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Life Extension Magazine December 2012

Prostate Cancer

Prostate cancer screening: Attitudes and practices of family physicians in Ontario.

INTRODUCTION: : The utility of prostate cancer screening is controversial. We sought to determine whether Ontario's family physicians believe it is beneficial and to characterize their screening protocols. METHODS: A survey was developed with input from urologists, family physicians and the Ontario Medical Association's Section on General and Family Practice. Questions covered three domains: (1) demographics, (2) beliefs about screening utility and (3) screening practices. All 7,302 family physicians in Ontario were invited by email to complete the online survey. RESULTS: A total of 969 physicians completed the survey; 955 (52.0% male, 48.0% female) were included. Most (80.97%) use prostate-specific antigen (PSA) and digital rectal examination (DRE) for screening; 9.4% use DRE alone and 7.15% PSA. Of the respondents, 8.3% do not offer prostate cancer screening. Most physicians begin offering screening at age 50 (72.9%) and stop at ages 70 or 80 (68.4%); 17.9% offer lifelong screening. In response to the statement "screening with DRE provides a survival benefit," 37.6% and 32.6 agreed and disagreed, respectively. For "screening with PSA provides a survival benefit," 43.3% agreed and 31.0% disagreed. For the statement "the benefits of prostate cancer screening outweigh the risks," 51.4% agreed and 22.0% disagreed. DISCUSSION: Although 91.7% of respondents offer prostate cancer screening, they are divided over its utility. Only 51.4% were convinced that the benefits outweighed the harms. There is significant variability between physicians' screening protocols. A limitation of this study is the possibility of selection bias. Nevertheless, this is the largest sample of Ontario family physicians ever surveyed about prostate cancer screening and highlights divergent physician practices and a need for more conclusive evidence on screening utility.

Can Urol Assoc J. 2012 Jun;6(3):188-93

Screening for Prostate Cancer: U.S. Preventive Services Task Force Recommendation Statement.

DESCRIPTION: Update of the 2008 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for prostate cancer. METHODS: The USPSTF reviewed new evidence on the benefits and harms of prostate-specific antigen (PSA)-based screening for prostate cancer, as well as the benefits and harms of treatment of localized prostate cancer. RECOMMENDATION: The USPSTF recommends against PSA-based screening for prostate cancer (grade D recommendation).This recommendation applies to men in the general U.S. population, regardless of age. This recommendation does not include the use of the PSA test for surveillance after diagnosis or treatment of prostate cancer; the use of the PSA test for this indication is outside the scope of the USPSTF.

Ann Intern Med. 2012 Jul 17;157(2):120-134

Primary care providers' perspectives on discontinuing prostate cancer screening.

BACKGROUND: Clinical guidelines recommend against routine prostate-specific antigen (PSA) screening for older men and for those with lower life expectancies. The authors of this report examined providers' decision-making regarding discontinuing PSA screening. METHODS: A survey of primary providers from a large, university-affiliated primary care practice was administered. Providers were asked about their current screening practices, factors that influenced their decision to discontinue screening, and barriers to discontinuing screening. Bivariate and multivariable logistic regression analyses were used to examine whether taking age and/or life expectancy into account and barriers to discontinuing were associated with clinician characteristics and practice styles. RESULTS: One hundred twenty-five of 141 providers (88.7%) participated in the survey. Over half (59.3%) took both age and life expectancy into account, whereas 12.2% did not consider either in their decisions to discontinue PSA screening. Providers varied in the age at which they typically stopped screening patients, and the majority (66.4%) reported difficulty in assessing life expectancy. Taking patient age and life expectancy into account was not associated with provider characteristics or practice styles. The most frequently cited barriers to discontinuing PSA screening were patient expectation (74.4%) and time constraints (66.4%). Black providers were significantly less likely than nonblack providers to endorse barriers related to time constraints and clinical uncertainty, although these results were limited by the small sample size of black providers. CONCLUSIONS: Although age and life expectancy often figured prominently in decisions to use screening, providers faced multiple barriers to discontinuing routine PSA screening.

Cancer. 2012 Apr 19. doi: 10.1002/cncr.27577

The influence of ejaculation on serum levels of prostate specific antigen.

PURPOSE: While prostatic manipulation and surgery have been shown to increase serum prostate specific antigen (PSA), the influence of ejaculation on serum PSA remains controversial. We examined the effect of ejaculation on serum PSA levels. MATERIALS AND METHODS: We evaluated 100 men 25 to 35 years old with no history of surgery or inflammatory disease of the urogenital tract. Serum PSA was evaluated 1 and 24 hours after ejaculation, and serum testosterone and seminal fluid PSA levels were determined. RESULTS: In all men a baseline PSA level was detected. There were no statistically significant changes in serum PSA and testosterone 1 and 24 hours after ejaculation. Mean PSA concentration was significantly higher in seminal plasma than in serum. However, we did not observe a correlation between serum and seminal plasma PSA levels. CONCLUSIONS: Based on our data ejaculation does not affect serum PSA concentration in young men, and there seems to be no physiological relationship between ejaculation and PSA level.

J Urol. 1997 Jan;157(1):209-11

Effect of ejaculation on serum total and free prostate-specific antigen concentrations.

OBJECTIVES: Measurement of total serum prostate-specific antigen (PSA) is widely used as an aid to early detection of prostate cancer. Measurement of the ratio of free to total PSA may increase the specificity of PSA testing. To improve specificity further, other factors that may cause transient increases in PSA, such as ejaculation, have been identified. We prospectively studied the effect of ejaculation on total and free PSA levels and examined whether changes induced by ejaculation would affect recommendations for performing prostatic biopsy. METHODS: We measured the baseline total and free serum PSA levels and obtained measurements 1.6, and 24 hours after ejaculation in 20 volunteers (mean age 59 years). All men had baseline PSA levels less than 4.0 ng/mL. We used repeated-measures analysis of variance to test for changes in total, free, and percent free PSA after ejaculation. We also calculated the proportion of men with PSA levels greater than the expected biologic variability at each timepoint. RESULTS: The mean total, free, and percent free serum PSA increased 1 hour after ejaculation. Mean total PSA levels remained significantly increased 6 and 24 hours after ejaculation. Mean free PSA decreased to baseline levels by 6 hours after ejaculation, and percent free PSA returned to baseline by 6 hours after ejaculation and then decreased below baseline by 24 hours. When normal biologic variation was accounted for, 40% of men, at 24 hours after ejaculation, had total PSA levels above the baseline level. Similarly, 24 hours after ejaculation, the percent free PSA remained above baseline level in 10% and below baseline level in 35% of the men. CONCLUSIONS: Both total and free PSA increase immediately after ejaculation, with differing rates of return to baseline levels. PSA testing within 24 hours after ejaculation may lead to an erroneous interpretation of the results of both total and percent free PSA measurements in a small proportion of men.

Urology. 1997 Aug;50(2):239-43

The use of PCA3 in the diagnosis of prostate cancer.

Although the routine use of serum PSA testing has undoubtedly increased prostate cancer detection, one of its main drawbacks has been its lack of specificity, which results in a high negative biopsy rate. Consequently, a large population of men with chronically elevated serum PSA and one or more negative biopsies has emerged. More accurate tests are needed that can help identify which patients are at high risk of developing prostate cancer, and for whom repeat prostate biopsies are mandatory. To improve the specificity of prostate cancer diagnosis, prostate-cancer-specific markers, such as prostate cancer gene 3 (PCA3), are needed. The strong association between PCA3 mRNA overexpression and malignant transformation of prostate epithelium indicates its potential as a diagnostic biomarker. Quantification of PCA3 mRNA levels in urine was found to help predict the outcome of prostate biopsies. The intensive and time-consuming reverse-transcriptase polymerase chain reaction PCA3 urine test has been translated successfully into the fast and easy transcription-mediated amplification (TMA)-based PCA3 test. This test is the first RNA-based molecular diagnostic assay in body fluids for prostate cancer that is available to urologists. This Review describes the translation of the molecular marker PCA3 from the research laboratory to clinical practice.

Nat Rev Urol. 2009 May;6(5):255-61

Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans.

A large part of the aging phenotype, including immunosenescence, is explained by an imbalance between inflammatory and anti-inflammatory networks, which results in the low grade chronic pro-inflammatory status we proposed to call inflammaging. Within this perspective, healthy aging and longevity are likely the result not only of a lower propensity to mount inflammatory responses but also of efficient anti-inflammatory networks, which in normal aging fail to fully neutralize the inflammatory processes consequent to the lifelong antigenic burden and exposure to damaging agents. Such a global imbalance can be a major driving force for frailty and common age-related pathologies, and should be addressed and studied within an evolutionary-based systems biology perspective. Evidence in favor of this conceptualization largely derives from studies in humans. We thus propose that inflammaging can be flanked by anti-inflammaging as major determinants not only of immunosenescence but eventually of global aging and longevity.

Mech Ageing Dev. 2007 Jan;128(1):92-105

Inflammaging: the driving force in osteoporosis?

With advancing age, the balance between the amounts of old bone removed and new bone formed during the remodelling process becomes negative. In the past, it was commonly thought that skeletal involution was the result of age-related changes in other organs, and in particular from the decline in ovarian function in women at menopause. Nonetheless, with regard to emerging epidemiologic studies, the hypothesis suggesting that age-related changes such as inflammatory modifications importantly account for age-related bone loss is gaining increasing interest. Aging is indeed associated with immune dysfunction that coexists with a chronic subclinical inflammatory status. The latter is illustrated by a 2-4-fold increase in the levels C-reactive protein (CRP) or interleukin (IL)-6. This inflammatory status, which has been referred to by the neologism "inflammaging", is of sufficient magnitude to impact health and survival time, and correlates with age-related diseases such as atherosclerosis, insulin resistance and Alzheimer's disease. In this article, we first present the factors that condition inflammaging, and propose the hypothesis that inflammaging may be the driving force in age-related bone loss and may even be responsible for osteoporosis due to estrogen deficiency. Finally, we discuss the possibility that pro-inflammatory biomarkers may be used to provide clinical information for identifying patients at risk for osteoporosis, and the possibility that inflammatory cytokines may be targeted to improve bone formation in aged patients undergoing orthopaedic surgery.

Med Hypotheses. 2011 Mar;76(3):317-21

BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients.

BACKGROUND: A family history of prostate cancer (PrCa) is a strong risk factor for the disease, indicating that inherited factors are important in this disease. We previously estimated that about 2% of PrCa cases diagnosed ≤ 55 years harbour a BRCA2 mutation and PrCa among BRCA2 carriers has been shown to be more aggressive, with poorer survival. METHODS: To further evaluate the role of BRCA2 in PrCa predisposition, we screened 1864 men with PrCa aged between 36 and 88 years. We analysed the BRCA2 gene using a novel high-throughput multiplex fluorescence heteroduplex detection system developed for the ABI3130xl genetic analyzer. RESULTS: We identified 19 protein-truncating mutations, 3 in-frame deletions and 69 missense variants of uncertain significance (UV) in our sample set. All the carriers of truncating mutations developed PrCa at ≤ 65 years, with a prevalence of BRCA2 mutation of 1.20% for cases in this age group. CONCLUSION: Based on the estimated frequency of BRCA2 mutations in the United Kingdom we estimate that germline mutations in the BRCA2 gene confer an ∼ 8.6-fold increased risk of PrCa by age 65, corresponding to an absolute risk of ∼ 15% by age 65. These results suggest that routine testing of early onset PrCa cases for germline BRCA2 mutations will further help to refine the prevalence and risk associated with BRCA2 mutations and may be useful for guiding management options.

Br J Cancer. 2011 Oct 11;105(8):1230-4

Hereditary/familial versus sporadic prostate cancer: few indisputable genetic differences and many similar clinicopathological features.

Genetic factors and their interactions with environmental conditions and internal microenvironment influence the prostate cancer (PC) development, so that gene expression couldn't strictly occur on the basis of reductionist determinisms of DNA causality but should also conform to multifactorial and stochastic events, moreover, considering the pre-RNA alternative splicing-mediated multi-protein assemblying mechanisms. Nevertheless, after age and ethnic background, the strongest epidemiological risk factor for PC is a positive family history. However, apart from RNaseL-, ElaC2-, MSR1-genes, there are not other identified high-risk genetic variants which might be considered responsible for hereditary PC, moreover suggesting that familial PC is a genetically heterogeneous disease, many gene loci rather than a specific major susceptibility gene predisposing to it. Gene-environment interactions play a crucial role in cancer development especially when low penetrance genes, such as in case of genetic polymorphisms, are the major players. Several epidemiological studies show, in some families, a possible, either syncronous or metachronous, association of other tumors (breast, brain, gastrointestinal tumors, lymphomas) with PC, thus suggesting a common genetic background. As far as the role of androgen metabolism and androgen receptor (AR)-related genes in the development of familial PC is concerned, a small number of either guanine-guanine-cytosine (< 16) or cytosine-adenine-guanine (< 18) repeats appears to increase the AR activity, resulting in a raising PC risk. Regarding the expression of both androgen and estrogen receptor-related genes in sporadic and hereditary PC, the immunohistochemistry findings show that the percentage of AR-positive cancer cells is higher in hereditary PC than in sporadic forms, whereas the mean number of estrogen-alpha-receptor-positive stromal cells is higher in sporadic PC rather than in that hereditary. As for 5-alpha-steroid-reductase-2 gene, the dinucleotide thymine-adenine repeated 18 times on the last exon, confers an increased PC predisposition, as it is mainly shown in African-American populations. Also VDR gene, that is a component of ligand (steroid)-dependent nuclear transcription factor superfamily, shows various polymorphisms which appear to be associated with PC risk. Except an earlier age of onset, no anatomo-clinical and tumor progression peculiarities between hereditary and sporadic PC have been generally identified. Indeed, tumor progression and metastasis, both in hereditary and sporadic PC, are mainly influenced by a variety of biochemical and immune-mediated tumor microenvironmental conditions rather than by the hereditary genetic factors, thus gene expression associated with invasive ability representing a newly acquired genetic variant rather than a selection of pre-existent gene abnormalities in PC cells. It's questionable whether genetic testing of unaffected men of hereditary PC families might be actually useful. Nevertheless a suitable counselling must be proposed. Family history and/or gene profiling-guided preventive strategies for men at high risk of familial PC, range from dietary to drug measures. Cancer chemopreventive approaches may include 5-alpha-reductase inhibitors, histone deacetylase inhibitors, antioxidans, non-steroidal anti-inflammatory drugs, cholesterol-lowering statins, vitamin D analogues.

Eur Rev Med Pharmacol Sci. 2010 Jan;14(1):31-41

Silibinin inhibits established prostate tumor growth, progression, invasion, and metastasis and suppresses tumor angiogenesis and epithelial-mesenchymal transition in transgenic adenocarcinoma of the mouse prostate model mice.

PURPOSE: The chronic nature of prostate cancer growth and progression leading to metastasis provides a large window for intervention. Herein, for the first time, we investigated the effect and associated mechanisms of silibinin phosphatidylcholine (silybin-phytosome) on established prostate tumors in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. EXPERIMENTAL DESIGN: Twenty-week-old TRAMP male mice having palpable prostate tumor were fed with control or 0.5% and 1%, w/w, silybin-phytosome diets for 11 weeks and then sacrificed. RESULTS: Dietary silibinin inhibited the growth of prostate tumors (up to 60%, P < 0.001) and suppressed tumor progression from prostatic intraepithelial neoplasia to differentiated adenocarcinoma and poorly differentiated adenocarcinoma, with a complete absence of poorly differentiated adenocarcinoma at higher doses. It also inhibited the incidence of tumor invasion of seminal vesicle (up to 81%, P < 0.001) with complete absence of distant metastasis. Silibinin moderately inhibited tumor cell proliferation and induced apoptosis, but strongly suppressed tumor microvessel density (up to 60%, P < 0.001), vascular endothelial growth factor, and vascular endothelial growth factor receptor-2 expression. Antibody array analysis of plasma showed a decrease in the circulatory levels of vascular endothelial growth factor and basic fibroblast growth factor. Decreased levels of matrix metalloproteinases (MMP), snail-1, and vimentin, and an increased level of E-cadherin were also observed, indicating the anti-epithelial-mesenchymal transition effect of silibinin in tumors. CONCLUSIONS: Overall, silibinin treatment of TRAMP mice bearing prostate tumor inhibited tumor growth, progression, local invasion, and distant metastasis involving suppression of tumor angiogenesis and epithelial-mesenchymal transition. These findings would have greater relevance for the ongoing phase II clinical trial with silibinin-phytosome in prostate cancer patients.

Clin Cancer Res. 2008 Dec 1;14(23):7773-80

Remnant lipoproteins induced proliferation of human prostate cancer cell, PC-3 but not LNCaP, via low density lipoprotein receptor.

BACKGROUND: Hypertriglyceridemia has been shown to be one of the risk factors for prostate cancer. In this study, we investigated the effect of remnant lipoproteins on cell growth in prostate cancer cell lines. METHODS: Remnant lipoproteins were isolated as remnant like particles (RLP) from human plasma. We used RLP for TG-rich lipoproteins and low density lipoproteins (LDL) for cholesterol-rich lipoproteins respectively and examined the effect of lipoproteins on proliferation of PC-3 and LNCaP cells using MTS assays. Moreover, we studied the effect of RLP and LDL treatment on the regulation of lipoprotein receptors in prostate cancer cells to investigate the relationship between lipoprotein-induced cell proliferation and lipoprotein receptor expression using real-time PCR, Western blotting assays and siRNA. RESULTS: RLP effectively induced PC-3 cell proliferation more than LDL, whereas both RLP and LDL could not induce LNCaP cell proliferation except at a higher concentration of RLP. LDL receptor (LDLr) was expressed in both prostate cancer cells but there was a sharp difference of sterol regulation between two cells. In PC-3 cells, LDL decreased the LDLr expression in some degree, but RLP did not. Meanwhile LDLr expression in LNCaP was easily downregulated by RLP and LDL. Blocking LDLr function significantly inhibited both RLP- and LDL-induced PC-3 cell proliferation. CONCLUSIONS: This study demonstrated that RLP-induced PC-3 cell proliferation more than LDL; however, both RLP and LDL hardly induced LNCaP cell proliferation. The differences of proliferation by lipoproteins might be involved in the regulation of LDLr expression.

Cancer Epidemiol. 2009 Jul;33(1):16-23

Serum total homocysteine increases with the rapid proliferation rate of tumor cells and decline upon cell death: a potential new tumor marker.

BACKGROUND: We were interested to know why cancer patients are frequently associated with elevated circulating total homocysteine (tHcy) even though they are not treated with anti-folate drugs. METHODS: We employed tissue cultures to compare both the homocysteine (Hcy)-released and production of tumor markers between tumor and normal cell lines. RESULTS: We detected much higher concentrations of homocysteine (Hcy) released by the tumor cells. However, much less difference was found between normal and tumor cell lines when Hcy concentration was expressed per the same number of cells. During the cell culture, the increase of Hcy and the increase of tumor marker concentration paralleled each other for the first 7 days. After the seventh day of the culture when cells started dying, tumor markers continued to rise, whereas levels of Hcy and cell numbers leveled off. We found that the serum concentration of Hcy fluctuated in circulation coinciding with that of tumor marker in individual cancer patients unless taking anti-neoplastic drug. CONCLUSIONS: The elevation of tHcy concentration may be caused by the rapid tumor cell proliferation and reflect only the number of live cells. Serum Hcy may be a potentially useful tumor marker to monitor tumor activity.

Clin Chim Acta. 2002 Jul;321(1-2):55-62

Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance.

CONTEXT: We wanted to investigate vitamin D in low-risk prostate cancer. OBJECTIVES: The objective of the study was to determine whether vitamin D(3) supplementation at 4000 IU/d for 1 yr is safe and would result in a decrease in serum levels of prostate-specific antigen (PSA) or in the rate of progression. DESIGN: In this open-label clinical trial (Investigational New Drug 77,839), subjects were followed up until repeat biopsy. SETTING: All subjects were enrolled through the Medical University of South Carolina and the Ralph H. Johnson Veterans Affairs Medical Center, both in Charleston, SC. PATIENTS AND OTHER PARTICIPANTS: All subjects had a diagnosis of low-risk prostate cancer. Fifty-two subjects were enrolled in the study, 48 completed 1 yr of supplementation, and 44 could be analyzed for both safety and efficacy objectives. INTERVENTION: The intervention included vitamin D(3) soft gels (4000 IU). MAIN OUTCOME MEASURES: Adverse events were monitored throughout the study. PSA serum levels were measured at entry and every 2 months for 1 yr. Biopsy procedures were performed before enrollment (for eligibility) and after 1 yr of supplementation. RESULTS: No adverse events associated with vitamin D(3) supplementation were observed. No significant changes in PSA levels were observed. However, 24 of 44 subjects (55%) showed a decrease in the number of positive cores or decrease in Gleason score; five subjects (11%) showed no change; 15 subjects (34%) showed an increase in the number of positive cores or Gleason score. CONCLUSION: Patients with low-risk prostate cancer under active surveillance may benefit from vitamin D(3) supplementation at 4000 IU/d.

J Clin Endocrinol Metab. 2012 Jul;97(7):2315-24

Peptide hormone regulation of angiogenesis.

It is now apparent that regulation of blood vessel growth contributes to the classical actions of hormones on development, growth, and reproduction. Endothelial cells are ideally positioned to respond to hormones, which act in concert with locally produced chemical mediators to regulate their growth, motility, function, and survival. Hormones affect angiogenesis either directly through actions on endothelial cells or indirectly by regulating proangiogenic factors like vascular endothelial growth factor. Importantly, the local microenvironment of endothelial cells can determine the outcome of hormone action on angiogenesis. Members of the growth hormone/prolactin/placental lactogen, the renin-angiotensin, and the kallikrein-kinin systems that exert stimulatory effects on angiogenesis can acquire antiangiogenic properties after undergoing proteolytic cleavage. In view of the opposing effects of hormonal fragments and precursor molecules, the regulation of the proteases responsible for specific protein cleavage represents an efficient mechanism for balancing angiogenesis. This review presents an overview of the actions on angiogenesis of the above-mentioned peptide hormonal families and addresses how specific proteolysis alters the final outcome of these actions in the context of health and disease.

Physiol Rev. 2009 Oct;89(4):1177-215

Functional consequences of prolactin signalling in endothelial cells: a potential link with angiogenesis in pathophysiology?

Prolactin is best known as the polypeptide anterior pituitary hormone, which regulates the development of the mammary gland. However, it became clear over the last decade that prolactin contributes to a broad range of pathologies, including breast cancer. Prolactin is also involved in angiogenesis via the release of pro-angiogenic factors by leukocytes and epithelial cells. However, whether prolactin also influences endothelial cells, and whether there are functional consequences of prolactin-induced signalling in the perspective of angiogenesis, remains so far elusive. In the present study, we show that prolactin induces phosphorylation of ERK1/2 and STAT5 and induces tube formation of endothelial cells on Matrigel. These effects are blocked by a specific prolactin receptor antagonist, del1-9-G129R-hPRL. Moreover, in an in vivo model of the chorioallantoic membrane of the chicken embryo, prolactin enhances vessel density and the tortuosity of the vasculature and pillar formation, which are hallmarks of intussusceptive angiogenesis. Interestingly, while prolactin has only little effect on endothelial cell proliferation, it markedly stimulates endothelial cell migration. Again, migration was reverted by del1-9-G129R-hPRL, indicating a direct effect of prolactin on its receptor. Immunohistochemistry and spectral imaging revealed that the prolactin receptor is present in the microvasculature of human breast carcinoma tissue. Altogether, these results suggest that prolactin may directly stimulate angiogenesis, which could be one of the mechanisms by which prolactin contributes to breast cancer progression, thereby providing a potential tool for intervention.

J Cell Mol Med. 2012 Sep;16(9):2035-2048

Long-term outcomes after treatment with external beam radiation therapy and palladium 103 for patients with higher risk prostate carcinoma: influence of prostatic acid phosphatase.

BACKGROUND: The objective of this study was to define the long-term prognostic significance of prostatic acid phosphatase (PAP) levels in patients with higher risk, early-stage prostate carcinoma. METHODS: One hundred sixty-one consecutive patients with Stage T1-T3 prostate carcinoma (according to the 1992 criteria of the American Joint Committee on Cancer) were treated from 1992 through 1996. Each patient had a Gleason score > or = 7 and/or a prostate specific antigen (PSA) level > 10 ng/mL. The original biopsy slides for 130 of 161 patients were retrieved and rereviewed by a single pathologist (L.T.). Enzymatic PAP measurements were determined using a standard method. Values up to 2.5 Units were considered normal. Patients received 41 grays (Gy) of external beam radiation therapy to a limited pelvic field followed 4 weeks later by a palladium 103 (Pd-103) boost using transrectal ultrasound and fluoroscopic guidance as described previously. The prescribed minimum Pd-103 dose to the prostate was 80 Gy (pre-National Institute of Standards and Technology [NIST]-99). Freedom from biochemical failure was defined as a serum PSA level < or =0.2 ng/mL at last follow-up. RESULTS: There was little correlation between pretreatment PSA levels, Gleason scores, and PAP measurements. Thirty-eight patients developed biochemical failure. The overall actuarial freedom from biochemical progression at 10 years is 79%, with 118 patients followed for > 5 years. In a multivariate Cox proportional hazards analysis that considered each factor as a continuous variable, the strongest predictor of failure was PAP (P = 0.0001), followed by Gleason score (P = 0.13), and PSA (P = 0.04). PAP was especially helpful in stratifying patients with pretreatment PSA levels between 4 ng/mL and 20 ng/mL, for whom the prognosis does not different when they are subdivided into PSA categories. When the PAP subgroup analysis was limited to this relatively favorable group, there was a wide range of prognoses. CONCLUSIONS: The biochemical cure rate was remarkably high among the 161 patients evaluated. The fact that the PAP was the strongest predictor of long-term biochemical failure in patients with otherwise higher risk features reported here suggests that it may be a more accurate indicator of micrometastatic disease compared with the Gleason score and the PSA level. This report adds to the rationale for reintroducing PAP measurement into general practice.

Cancer. 2003 Feb 15;97(4):979-83

Green tea constituent epigallocatechin-3-gallate selectively inhibits COX-2 without affecting COX-1 expression in human prostate carcinoma cells.

Overexpression of cyclooxygenase (COX)-2 has been implicated in many pathologic conditions, including cancer. One practical inference of this finding is that sustained inhibition of COX-2 could serve as a promising target for prevention or therapy of cancer. Conventional nonsteroidal antiinflammatory drugs (NSAIDs) and recently developed COX-2-specific inhibitors have shown considerable promise in prevention of some forms of human cancer; however, its application is limited due to severe toxic side effects on normal cells. Therefore, there is a need to define novel, nontoxic dietary constituents with proven chemopreventive effects through other pathways that also possess COX-2 but not COX-1 inhibitory activity. Recent studies on green tea and its major polyphenolic constituent (-)epigallocatechin-3-gallate (EGCG) have established its remarkable cancer preventive and some cancer therapeutic effects. Here, we show that EGCG inhibits COX-2 without affecting COX-1 expression at both the mRNA and protein levels, in androgen-sensitive LNCaP and androgen-insensitive PC-3 human prostate carcinoma cells. Based on our study, it is tempting to suggest that a combination of EGCG with chemotherapeutic drugs could be an improved strategy for prevention and treatment of prostate cancer.

Int J Cancer. 2005 Feb 10;113(4):660-9

Combined inhibitory effects of green tea polyphenols and selective cyclooxygenase-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo.

PURPOSE: Cyclooxygenase-2 (COX-2) inhibitors hold promise for cancer chemoprevention; however, recent toxicity concerns suggest that new strategies are needed. One approach to overcome this limitation is to use lower doses of COX-2 inhibitors in combination with other established agents with complementary mechanisms. In this study, the effect of (-)epigallocatechin-3- gallate (EGCG), a promising chemopreventive agent from green tea, was tested alone and in combination with specific COX-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo. EXPERIMENTAL DESIGN: Human prostate cancer cells LNCaP, PC-3, and CWR22Rnu1 were treated with EGCG and NS398 alone and in combination, and their effect on growth and apoptosis was evaluated. In vivo, athymic nude mice implanted with androgen-sensitive CWR22Rnu1 cells were given green tea polyphenols (0.1% in drinking water) and celecoxib (5 mg/kg, i.p., daily, 5 days per week), alone and in combination, and their effect on tumor growth was evaluated. RESULTS: Combination of EGCG (10-40 micromol/L) and NS-398 (10 micromol/L) resulted in enhanced (a) cell growth inhibition; (b) apoptosis induction; (c) expression of Bax, pro-caspase-6, and pro-caspase-9, and poly(ADP)ribose polymerase cleavage; (d) inhibition of peroxisome proliferator activated receptor gamma; and (e) inhibition of nuclear factor-kappaB compared with the additive effects of the two agents alone, suggesting a possible synergism. In vivo, combination treatment with green tea polyphenols and celecoxib resulted in enhanced (a) tumor growth inhibition, (b) lowering of prostate-specific antigen levels, (c) lowering of insulin-like growth factor-I levels, and (d) circulating levels of serum insulin-like growth factor binding protein-3 compared with results of single-agent treatment. CONCLUSIONS: These data suggest synergistic and/or additive effects of combinatorial chemopreventive agents and underscore the need for rational design of human clinical trials.

Clin Cancer Res. 2007 Mar 1;13(5):1611-9