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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate cancer chemoprevention can be described as the administration of natural products and pharmaceutical agents that inhibit one or more steps in the natural history of prostatic carcinogenesis. The principle components of the chemoprevention strategy are closely connected to this natural history and include: (a) agents and their molecular targets; (b) strategic intermediate endpoint biomarkers (IEBs) and their critical pathways; (c) cohorts identified by genetic and acquired risk factors and (d) efficient designs that combine these elements into a cohesive clinical trial. The primary goal is to find effective noncytotoxic agents that modulate the promotion and progression from normal epithelium to dysplasia to high-grade prostatic intraepithelial neoplasia (HGPIN) to locally invasive cancer and metastatic disease. Another important target for chemoprevention is to modulate progression to clinically aggressive disease and to maintain an androgen-sensitive clinical state and delay the emergence of androgen resistance. There is a rationale for use of antiandrogens as the lead class, e.g., 5 alpha receptor inhibitors (5ARI), for chemoprevention of prostate cancer. Nevertheless, the desire to improve the therapeutic index, achieve synergy (5ARI may have only modest anticancer effects) and prevent the emergence of drug (androgen) resistance provide incentives for developing other effective agents and combinations. The availability of more than a dozen classes of noncytotoxic pharmaceutical and natural products already in clinical development create many opportunities for rational combination therapy. Several agent classes have a pharmacodynamic basis for combination with antiandrogens including antiproliferatives, selective estrogen receptor modulators (SERMs), proapoptotic antioxidant micronutrients and selective cyclo-oxygenase (COX)-2 inhibitors. Many other rational pharmacodynamic combinations without antiandrogens are feasible. It is anticipated that in the future, a selective COX-2 inhibitor may be combined with other agent classes such as proapoptotic antioxidant micronutrients, receptor tyrosine kinase modulators, antiangiogenic modulators, antiproliferative/differentiating agents, NFkappaB modulators, IGF-1 modulators and other novel proapototic nonsteroidal drugs. A novel target for rational combinations is the hypermethylation of GST-PI leading to functional silencing of this key anticarcinogen defense enzyme in precursors (HGPIN) and prostate cancer. Factorial designs are well suited for evaluating the individual and combined effects of each agent in a single trial design. There are a number of moderate to high-risk cohorts and clinical models of primary and secondary prevention that can be employed in both short-term developmental (translational) trials for proof of biologic activity and in intermediate sized longer-term chemoprevention trials for proof of efficacy against prostate cancer. Strategic IEBs are needed to more efficiently monitor short-term biologic activity and validate efficacy. The emergence of new powerful tools such as gene chip cDNA microarrays for multiplex gene expression profiling and proteomic analysis of tissue based and secreted proteins will accelerate the identification of new molecular targets, strategic endpoints, cohorts at risk and the design of rational combination trials.
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PMID:Chemoprevention of prostate cancer: current status and future directions. 1254 68

In recent years a dramatic surge has occurred on studies defining to the role of cyclooxygenase (COX)-2 in causation and prevention of cancer. Prostaglandin (PG) endoperoxidase synthase also commonly referred to as COX is a key enzyme involved in the conversion of arachidonic acid to PGs and other eicosanoids. COX exists as two isoforms, namely COX-1 and COX-2 with distinct tissue distribution and physiological functions. COX-1 is constitutively expressed in many tissues and cell types and is involved in normal cellular physiological functions whereas COX-2 is pro-inflammatory in nature and is inducible by mitogens, cytokines, tumor promoters and growth factors. A large volume of data exists showing that COX-2 is overexpressed in a large number of human cancers and cancer cell lines. The possibility of COX-2 as a candidate player in cancer development and progression evolved from the epidemiological studies which suggest that regular use of aspirin or other non-steroidal anti-inflammatory drugs could significantly decrease the risk of developing cancers in experimental animals and in humans. In our recently published study (Prostate, 42 2000 73-78), we provided the first evidence that COX-2 is overexpressed in human prostate adenocarcinoma. Many other studies verified our initial observation and reported that compared to normal tissue, COX-2 is overexpressed in human prostate cancer. It should be noted that some recent work has suggested that COX-2 is only up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. In this scenario, COX-2 inhibitors could afford their effects against prostate carcinogenesis by modulating COX-2 activity in other cells in prostate. An exciting corollary to this ongoing work is that selective COX-2 inhibitors may exhibit chemopreventive and even chemotherapeutic effects against prostate carcinogenesis in humans.
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PMID:Cyclooxygenase-2 and prostate carcinogenesis. 1261 25

The etiology of prostate cancer remains virtually unknown. Although there are a number of new leads with regard to risk factors for prostate cancer, more research is required to confirm them. There is little purpose in conducting further case-control studies of prostate cancer-particularly since the use of PSA testing has become wide-spread. Instead, future epidemiologic studies should focus on prostate tumor subclassification, in terms of method of detection, markers of biological "aggressiveness," and genetic changes. Many of these new leads involve the possible influence of polymorphisms in key genes involved in important physiologic processes in the prostate. To fully explore the complexity of interrelationships between the several elements in these pathways will require large cohort studies in which blood is sampled prior to diagnosis. Such studies will be important for identifying which modifiable aspects of lifestyle (such as diet, alcohol, tobacco, physical activity) might be targeted for intervention, to reduce risk. The detection of early prostate cancers by PSA testing relatives of men with prostate cancer has affected the prevalence of phenocopies and, hence, the meaningfulness of risk estimation in prostate cancer families. Because multiple-case families form the substrate for gene hunting via linkage analysis, this phenocopy phenomenon is going to cause considerable confusion and wasted effort. Presently, men with a family history of prostate cancer can be provided with little advice in terms of preventive action. It is likely that one or more genetic mutations associated with a high risk for prostate cancer will be identified in the near future. Even so, the risks probably will be similar to those for mutations in the first two breast cancer genes--informative for very few families. It is difficult to foresee, as and when high-risk mutation carriers are identified, what advice should be offered to them: prophylactic prostatectomies seem to have less attraction than do prophylactic mastectomies for women at high risk of breast cancer. This issue becomes more complex when considering counseling on the basis of a genetic profile involving many low-risk polymorphisms. Hopefully, such genetic screening should occur only after its efficacy has been established; when there is a better understanding of prostate biology, tumor heterogeneity, and prognosis; and when there are proven treatment or prevention options available. Prevention is held to be better than cure, and there are some potentially interesting chemopreventive agents that require careful trial before public health initiatives can be promoted. Potential candidates include vitamin E, selenium, zinc, and lycopene as dietary supplements. There are other agents that may be appropriate for pharmaceutical development, including inhibitors of COX-2 and IGF-1 activity. It is important that chemoprevention trials are followed-up for a sufficient period of time and that other endpoints also are captured, because the supplementation of diets with superphysiologic doses of individual micronutrients sometimes has caused unexpected and unwanted results--for example, an 18% increase in lung cancers observed in the beta-carotene arm of the ATBC trial.
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PMID:The epidemiology of prostate cancer. 1273 98

By 2004-2005, the final results of the Prostate Cancer Prevention Trial should be available. Within several years thereafter, results of the SELECT should be available. The growing list of potential agents for prostate cancer prevention continues to grow and includes COX-2 inhibitors, vitamin D, dietary interventions (soy, isoflavenoids, low-fat diet), and many others. As prospective trials are completed and molecular genetic correlations are developed, it is almost certain that specific recommendations, tailored to the individual patient, will be developed. Ultimately, through these efforts, it can be anticipated that the primary focus for control of prostate cancer will shift from early detection and treatment to prevention.
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PMID:Chemoprevention of prostate cancer. Focus on key opportunities and clinical trials. 1273

Chemoprevention of cancer is reviewed from the viewpoints of action mechanisms and methodology of clinical trials in order to introduce promising agents discovered by in vitro and/or in vivo studies to applications in humans. The clinical trial procedure essentially follows the phase study which has been employed for chemotherapeutic drugs. Chemoprevention of bladder cancer, prostate cancer, gastric cancer, hepatocellular carcinoma, breast cancer, head and neck cancer, colorectal cancer and lung cancer is reviewed, mainly focusing on clinical trials. Previous clinical trials have shown the effectiveness of the following: polyprenoic acid (acyclic retinoid) for hepatocellular carcinoma; tamoxifen for breast cancer; retinoic acids for head and neck tumor; and aspirin, a COX-2 inhibitor, for colorectal cancer. Despite the advantageous effects of some of these agents, their toxic effects must also be of concern at the same time. For example, in a chemoprevention trial of lung cancer, beta-carotene was unexpectedly found to increase the risk of lung cancer among high-risk groups. It is also noted that large-scale clinical trials demand large research grants, which may not be affordable in Japan. Chemoprevention is still an emerging field of oncology where researchers in both basic and clinical sciences face great challenges.
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PMID:Chemoprevention of cancer--focusing on clinical trials. 1459 36

Arachidonic acid metabolism through cyclooxygenase, lipoxygenase, or P-450 epoxygenase pathways can generate a variety of eicosanoids. Thromboxane synthase (TxS) metabolizes the cyclooxygenase product, prostanglandin H(2), into thromboxane A(2) (TXA(2)), which can cause vessel constriction, platelet activation, and aggregation. Here we demonstrate that human prostate cancer (PCa) cells express enzymatically active TxS and that this enzyme is involved in cell motility. In human PCa cell lines, PC-3, PC-3M, and ML-2 cells expressed higher levels of TxS than normal prostate epithelial cells or other established PCa cell lines such as DU145, LNCaP, or PPC-1. We cloned and sequenced the full-length TxS cDNA from PC-3 cells and found two changes in the amino acid residues. Immunohistochemical analysis of tumor specimens revealed that expression of TxS is weak or absent in normal differentiated luminal, or secretory cells, significantly elevated in less differentiated or advanced prostate tumors, and markedly increased in tumors with perineural invasion. TxS expressed in PC-3 cells was enzymatically active and susceptible to carboxyheptal imidazole, an inhibitor of TxS. The biosynthesis of TXA(2) in PC-3 cells was dependent on COX-2, and to a lesser extent, COX-1. Treatment of PC-3 cells with a COX-1 selective inhibitor, piroxicam, reduced TXA(2) synthesis by approximately 40%, while the COX-2 specific inhibitor NS398 reduced TXA(2) production by approximately 80%. Inhibition of TxS activity or blockade of TXA(2) function reduced PC-3 cell migration on fibronectin, while having minimal effects on cell cycle progression or survival. Finally, increased expression of TxS in DU145 cells increased cell motility. Our data suggest that human PCa cells express TxS and that this enzyme may contribute to PCa progression through modulating cell motility.
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PMID:Differential expression of thromboxane synthase in prostate carcinoma: role in tumor cell motility. 1474 49

The aims of this study were to examine the anti-proliferative effects of different concentrations of a commercial preparation of conjugated linoleic acids (CLA) mixture of isomers [cis-9, trans-11 CLA (c9,t11 CLA): trans-10, cis-12 CLA (50:50)] and their constituent isomers on PC-3, a human prostatic carcinoma cell line, and to study their effects on gene expression (mRNA and protein levels) of different enzymes and oncoproteins involved in oncogenesis and progression of prostate cancer. This includes pathways for arachidonic acid metabolism [cyclooxygenase 1 (COX-1), 2 (COX-2) and 5-lipoxygenase (5-LOX)], apoptosis (bcl-2) and cell cycle control (p21(WAF/Cip1)). Our results indicate a significant decrease in PC-3 proliferation elicited by CLA, although with high variability between isomers. The trans-10, cis-12 CLA was the most effective isomer (55% inhibition). This isomer was also able to decrease bcl-2 gene expression and to increase p21(WAF1/Cip1) mRNA levels (60% increase at highest concentration). In contrast, cis-9, trans-11 had no effect on these proteins but had a clear effect on 5-LOX expression and to a lesser degree on COX-2 protein level isomers. In conclusion, the anti-proliferative effects on PC-3 of CLA mixture and their constituent isomers are not equivalent, due to the different pathways involved for individual isomers. Trans-10, cis-12 seems to work preferentially through modulation of apoptosis and cell cycle control, while c9,t11 CLA isomer affects arachidonic acid metabolism.
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PMID:Conjugated linoleic acids (CLAs) decrease prostate cancer cell proliferation: different molecular mechanisms for cis-9, trans-11 and trans-10, cis-12 isomers. 1497 30

Experimental and epidemiologic studies have demonstrated that nonsteroidal antiinflammatory drugs (NSAIDs) are effective in the prevention of human cancers. Nonsteroidal antiinflammatory drugs inhibit the cyclooxygenase (COX) enzyme that functions to convert arachidonic acid to prostaglandins (PGs). Cyclooxygenase-2, a key COX isoenzyme, is rapidly induced in response to inflammatory stimuli, growth factors, cytokines, and promoters of neoplastic growth. Cyclooxygenase-2-catalyzed reactions may be involved in carcinogenesis via 2 distinct mechanisms: (1). DNA damage and (2). PG-mediated effects. Reactions mediated by COX-2 form reactive oxygen species that can directly induce the oxidation of DNA or instigate the bioactivation of carcinogens. Prostaglandin E2, a byproduct of COX-2-mediated arachidonic acid metabolism, exhibits several biologic actions that have been shown to promote tumorigenesis and tumor progression. These actions include increased cell proliferation, promotion of angiogenesis, and the elevated expression of the antiapoptotic protein Bcl-2. In addition, PGE2 decreases natural killer cell activity and alters immune surveillance. In vitro experimental studies find that COX-2 inhibitors decrease cellular proliferation, increase apoptosis, and modulate genes involved in cell cycle regulation. Evidence from animal studies supports a role for NSAIDs in prostate cancer (CaP) prevention. Population-based studies have observed a reduced incidence of CaP among men using NSAIDs. Because CaP evolves slowly and rarely strikes men before the sixth or seventh decade of life, any strategy to delay or lengthen the time to development of clinically evident CaP, such as chemoprevention strategies, would greatly impact the natural history of this disease. Recent progress and critical analyses in the roles of COX-2 inhibition on prostate carcinogenesis and CaP prevention will be presented.
Clin Prostate Cancer 2003 Sep
PMID:The role of cyclooxygenase-2 inhibition for the prevention and treatment of prostate carcinoma. 1504 Aug 74

Senescence-associated changes in the prostate are believed to play an important role in the genesis of prostate cancer. In order to provide further information on how aging increases the prostate susceptibility to cancer, we examined the pattern of cyclooxygenase (COX)-2 expression and the concomitant alterations in prostaglandin E(2) (PGE(2)) synthesis in the prostate glands of 4-, 10-, 50- and 100-week-old Fischer 344 rats. This was carried out in the prostatic areas where hormone-induced tumors arise, namely the periurethral ducts of the dorsolateral prostate (DLP). Age-associated changes were also evaluated for pro- and anti-apoptotic factors linked to COX-2 signaling and known to be involved in the normal development of the prostate gland as well as in carcinogenesis. COX-2 expression was increased in the DLP in an age-dependent manner where senescent rats had >3-4-fold higher COX-2 mRNA and protein levels than their juvenile counterparts (P<0.05). The age-related changes in COX-2 were accompanied by a similar up-regulation in the PGE(2) synthesis. Evaluation of mediators of apoptotic signaling showed a significant (P<0.05) decline in the expression levels of the pro-apoptotic BAX (>6-fold) and peroxisome proliferator-activated receptor gamma (>3-fold) and in caspase-3 activity (>2-fold) and an up-regulation of the anti-apoptotic Bcl(2) (>8-fold), PKCalpha (>2-fold) and pAkt (>4-fold) in the 100-week-old rats versus the 4-week-old animals. There was an approximately 15-fold age-dependent decrease in the pro-apoptotic ratio BAX:Bcl(2) and an increase in the anti-apoptotic variable PKCalpha(*)Bcl(2)/BAX in the senescent rats compared with the juvenile ones. These results suggest that increased COX-2 expression can be linked to the decline in the pro-apoptotic signaling in the prostate gland during aging. Subsequently, COX-2 inhibitors can be considered as a promising class of agents to attenuate the increased cell survival and, hence, protect against tumorigenesis in the aging prostate.
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PMID:Age-associated changes in the expression pattern of cyclooxygenase-2 and related apoptotic markers in the cancer susceptible region of rat prostate. 1511 12

Epidemiological studies and clinical observations suggest that nonsteroidal anti-inflammatory drugs and certain selective cyclooxygenase (COX)-2 inhibitors may reduce the relative risk of clinically evident prostate cancer. This prompted us to investigate the chemopreventive potential of celecoxib, a selective COX-2 inhibitor, against prostate carcinogenesis in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Similar to prostate cancer in humans, prostate malignancies in TRAMP mice progress from precursor intraepithelial lesions, to invasive carcinoma that metastasizes to lymph nodes, liver, lungs, and occasionally to bone. The basal enzyme activity and protein expression of COX-2 is significantly higher (>4-fold) in the dorsolateral prostate of TRAMP mice up to 24 weeks of age compared with their nontransgenic littermates. Eight-week-old TRAMP mice were randomly divided and fed either control diet (AIN 76A) or a custom prepared AIN 76A diet containing 1500-ppm celecoxib ad libitum for 24 weeks, a dosage that would compare with the normal recommended dose for the treatment of human disease. Studies from two independent experiments, each consisting of 10 mice on test, showed that the cumulative incidence of prostate cancer development at 32 weeks of age in animals fed with AIN 76A diet was 100% (20 of 20) as observed by tumor palpation, whereas 65% (13 of 20), 35% (7 of 20), and 20% (4 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, and liver. Celecoxib supplementation to TRAMP mice from 8-32 weeks of age exhibited significant reduction in tumor development (5 of 20) with no signs of metastasis. Celecoxib feeding resulted in a significant decrease in prostate (56%; P < 0.0003) and genitourinary weight (48%; P < 0.008). Sequential magnetic resonance imaging analysis of celecoxib-fed mice documented lower prostate volume compared with the AIN 76A-fed group. Histopathological examination of celecoxib-fed animals showed reduced proliferation, and down-modulation of COX-2 and prostaglandin E2 levels in the dorsolateral prostate and plasma, respectively. These results correlated with retention of antimetastasis markers, viz E-cadherin, and alpha- and beta-catenin, along with a significant decrease in vascular endothelial growth factor protein expression. Celecoxib supplementation also resulted in enhanced in vivo apoptosis in the prostate as monitored by several techniques including a recently perfected technique of 99mTc-labeled annexin V in live animals followed by phosphor imaging. One striking observation in an additional study was that celecoxib feeding to mice with established tumors (16 weeks of age) significantly improved their overall survival (P = 0.014), compared with AIN 76A-fed group. Our findings suggest that celecoxib may be useful in chemoprevention of prostate cancer.
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PMID:Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model. 1512 78


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