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P Greenwald

Publications and source records attributed to P Greenwald.

At least 19 recordsLinked to original sources
PubMed2005

Allellic variants in regulatory regions of cyclooxygenase-2: association with advanced colorectal adenoma.

Cyclooxygenase 2 (Cox-2) is upregulated in colorectal adenomas and carcinomas. Polymorphisms in the Cox-2 gene may influence its function and/or its expression and may modify the protective effect of nonsteroidal anti-inflammatory drugs (NSAIDs), thereby impacting individuals' risk of developing colorectal cancer and response to prevention/intervention strategies. In a nested case-control study, four polymorphisms in the Cox-2 gene (two in the promoter, -663 insertion/deletion, GT/(GT) and -798 A/G; one in intron 5-5229, T/G; one in 3'untranslated region (UTR)-8494, T/C) were genotyped in 726 cases of colorectal adenomas and 729 age- and gender-matched controls in the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial. There was no significant association between the Cox-2 polymorphisms and adenoma development in the overall population. However, in males, the relatively rare heterozygous genotype GT/(GT) at -663 in the promoter and the variant homozygous genotype G/G at intron 5-5229 appeared to have inverse associations (odds ratio (OR)=0.59, confidence interval (CI): 0.34-1.02 and OR=0.48, CI: 0.24-0.99, respectively), whereas the heterozygous genotype T/C at 3'UTR-8494 had a positive association (OR=1.31, CI: 1.01-1.71) with adenoma development. Furthermore, the haplotype carrying the risk-conferring 3'UTR-8494 variant was associated with a 35% increase in the odds for adenoma incidence in males (OR=1.35, CI: 1.07-1.70), but the one with a risk allele at 3'UTR-8494 and a protective allele at intron 5-5229 had no effect on adenoma development (OR=0.85, CI: 0.66-1.09). Gender-related differences in adenoma risk were also noted with tobacco usage and protective effects of NSAIDs. Our analysis underscores the significance of the overall allelic architecture of Cox-2 as an important determinant for risk assessment.

Adenoma↗
PubMed2001

From carcinogenesis to clinical interventions for cancer prevention.

During the last three decades, the scientific community has made immense progress in acquiring the knowledge needed to prevent cancer. Pioneering research helped to identify potential causes of cancer, particularly environmental factors such as diet, and provided insight regarding their mechanisms-of-action. Concurrently, promising inhibitors of cancer that appeared able to either arrest or reverse cancer development by interfering with one or more steps in the process of carcinogenesis were identified and systematically evaluated for their potential as chemopreventive agents. Numerous agents determined to be safe and effective in preclinical trials have been and continue to be tested in Phase I,II, and III clinical interventions for cancers at various sites, including breast, colon, prostate, esophagus, mouth, lung, cervix, endometrium, ovary, liver, bladder, and skin. The development of valid intermediate biomarkers that can serve as surrogate endpoints for clinical disease is urgently needed to accelerate advances in clinical trials for cancer prevention.

Anticarcinogenic Agents↗
PubMed2001

Diet and cancer prevention.

Research from several sources provides strong evidence that vegetables, fruits, and whole grains, dietary fibre, certain micronutrients, some fatty acids and physical activity protect against some cancers. In contrast, other factors, such as obesity, alcohol, some fatty acids and food preparation methods may increase risks. Unravelling the multitude of plausible mechanisms for the effects of dietary factors on cancer risk will likely necessitate that nutrition research moves beyond traditional epidemiological and metabolic studies. Nutritional sciences must build on recent advances in molecular biology and genetics to move the discipline from being largely 'observational' to focusing on 'cause and effect'. Such basic research is fundamental to cancer prevention strategies that incorporate effective dietary interventions for target populations.

Alcohol Drinking↗
PubMed2001

Molecular targets for nutrients involved with cancer prevention.

Dietary nutrients can influence cancer risk by inhibiting or enhancing carcinogenesis through diverse mechanisms of action. The identification and elucidation of their sites of action have been a focus of nutrition and cancer research for more than four decades. Transforming nutrition and cancer research from a predominantly observational to a molecular approach offers exciting opportunities for truly identifying those who will and will not benefit from dietary intervention strategies. The emerging field of nutritional genomics, defined here as the study of any genetic or epigenetic interaction with a nutrient, will be key to this evolution. Unraveling which genetic upregulation or downregulation leads to subsequent phenotype changes will not be easy. There is evidence that genetic polymorphisms can influence the dynamics between nutrients and molecular targets and, thus, contribute to variation in response among individuals. Because many molecular targets will likely be identified, it may be necessary to credential nutrients, that is, to determine which specific nutrient-related genetic and epigenetic changes bring about phenotypic changes, to establish which interactions are the most important and under what circumstances. Vitamin D, calcium, folate, selenium, genistein, and resveratrol are highlighted, because they represent specific classes of nutrients and illustrate the need to credential various nutrients to understand their physiological significance in cancer prevention. As the science of nutrition unfolds, a clearer understanding will emerge about how nutrients can modulate cancer risk through molecular interactions and how foods might be changed by agronomic approaches and/or biotechnology. Undeniably, embracing new genomic technologies offers exciting opportunities for advances in the broad area of nutrition, especially those related to cancer prevention.

Anticarcinogenic Agents↗
PubMed2000

Creating a new paradigm in nutrition research within the National Cancer Institute.

Almost two decades after Doll and Peto (1981) provided evidence that one third of cancer deaths are related to diet, it remains unclear which dietary components may be key in cancer prevention. Although the complexity of the diet can become overwhelming, the National Cancer Institute (NCI) of the National Institutes of Health (NIH) has remained steadfast in its commitment to defining the roles that diet and nutrition have in the development of cancer and has provided increased research and training support to assist in unraveling this interrelationship. Evidence for this sustained commitment is highlighted by a fourfold increase in NCI expenditures for nutrition research and training from 1983 to 1998; this substantial increase reflects a trend that is occurring in some universities and the private sector. More than one third of the nutrition-related NCI research is funded by the Division of Cancer Prevention. Supported investigations cover the gamut from basic mechanisms of action of dietary constituents, methodology development, human metabolic studies, clinical trials of dietary modification and the chemopreventive potential of individual nutrients to population-based studies.

Antioxidants↗
PubMed2000

Perspectives on surrogate end points in the development of drugs that reduce the risk of cancer.

This paper proposes a scientific basis and possible strategy for applying surrogate end points in chemopreventive drug development. The potential surrogate end points for cancer incidence described are both phenotypic (at the tissue, cellular, and molecular levels) and genotypic biomarkers. To establish chemopreventive efficacy in randomized, placebo-controlled clinical trials, it is expected that in most cases it will be critical to ensure that virtually all of the biomarker lesions are prevented or that the lesions prevented are those with the potential to progress. This would require that both the phenotype and genotype of the target tissue in agent-treated subjects, especially in any new or remaining precancers, are equivalent to or show less progression than those of placebo-treated subjects. In the National Cancer Institute chemoprevention program, histological modulation of a precancer (intraepithelial neoplasia) has thus far been the primary phenotypic surrogate end point in chemoprevention trials. Additionally, we give high priority to biomarkers measuring specific and general genotypic changes correlating to the carcinogenesis progression model for the targeted cancer (e.g., progressive genomic instability as measured by loss of heterozygosity or amplification at a specific microsatellite loci). Other potential surrogate end points that may occur earlier in carcinogenesis are being analyzed in these precancers and in nearby normal appearing tissues. These biomarkers include proliferation and differentiation indices, specific gene and general chromosome damage, cell growth regulatory molecules, and biochemical activities (e.g., enzyme inhibition). Serum biomarkers also may be monitored (e.g., prostate-specific antigen) because of their accessibility. Potentially chemopreventive drug effects of the test agent also may be measured (e.g., tissue and serum estrogen levels in studies of steroid aromatase inhibitors). These initial studies are expected to expand the list of validated surrogate end points for future use. Continued discussion and research among the National Cancer Institute, the Food and Drug Administration, industry, and academia are needed to ensure that surrogate end point-based chemoprevention indications are feasible.

Antineoplastic Agents↗
PubMed1999

Cancer chemoprevention: progress and promise.

Cancer chemoprevention is the use of agents to inhibit, delay or reverse carcinogenesis. The focus of chemoprevention research in the next millennium will include defining the genotypic and phenotypic (functional and histological) changes during carcinogenesis, the cancer risk conferred by these changes, their modulation in preclinical experimentation and randomised clinical trials by chemopreventive drugs, dietary agents and regimens and treatments resulting from early detection. The key elements of this research effort will be basic and translational risk evaluation programmes; chemopreventive and dietary agent drug discovery and development; development of transgenic animal models; required safety and pharmacology studies; well-designed phase I, II and III chemoprevention studies; and much expanded early detection programmes. The large number of chemoprevention research programmes now ongoing ensures that the promise of chemoprevention will continue to be realised in the next decade.

Anticarcinogenic Agents↗
PubMed1999

Cancer chemoprevention: progress and promise.

Cancer chemoprevention is the use of agents to inhibit, delay or reverse carcinogenesis. The focus of chemoprevention research in the next millennium will include defining the genotypic and phenotypic (functional and histological) changes during carcinogenesis, the cancer risk conferred by these changes, their modulation in preclinical experimentation and randomised clinical trials by chemopreventive drugs, dietary agents and regimens and treatments resulting from early detection. The key elements of this research effort will be basic and translational risk evaluation programmes; chemopreventive and dietary agent drug discovery and development; development of transgenic animal models; required safety and pharmacology studies; well-designed phase I, II and III chemoprevention studies; and much expanded early detection programmes. The large number of chemoprevention research programmes now ongoing ensures that the promise of chemoprevention will continue to be realised in the next decade.

Anticarcinogenic Agents↗
PubMed1997

Fat, caloric intake, and obesity: lifestyle risk factors for breast cancer.

Dietary fat is a likely important determinant of postmenopausal breast cancer as part of an intricate and inseparable interaction of lifestyle cancer risk factors that include dietary fat, type of fat, energy intake and expenditure, and obesity. These factors possibly build upon individual susceptibilities derived from a complex array of polygenetic risk determinants. Epidemiologic studies have not provided conclusive evidence for a dietary fat-breast cancer association, partly because studies that focus on a single nutrient cannot always evaluate readily the interactive effects of other lifestyle factors. Further, persons generally underestimate their usual dietary intake, measured by either food frequency questionnaires (FFQs) or diet records. A dietary measurement model that accounts for this underreporting demonstrated that FFQs and diet records may not be able to detect a dietary fat-breast cancer association because of measurement error biases. Although meta-analysis of epidemiologic data across individual studies suggests only a week association between breast cancer and dietary fat, this result is compatible with the dietary measurement model and does not rule out a contributing role for dietary fat, either alone or with other causative factors. Research is needed that focuses on a comprehensive approach to dietary lifestyle choices and breast cancer risk and that emphasizes a fat-caloric intake-obesity linkage. The best hope for a definitive answer may rest with randomized, controlled clinical trials. Two such trials, the Women's Health Initiative and the Women's Intervention Nutrition Study, are under way.

Animals↗
PubMed1997

Cancer Prevention: The Roles of Diet and Chemoprevention.

BACKGROUND: Reduction of cancer risk by either preventing carcinogenesis or stopping carcinogenesis in its early stages is a logical approach for reducing the cancer burden, both for high-risk individuals and for the general population. The areas of dietary modification and chemoprevention show considerable promise as effective approaches for cancer prevention and are a focus of research efforts. RESULTS: Diet and cancer studies show that, generally, vegetables and fruits, dietary fiber, and certain nutrients seem to be protective against cancer, whereas fat, excessive calories, and alcohol seem to increase cancer risk. Chemoprevention research is closely linked to diet and cancer research and represents a logical research progression. CONCLUSIONS: Dietary epidemiologic studies have helped to identify many naturally occurring chemopreventive agents. Currently, randomized clinical prevention trials sponsored by the NCI include dietary interventions (eg, low-fat and/or high-fiber vegetables and fruits) targeting breast and colorectal cancer, chemoprevention trials using micronutrients (eg, vitamin E, calcium, vitamin D) aimed at lung and colorectal cancer, and chemoprevention trials testing the effectiveness of pharmaceutical agents (eg, tamoxifen, finasteride, aspirin) for breast, prostate, and colorectal cancer.

Journal Article↗
PubMed1996

Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance.

BACKGROUND: Experimental and epidemiologic investigations suggest that alpha-tocopherol (the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains, nuts, and other foods) and beta-carotene (a plant pigment and major precursor of vitamin A found in many yellow, orange, and dark-green, leafy vegetables and some fruit) might reduce the risk of cancer, particularly lung cancer. The initial findings of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) indicated, however, that lung cancer incidence was increased among participants who received beta-carotene as a supplement. Similar results were recently reported by the Beta-Carotene and Retinol Efficacy Trial (CARET), which tested a combination of beta-carotene and vitamin A. PURPOSE: We examined the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of lung cancer across subgroups of participants in the ATBC Study defined by base-line characteristics (e.g., age, number of cigarettes smoked, dietary or serum vitamin status, and alcohol consumption), by study compliance, and in relation to clinical factors, such as disease stage and histologic type. Our primary purpose was to determine whether the pattern of intervention effects across subgroups could facilitate further interpretation of the main ATBC Study results and shed light on potential mechanisms of action and relevance to other populations. METHODS: A total of 29,133 men aged 50-69 years who smoked five or more cigarettes daily were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), alpha-tocopherol and beta-carotene, or a placebo daily for 5-8 years (median, 6.1 years). Data regarding smoking and other risk factors for lung cancer and dietary factors were obtained at study entry, along with measurements of serum levels of alpha-tocopherol and beta-carotene. Incident cases of lung cancer (n = 894) were identified through the Finnish Cancer Registry and death certificates. Each lung cancer diagnosis was independently confirmed, and histology or cytology was available for 94% of the cases. Intervention effects were evaluated by use of survival analysis and proportional hazards models. All P values were derived from two-sided statistical tests. RESULTS: No overall effect was observed for lung cancer from alpha-tocopherol supplementation (relative risk [RR] = 0.99; 95% confidence interval [CI] = 0.87-1.13; P = .86, logrank test). beta-Carotene supplementation was associated with increased lung cancer risk (RR = 1.16; 95% CI = 1.02-1.33; P = .02, logrank test). The beta-carotene effect appeared stronger, but not substantially different, in participants who smoked at least 20 cigarettes daily (RR = 1.25; 95% CI = 1.07-1.46) compared with those who smoked five to 19 cigarettes daily (RR = 0.97; 95% CI = 0.76-1.23) and in those with a higher alcohol intake (> or = 11 g of ethanol/day [just under one drink per day]; RR = 1.35; 95% CI = 1.01-1.81) compared with those with a lower intake (RR = 1.03; 95% CI = 0.85-1.24). CONCLUSIONS: Supplementation with alpha-tocopherol or beta-carotene does not prevent lung cancer in older men who smoke. beta-Carotene supplementation at pharmacologic levels may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake. IMPLICATIONS: While the most direct way to reduce lung cancer risk is not to smoke tobacco, smokers should avoid high-dose beta-carotene supplementation.

Age Factors↗