Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate apoptosis response-4 (Par-4) is the product of a gene up-regulated in prostate cancer cells undergoing apoptosis. We now report that Par-4 mRNA and protein levels rapidly and progressively increase 4-24 h following trophic factor withdrawal (TFW) in cultured embryonic rat hippocampal neurons. The increased Par-4 levels follow an increase of reactive oxygen species, and precede mitochondrial membrane depolarization, caspase activation, and nuclear chromatin condensation/fragmentation. Pretreatment of cultures with 17beta-estradiol, vitamin E, and uric acid largely prevented Par-4 induction and cell death following TFW, demonstrating necessary roles for oxidative stress and membrane lipid peroxidation in TFW-induced neuronal apoptosis. Par-4 antisense oligonucleotide treatment blocked Par-4 protein increases and attenuated mitochondrial dysfunction, caspase activation, and cell death following TFW. Collectively, our data identify Par-4 as an early and pivotal player in neuronal apoptosis resulting from TFW and suggest that estrogen and antioxidants may prevent apoptosis, in part, by suppressing Par-4 production.
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PMID:Prostate apoptosis response-4 mediates trophic factor withdrawal-induced apoptosis of hippocampal neurons: actions prior to mitochondrial dysfunction and caspase activation. 1042 45

Prostate cancer is the most common human malignancy and the second leading cause of cancer deaths among men in Western nations. Descriptive epidemiologic data suggest that androgens and/or environmental exposures, such as diet (in particular, dietary fat), play an important role in prostatic carcinogenesis. One plausible link between diet and prostate cancer is oxidative stress. This process refers to the generation of reactive oxygen species, which can then trigger a host of pro-carcinogenic processes. Recent studies also indicate that androgens increase oxidative stress within human prostate cancer cell lines. Recent data from our institution indicate that oxidative stress is higher within the benign epithelium of prostate cancer patients than men without the disease. This confirms our hypothesis and suggests that antioxidants such as lycopene, vitamin E, and selenium may play an important role in preventing disease progression. Large-scale clinical trials with some of these agents are currently in the design phase.
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PMID:Diet, androgens, oxidative stress and prostate cancer susceptibility. 1045 75

This population-based, case-control study in King County, Washington examined supplement use in 697 incident prostate cancer cases (ages 40-64) identified from the Puget Sound Surveillance, Epidemiology and End Results program registry and 666 controls recruited from the same overall population using random-digit dialing sampling. Participants reported their frequency of use of three types of multivitamins and single supplements of vitamins A, C, and E, calcium, iron, and zinc over the 2 years before diagnosis. Logistic regression analyses controlled for age, race, education, family history of prostate cancer, body mass index, number of prostate-specific antigen tests in the previous 5 years, and dietary fat intake. Adjusted odds ratios (95% confidence limits) for the contrast of > or =7/week versus no use were as follows: multivitamins, 0.96 (0.73, 1.26); vitamin A, 0.59 (0.32, 1.06); vitamin C, 0.77 (0.57, 1.04); vitamin E, 0.76 (0.54, 1.08); calcium, 1.04 (0.61, 1.78); iron, 0.50 (0.13, 1.76); and zinc, 0.55 (0.30, 1.00). Odds ratios differed little when cases were stratified by stage of disease at diagnosis or by histopathological grade. There were significant dose-response effects for zinc and ordered dose-response trends for vitamins C and E. Overall, these results suggest that multivitamin use is not associated with prostate cancer risk, but use of individual supplements of zinc, vitamin C, and vitamin E may be protective. Further study is needed to investigate the direct role of these dietary supplements, as well as the role of lifestyle variables associated with supplement use, on prostate cancer risk.
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PMID:Vitamin and mineral supplement use is associated with reduced risk of prostate cancer. 1054 17

A clinical trial of vitamin E and beta-carotene supplementation for lung cancer prevention among male smokers in Finland recently reported an unexpected, strong protective effect of vitamin E against prostate cancer incidence and mortality. Our objective was to prospectively examine supplemental vitamin E intake and prostate cancer risk in a distinct U.S. population. In 1986, we identified 47,780 U.S. male health professionals, free from diagnosed cancer, who completed a dietary and lifestyle questionnaire; supplemental vitamin E and prostate cancer incidence were updated biennially through 1996. We estimated relative risks (RRs) from multivariate pooled logistic regression models. There were 1896 total (non-stage A1), 522 extraprostatic, and 232 metastatic or fatal incident prostate cancer cases diagnosed between 1986-1996. Men consuming at least 100 IU of supplemental vitamin E daily had multivariate RRs of 1.07 (95% confidence interval [CI], 0.95-1.20) for total and 1.14 (95% CI, 0.82-1.59) for metastatic or fatal prostate cancer compared with those consuming none. Current use, dosage, and total duration of use of specific vitamin E supplements or multivitamins were not associated with risk. However, among current smokers and recent quitters, those who consumed at least 100 IU of supplemental vitamin E per day had a RR of 0.44 (95% CI, 0.18-1.07) for metastatic or fatal prostate cancer compared with nonusers. Thus, supplemental vitamin E was not associated with prostate cancer risk generally, but a suggestive inverse association between supplemental vitamin E and risk of metastatic or fatal prostate cancer among current smokers and recent quitters was consistent with the Finnish trial among smokers and warrants further investigation.
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PMID:Supplemental vitamin E intake and prostate cancer risk in a large cohort of men in the United States. 1054 18

There is evidence supporting a role for sex hormones in the etiology of prostate cancer. Supplementation with alpha-tocopherol reduced prostate cancer in the alpha-Tocopherol, beta-Carotene Prevention Study (ATBC Study). The objective of this study was to assess the relation of baseline levels of serum alpha-tocopherol and serum sex hormones in older men. A cross-sectional analysis of serum alpha-tocopherol and sex hormone concentrations was conducted within a subset of the ATBC Study. Serum was collected in the morning after an overnight fast at baseline from 204 men ages 50-69 years participating in the ATBC Study and free of prostate cancer. Hormones were measured by radioimmunoassay, and alpha-tocopherol was measured by high-performance liquid chromatography by standard procedures. Multivariate linear regression was used to evaluate the association of serum alpha-tocopherol with nine androgens and estrogens after controlling for age, body mass index, hormone assay batch, and serum cholesterol. Serum alpha-tocopherol was significantly inversely associated with serum androstenedione, testosterone, sex hormone-binding globulin, and estrone. The difference in hormone concentration per milligram of alpha-tocopherol was 1.8-2.6% for these four hormones. These results indicated that alpha-tocopherol is related to concentrations of several sex hormones in older men and may have implications for the observed protective effect of supplemental vitamin E in relation to prostate cancer in the ATBC Study.
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PMID:Association between serum alpha-tocopherol and serum androgens and estrogens in older men. 1062 1

A review is presented of studies on the effects of vitamin E on heart disease, studies encompassing basic science, animal studies, epidemiological and observational studies, and four intervention trials. The in vitro, cellular, and animal studies, which are impressive both in quantity and quality, leave no doubt that vitamin E, the most important fat-soluble antioxidant, protects animals against a variety of types of oxidative stress. The hypothesis that links vitamin E to the prevention of cardiovascular disease (CVD) postulates that the oxidation of unsaturated lipids in the low-density lipoprotein (LDL) particle initiates a complex sequence of events that leads to the development of atherosclerotic plaque. This hypothesis is supported by numerous studies in vitro, in animals, and in humans. There is some evidence that the ex vivo oxidizability of a subject's LDL is predictive of future heart events. This background in basic science and observational studies, coupled with the safety of vitamin E, led to the initiation of clinical intervention trials. The three trials that have been reported in detail are, on balance, supportive of the proposal that supplemental vitamin E can reduce the risk for heart disease, and the fourth trial, which has just been reported, showed small, but not statistically significant, benefits. Subgroup analyses of cohorts from the older three trials, as well as evidence from smaller trials, indicate that vitamin E provides protection against a number of medical conditions, including some that are indicative of atherosclerosis (such as intermittent claudication). Vitamin E supplementation also produces an improvement in the immune system and protection against diseases other than cardiovascular disease (such as prostate cancer). Vitamin E at the supplemental levels being used in the current trials, 100 to 800 IU/d, is safe, and there is little likelihood that increased risk will be found for those taking supplements. About one half of American cardiologists take supplemental vitamin E, about the same number as take aspirin. In fact, one study suggests that aspirin plus vitamin E is more effective than aspirin alone. There are a substantial number of trials involving vitamin E that are in progress. However, it is possible, or even likely, that each condition for which vitamin E provides benefit will have a unique dose-effect curve. Furthermore, different antioxidants appear to act synergistically, so supplementation with vitamin E might be more effective if combined with other micronutrients. It will be extremely difficult to do trials that adequately probe the dose-effect curve for vitamin E for each condition that it might affect, or to do studies of all the possible combinations of other micronutrients that might act with vitamin E to improve its effectiveness. Therefore, the scientific community must recognize that there never will be a time when the science is "complete." At some point, the weight of the scientific evidence must be judged adequate; although some may regard it as early to that judgement now, clearly we are very close. In view of the very low risk of reasonable supplementation with vitamin E, and the difficulty in obtaining more than about 30 IU/day from a balanced diet, some supplementation appears prudent now.
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PMID:Vitamin E and heart disease: basic science to clinical intervention trials. 1065

More than 40 promising agents and agent combinations are being evaluated clinically as chemopreventive drugs for major cancer targets. A few have been in vanguard, large-scale intervention trials--for example, the studies of tamoxifen and fenretinide in breast, 13-cis-retinoic acid in head and neck, vitamin E and selenium in prostate, and calcium in colon. These and other agents are currently in phase II chemoprevention trials to establish the scope of their chemopreventive efficacy and to develop intermediate biomarkers as surrogate end points for cancer incidence in future studies. In this group are fenretinide, 2-difluoromethylornithine, and oltipraz. Nonsteroidal anti-inflammatories (NSAID) are also in this group because of their colon cancer chemopreventive effects in clinical intervention, epidemiological, and animal studies. New agents are continually considered for development as chemopreventive drugs. Preventive strategies with antiandrogens are evolving for prostate cancer. Anti-inflammatories that selectively inhibit inducible cyclooxygenase (COX)-2 are being investigated in colon as alternatives to the NSAID, which inhibit both COX-1 and COX-2 and derive their toxicity from COX-1 inhibition. Newer retinoids with reduced toxicity, increased efficacy, or both (e.g., 9-cis-retinoic acid) are being investigated. Promising chemopreventive drugs are also being developed from dietary substances (e.g., green and black tea polyphenols, soy isoflavones, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol). Basic and translational research necessary to progress in chemopreventive agent development includes, for example, (1) molecular and genomic biomarkers that can be used for risk assessment and as surrogate end points in clinical studies, (2) animal carcinogenesis models that mimic human disease (including transgenic and gene knockout mice), and (3) novel agent treatment regimens (e.g., local delivery to cancer targets, agent combinations, and pharmacodynamically guided dosing).
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PMID:Progress in cancer chemoprevention. 1066 77

Increased intake of fruits and vegetables seems to be one of the simplest means of decreasing the risk for cancer. Cancer-preventive effects of fruits and vegetables have been observed in epidemiological studies, which could not, however, distinguish the effects of the various ingredients. Antioxidant defence has been proposed as a mechanism of chemoprevention, although inconclusive results have been obtained. The results of randomized intervention trials have shown that beta-carotene supplements are of limited value and may even be deleterious. Vitamins are a good marker of the ingestion of fruits and vegetables, and vitamin E (alpha-tocopherol) is a lipid-soluble antioxidant which can scavenge free radicals. It has no significant effect on the risk for lung cancer of long-term smokers in an intervention trial, but it decreased both the incidence of and mortality from prostate cancer; however, there was a 50% increase in the occurrence of cerebral haemorrhage among the men given vitamin E. Aspirin and aspirin-like drugs appear to decrease the risk for intestinal tumours; the mechanism of action appears to involve diminishing prostaglandin production due to inhibition of cyclooxygenases. Dietary fibre has been linked to a reduced risk for colorectal cancer in many observational studies, but opposite findings were reported recently. In order to resolve these paradoxes, we need to understand better the underlying biology, develop mechanistic hypotheses and test them in clinical trials in humans. Until that time, we should confine any premature enthusiasm for chemopreventive micronutrient supplementation.
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PMID:Chemoprevention of cancer: a controversial and instructive story. 1074 49

Recent clinical trials have demonstrated the significant cancer preventive potential of vitamin E in many different cancer sites, ranging from oral and pharyngeal cancer to prostate cancer. There is an extensive experimental basis for this clinical cancer inhibition. The experimental background includes animal studies (experimental pathology, immunology and molecular biology, synergism, selectivity and safety), in vitro biochemical studies, and human studies (epidemiology and biomarkers, prevention of many pathologic entities other than cancer).
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PMID:Experimental basis for cancer prevention by vitamin E. 1075 90

If one were to wait for the perfect set of experimental results before launching a multi-agent chemoprevention or large risk reduction study, the trial would never be launched. On the other hand, non-scientific considerations have led to the premature launching of at least three prominent studies (CARET, Carotene and Retinol Efficacy Trial; ATBC, Apha Tocopherol Beta Carotene; PCPT, Prostate Cancer Prevention Trial) and the much delayed start-up of another, BCPT, the Breast Cancer Prevention Trial. Strong epidemiologic data by itself should not be adequate to justify starting a large trial; experimental and/or clinical data should be developed. On the other hand fear of secondary adverse events that are of low incidence should not be enough to delay a trial if the overall health benefit could be high. The development of multiagent chemoprevention trials requires that each agent is active and additively or synergistically so in combination in preclinical models. Additionally, side effects of each agent should be non-overlapping and low to non-existent, preferably a feature determined in formal phase IIa and IIb trials. These principles will be discussed in the context of prior (CARET, ATBC) and ongoing (EUROSCAN, acetylcysteine/retinol), as well as proposed future trials (difluromethyl/sulindac).
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PMID:Criteria for implementation of large and multiagent clinical chemoprevention trials. 1076 23


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