings suggest that favorable therapeutic efficacies and an improved quality of life for patients can be obtained by intra-arterial chemotherapy using an implantable injection pump.

Aged↗
PubMed1995

Prostate-specific antigen density: correlation with histological diagnosis of prostate cancer, benign prostatic hyperplasia and prostatitis.

OBJECTIVE: To assess the additional value of prostate-specific antigen density in the diagnosis of prostate cancer in patients who undergo prostate biopsies. PATIENTS AND METHODS: The study comprised 376 patients with symptoms of prostatism who were undergoing prostate biopsy. Digital rectal examination (DRE) and transrectal ultrasonography (TRUS) were performed and the prostate specific antigen level (PSA) and density (PSAD) were determined for each patient. RESULTS: Both PSA and PSAD significantly differentiated (P < 0.001) between benign and malignant histology. Of the 376 patients, 91 (24%) had a PSA level in the intermediate range (4.0-10.0 ng/mL). In these patients PSAD was significantly better than PSA in differentiating between benign and malignant histology (P = 0.027 vs 0.316). With a PSAD limit of 0.15 ng/mL/cm3 in these patients, the sensitivity was 92% and the specificity was 54% for the diagnosis of prostate cancer. No patient with a positive biopsy had a PSAD < 0.11 ng/mL/cm3. No limiting value could be found for PSAD that combined both an acceptable sensitivity and specificity. Of the patients with a malignancy detected by the biopsy, 92% also had a suspect DRE. CONCLUSION: In patients with intermediate PSA levels, PSAD is of limited additional value when compared to DRE in correctly diagnosing prostate cancer. Acute prostatitis is also a possible cause of elevated PSA. Both PSA and PSAD had no additional value in differentiating between benign prostatic hyperplasia (BPH) and histologically proven extensive prostatitis.

Aged↗