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P Greenwald

Publications and source records attributed to P Greenwald.

At least 37 records · Page 2Linked to original sources
PubMed1996

Strategy and planning for chemopreventive drug development: clinical development plans II.

This is the second publication of Clinical Development Plans from the National Cancer Institute, Division of Cancer Prevention and Control, Chemoprevention Branch and Agent Development Committee. The Clinical Development Plans summarize the status of promising chemopreventive agents regarding evidence for safety and chemopreventive efficacy in preclinical and clinical studies. They also contain the strategy for further development of these drugs, addressing pharmacodynamics, drug effect measurements, intermediate biomarkers for monitoring efficacy, toxicity, supply and formulation, regulatory approval, and proposed clinical trials. Sixteen new Clinical Development Plans are presented here: curcumin, dehydroepiandrosterone, folic acid, genistein, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, 13-cis-retinoic acid, l-selenomethionine and 1, 4-phenylenebis(methylene)selenocyanate, sulindac sulfone, tea, ursodiol, vitamin A, and (+)-vorozole. The objective of publishing these plans is to stimulate interest and thinking among the scientific community on the prospects for developing these and future generations of chemopreventive drugs.

Animals↗
PubMed1996

The role of chemoprevention in cancer control.

Chemoprevention is a promising strategy for cancer prevention that is international in application and may be more immediate in worldwide impact than either dietary modification or prevention of exposure to carcinogens. Precedent for a chemopreventive approach is found in cardiology, where cholesterol-lowering, antihypertensive and antiplatelet agents are administered to prevent heart disease progression in high-risk individuals. The multistep nature of carcinogenesis provides many opportunities for chemopreventive interventions with agents targeted to specific mechanisms involved in cancer initiation, promotion and progression. The well-defined strategy for development of chemopreventive agents includes evaluation of leads from epidemiological and experimental research; preclinical efficacy testing of candidate agents; and assessments of the preclinical and clinical safety, toxicity, bioavailability and pharmacokinetics of those that are the most promising. Short-term clinical trials then determine optimal dosing and characterize the efficacy of the best agents against intermediate biomarkers of cancer. Large-scale randomized trials, the final stage of this strategy, evaluate whether the chemopreventive agents actually do reduce cancer risk. The systematic development of agents is coupled with basic research into mechanisms of action and subsequent application of the findings to agent design and discovery. Major objectives of chemopreventive drug development include identification and validation of intermediate biomarkers that are accurate predictors of future cancer incidence and that can serve as surrogate and points for clinical disease. Complementary international efforts to standardize chemopreventive trial designs and protocols among communities worldwide would help ensure a valid comparison of results across countries and more efficient and effective cancer-preventive regimens.

Anticarcinogenic Agents↗
PubMed1996

Mechanistic considerations in the evaluation of chemopreventive data.

Possible chemopreventive mechanisms include carcinogen-blocking activities, antioxidant/anti-inflammatory activities and antiproliferation/antiprogression activities. Carcinogen-blocking activities encompass inhibition of carcinogen uptake, inhibition of carcinogen formation or activation, deactivation or detoxification of carcinogens, prevention of carcinogen binding to DNA, and enhancement of the level or fidelity of DNA repair. Antioxidant/anti-inflammatory activities include scavenging of reactive electrophiles and oxygen radicals, and inhibition of arachidonic acid metabolism. Antiproliferation/antiprogression activities comprise modulation of signal transduction, modulation of hormonal and growth factor activity, inhibition of aberrant oncogene activity, inhibition of polyamine metabolism, induction of terminal differentiation, restoration of immune responses, enhancement of intercellular communication, restoration of tumour suppressor function, induction of apoptosis, telomerase inhibition, correction of DNA methylation imbalances, inhibition of angiogenesis, inhibition of basement membrane degradation, and activation of antimetastasis genes. In evaluating the potential efficacy of chemopreventive agents several mechanistic parameters are weighed: (1) the number of chemoprevention-related pharmacological activities, (2) the impact of the agent on likely carcinogenesis pathways to the targeted cancer, (3) pharmacodynamics, and (4) specificity for chemopreventive activity compared with interference with normal cellular function. Mechanistic data are important throughout the development process for chemopreventive drugs, and they are particularly important in the earlier phases of identifying promising candidate agents and characterizing efficacy. In vitro mechanistic assays are a first step in evaluating chemopreventive potential. Mechanistic considerations are also useful in defining animal efficacy models and in interpreting the results of assays in these models. Mechanistic data are also applied in designing short-term Phase II clinical chemoprevention trials that use reductions in intermediate biomarkers of cancer rather than cancer incidence as end points. The basis for identifying and evaluating these biomarkers is in understanding carcinogenesis and chemopreventive mechanisms.

Anticarcinogenic Agents↗
PubMed1996

Cancer risk factors for selecting cohorts for large-scale chemoprevention trials.

Many anticipate that application of findings in molecular genetics will help to achieve greater precision in defining high-risk populations that may benefit from chemopreventive interventions. We must recognize, however, that genetic susceptibility, environmental factors, and complex gene-environment interactions are all likely to be risk determinants for most cancers. Cohort studies of twins and cancer indicate that having "identical" genes is generally not a very accurate predictor of cancer incidence. Data from twin studies support the suggestion that environmental factors such as tobacco use significantly influence cancer risk. The complexities of the genetic contribution to disease risk are exemplified by the development of Duchenne muscular dystrophy in only one of monozygotic twin girls, hypothesized to be the result of X chromosome inactivation, with the distribution patterns of the X chromosome being skewed to the female X in the manifesting twin and to the male X in the normal twin. Evidence from transgenic and genetic-environmental studies in animals support the possibility of genetic-environmental interactions. Calorie restriction modifies tumor expression in p53 knockout mice; a high-fat, low-calcium, low-vitamin D diet increases prepolyp hyperplasia formation in Apc-mutated mice; and calorie restriction early in life influences development of obesity in the genetically obese Zucker rat (fafa). Such environmental modulation of gene expression suggests that chemoprevention has the potential to reduce risk for both environmentally and genetically determined cancers. In view of the growing research efforts in chemoprevention, the NCI has developed a Prevention Trials Decision Network (PTDN) to formalize the evaluation and approval process for large-scale chemoprevention trials. The PTDN addresses large trial prioritization and the associated issues of minority recruitment and retention; identification and validation of biomarkers as intermediate endpoints for cancer; and chemopreventive agent selection and development. A comprehensive database is being established to support the PTDN's decision-making process and will help to determine which agents investigated in preclinical and early phase clinical trials should move to large-scale testing. Cohorts for large-scale chemoprevention trials include individuals who are determined to be at high risk as a result of genetic predisposition, carcinogenic exposure, or the presence of biomarkers indicative of increased risk. Current large-scale trials in well-defined, high-risk populations include the Breast Cancer Prevention Trial (tamoxifen), the Prostate Cancer Prevention Trial (finasteride), and the N-(4-hydroxyphenyl) retinamide (4-HPR) breast cancer prevention study being conducted in Milan. Biomarker studies will provide valuable information for refining the design and facilitating the implementation of future large-scale trials. For example, potential biomarkers are being assessed at biopsy in women with ductal carcinoma in situ (DCIS). The women are then randomized to either placebo, tamoxifen, 4-HPR, or tamoxifen plus 4-HPR for 2-4 weeks, at which time surgery is performed and the biomarkers reassessed to determine biomarker modulation by the interventions. For prostate cancer, modulation of prostatic intraepithelial neoplasia (PIN) by 4-HPR and difluoromethylornithine is being investigated; similar studies are being planned for oltipraz, dehydroepiandrosterone, and vitamin E plus selenomethionine. The validation of biomarkers as surrogate endpoints for cancer incidence in high-risk cohorts will allow more agents to be evaluated in shorter studies that use fewer subjects to achieve the desired statistical power.

Animals↗
PubMed1995

New directions in dietary studies in cancer: the National Cancer Institute.

Through an orderly sequence incorporating epidemiologic and laboratory research, human clinical/metabolic studies, and clinical intervention trials, the NCI develops and maintains cancer prevention and control programs that are directed toward the overall goal to reduce cancer incidence, morbidity, and mortality. Epidemiologic studies have shown correlations between consumption of numerous dietary constituents and cancer risk. Results of in vitro and animal studies have reinforced many of these epidemiologic associations and data from clinical/metabolic studies are being used to evaluate the relevance of these associations in humans. Although much remains to be learned about the influence of specific dietary constituents and dietary patterns on cancer risk, it is clear that diet can have a significant impact in cancer prevention and control. Investigations on the cellular and molecular effects of dietary constituents, as well as their metabolic and physiologic effects should provide better insight on the mechanisms of action of these dietary constituents. There also is a need to develop biomarkers of dietary intake that could be used to monitor compliance in intervention studies, as well as biomarkers as clinical trial endpoints that can be used to predict the emergence and progression of cancer. Working with other agencies and the private sector, the NCI will continue to design and implement information programs that translate the knowledge gained from these diet and cancer prevention studies to help Americans adopt dietary patterns that may reduce cancer risk. Continued emphasis will be placed on intervention programs targeted toward high-risk and underserved segments of the U.S. population in an effort to reduce the high incidence of cancers in these groups.

Animals↗
PubMed1994

Dietary beta carotene and lung cancer risk in U.S. nonsmokers.

BACKGROUND: Approximately 15% of all lung cancer deaths in the United States (about 22,350 deaths annually) may not be directly attributable to active cigarette smoking. Consumption of beta carotene, which is derived almost exclusively from intake of fruits and vegetables, has been associated with a reduced risk of lung cancer in smokers. However, studies examining this association in nonsmokers, particularly nonsmoking men, are limited. PURPOSE: The purpose of this study was to examine whether dietary factors including beta carotene and retinol are associated with a reduced risk for lung cancer in nonsmoking men and women. METHODS: A population-based, matched case-control study of lung cancer in nonsmokers was conducted in New York State from 1982 to 1985. Dietary interviews were completed for 413 individually matched case-control pairs of subjects. To determine whether the relationship between dietary intake from specific food groups and lung cancer differed by type of interview, smoking history, sex, age, or histologic type, we examined data on the case-control pairs from each subgroup separately. The intake of beta carotene and retinol was calculated as the weighted sum of the monthly frequencies of consumption of food items containing these nutrients, where the weights correspond to the nutrient content of a typical portion of the food items. RESULTS: Consumption of greens (P for trend < .01), fresh fruits (P for trend < .01), and cheese (P for trend < .05) was associated with a significant dose-dependent reduction in risk for lung cancer, whereas consumption of whole milk (P for trend < .01) was associated with a significant dose-dependent increase in risk. Use of vitamin E supplements was also protective (odds ratio = 0.55; 95% confidence interval [CI] = 0.35-0.85). Increased consumption of the following food groups was associated with a reduction in risk among females: vegetables (P for trend < .025), raw fruits and vegetables (P for trend < .005), and dairy products (P for trend < .025). In males, increased consumption of raw fruits and vegetables was associated with a reduced risk for lung cancer (P for trend < .005). Dietary beta carotene (OR = 0.70; 95% CI = 0.50-0.99), but not retinol (OR = 0.98; 95% CI = 0.82-1.17), was significantly associated with risk reduction. CONCLUSIONS: This is the largest study to date of dietary factors and lung cancer in nonsmokers; results suggest that dietary beta carotene, raw fruits and vegetables, and vitamin E supplements reduce the risk of lung cancer in nonsmoking men and women.

Adult↗
PubMed1994

Strategy and planning for chemopreventive drug development: clinical development plans. Chemoprevention Branch and Agent Development Committee. National Cancer Institute.

At the National Cancer Institute, Division of Cancer Prevention and Control, the Chemoprevention Branch and Agent Development Committee develop strategies for efficiently identifying, procuring, and advancing the most promising drugs into clinical trials. Scientific expertise is applied at each phase of development to critically review the testing methods and results, and to establish and apply criteria for evaluating the agents for further development. The Clinical Development Plan, prepared by the Chemoprevention Branch and the Agent Development Committee, is a summary of the status of the agent regarding evidence for safety and chemopreventive efficacy in preclinical and clinical studies. It also contains the strategy for further development of the drug that addresses pharmacodynamics, drug effect measurements, intermediate biomarkers for monitoring efficacy, toxicity, supply and formulation, regulatory approval, and proposed clinical trials. Sixteen Clinical Development Plans are presented here: N-acetyl-l-cysteine (NAC), aspirin, calcium, beta-carotene, 2-difluoromethylornithine (DFMO), DHEA analog 8354, 18 beta-glycyrrhetinic acid, N-(4-hydroxyphenyl)retinamide (4-HPR), ibuprofen, oltipraz, piroxicam, Proscar, sulindac, tamoxifen, vitamin D3 and analogs, and vitamin E. The objective of publishing these plans is to stimulate interest and thinking among the scientific community on the prospects for developing chemopreventive drugs.

Clinical Trials as Topic↗
PubMed1994

Overview of U.S. National Cancer Institute (USNCI) chemoprevention research.

The National Cancer Institute's (NCI) chemoprevention plan employs a strategy of basic and epidemiologic studies, followed by a structured preclinical process to bring chemopreventive agents into clinical testing. The field of chemoprevention is progressing rapidly and has reached the point where a coordinated international approach for large-scale trials would be useful. At present, NCI is sponsoring nine large trials (over $1 million per year per trial); in addition, nine agents are in phase I or II clinical testing. A number of these agents should be ready soon for phase III testing. Resources required for large-scale trials compel greater attention to efficient trial design, concept development and review, priority setting, management, budgeting, and collaboration.

Antineoplastic Agents↗
PubMed1994

Experience from clinical trials in cancer prevention.

Conduct of randomized, controlled, large-scale prevention trials is fundamental to the full assessment of the efficacy of interventions to prevent cancer. Clinical trials in cancer prevention, which include dietary modification and chemoprevention, are based on leads from epidemiological and laboratory studies. Dietary intervention trials involve the modification of overall eating patterns, whereas chemoprevention trials involve the administration of natural or synthetic substances reported to have anticarcinogenic properties, e.g. vitamins, minerals, and pharmaceuticals. Clinical/metabolic studies can help advance knowledge of the role of diet in the etiology and prevention of cancer by investigating the metabolism of factors thought to influence cancer risk; thus, these studies have the potential to provide a stronger scientific base for progression to randomized, controlled clinical trials. Cancer prevention trials supported by the National Cancer Institute include the Polyp Prevention Trial, which is testing a low-fat, high-fibre, and vegetable- and fruit-enriched eating pattern on the prevention of polyp recurrence, and the Nutrition Intervention Trials of Oesophageal Cancer in Linxian, China, which are testing the efficacy of vitamin-mineral supplements in the prevention of oesophageal cancer in high-risk populations. Results from clinical cancer prevention trials will enable investigators to establish more firmly the relationships between diet and cancer and to translate the information effectively into significant reductions in cancer incidence and mortality.

Clinical Trials as Topic↗