Symposium 14: Apoptosis in Carcinogenesis and Chemoprevention. "Proapoptotic effects of chemopreventive agents", by Reuben Lotan, UT M.D. Anderson Cancer Center, Houston, TX. "There are indications that carcinogenesis and tumor progression involve the development of resistance to apoptosis. Deficiencies in apoptosis can create a permissive environment for genetic instability and cumulative genetic alterations that lead to cancer development. Chemoprevention of cancer can be accomplished by inhibition of the initiation of cells by carcinogenic agents or by suppression of the promotion and progression of preneoplastic lesions to invasive cancer by using specific natural or synthetic chemical agents." "Interestingly, an increasing number of previously identified chemopreventive agents including retinoids, vitamin D3 analogs, mono-and tri-terpinoids, vanilloids, non-steroidal anti-inflammatory agents, histone deacetylase inhibitors, farnesyltransferase inhibitors, and others were found recently to enhance apoptosis in a variety of premalignant or malignant cell types in vitro and in a few animal models in vivo. Further understanding of the effects of potential chemopreventive agents on specific components of the apoptosis pathways may provide a rational approach to using such agents alone or in combination with other agents to enhance apoptosis as a strategy for effective chemoprevention of cancer by elimination of aberrant clones." "Premature senescence in tumor suppression", presented by Scott W. Lowe, Cold Spring Harbor Lab, Cold Spring Harbor, NY. "Work from out laboratory and elsewhere suggests that premature senescence acts a natural brake to tumor development and contributes to the cytotoxic action of chemotherapeutic drugs. In this manner, senescence parallels apoptosis as a cellular response to stress." "Our studies provide strong evidence that cellular senescence acts as a bona fide anti-tumor mechanism in vivo, and provide new mechanistic insights into how Rb (tumor supressor) might influence the senescence state." Symposium 15: Cancer Prevention and Diet: Getting Closer to the Mechanisms. "Understanding prevention interventions: Epidemiology, clinical trials and laboratory science", presented by John A. Baron, Dartmouth Medical School, Hanover, NH. "Understanding the effects of nutrients or dietary patterns on human cancer risk presents many difficult challenges. Laboratory sciences and epidemiological approaches can each study only part of the issue, and any one approach necessarily can only approximate the usual human situation. Animal models of carcinogenesis are only that - abstractions that approximate to varying degrees the human biology. In vitro investigations can suggest possible mechanistic patterns but these may not be operative in the human situation - or may not dominate there. Epidemiological studies also face questions of generalizability, and of course may be affected by confounding or other biases such as those due to measurement error or differential reporting of exposures. Clinical trials may also be limited by issues of generalizability. Investigation of the association between beta carotene (or other nutrients) and cancer risk provides an excellent example of the different perspectives through which laboratory sciences, epidemiology, and clinical trials approach the identification and understanding of preventive interventions. The initial excitement over beta carotene as a possible cancer prevention agent derived largely from epidemiological associations of cancer risk with fruit and vegetable intake and mechanistic considerations of its antioxidant properties. This potential benefit led to several human clinical trails, including three studies that were targeted largely to lung cancer and cardiovascular disease, and several smaller trials aimed at colorectal adenomas, non-melanoma skin cancer, and other conditions. The large trials showed no evidence of reduction in risk of lung cancer or cardiovascular disease with beta carotene supplementation. Indeed, there was evidence of increased risk of both outcomes. Other trials were convincingly negative regarding the potential for beta carotene to reduce the risk of non-melanoma skin cancer or colorectal adenomas. Thus clinical trial data clearly do not support any role for beta carotene in cancer prevention. How was it that an agent so clearly disappointing in clinical trials seems so promising? Do the findings reflect different capabilities of the various scientific disciplines involved? Arguably, the findings from in-vitro investigations were incomplete: the antioxidant properties of beta carotene are now understood to be less powerful than initially hoped for, and at high oxygen tensions, beta carotene may have pro-oxidant properties. This finding is particularly relevant for carcinogenesis in the lung, though probably not for carcinogenesis in other organs. Epidemiology has been "blamed" for leading the scientific community astray regarding beta carotene. The lung cancer and colorectal cancer findings generally involved fruit and vegetable intake or total carotenoid levels - beta carotene was a prominent candidate to explain the inverse associations. Now using up-to-date food composition data and carefully differentiating any fruit/vegetable effects from those for beta carotene, there seems to be little relationship between beta carotene intake and lung cancer risk. Epidemiological data regarding non-melanoma skin cancer do not suggest any association. Thus, with appropriate attention to confounding and exposure assessment, epidemiological investigation actually corresponds well to the findings of the clinical trials. The human biomarker data regarding the effects of beta carotene supplementation, on lung carcinogenesis no benefit or harm. For colorectal neoplasia, the human biomarker data also indicate that beta carotene is unlikely to be protective. However biomarker studies in humans clearly do suggest a benefit of beta carotene for non-melanoma skin cancer. Thus human biomarker studies were generally correct in predicting the findings from the clinical trials, but the skin biomarkers were not the relevant ones. Animal carcinogenesis studies regarding lung cancer were apparently never published as individual articles but available data suggest they never supported a role for beta carotene in prevention of lung cancer. Animal findings regarding colorectal cancer were mixed; most studies suggested no effect of supplementation. For non-melanoma skin cancer, however, animal carcinogenesis studies clearly did suggest a benefit of beta carotene and so were misleading. During this discussion, the human clinical trials have more or less been accepted as definitive - probably appropriately. However, clinical trials may be conservative because of their emphasis on analysis by intent-to-treat and rather strict avoidance of subgroup analyses. Also the results nominally apply only to timing, duration, and dose of the interventions used. The degree to which such caveats limit broad generalization has been controversial regarding beta carotene and other nutrients. Investigation of biological mechanisms per se raises a somewhat different set of issues. For animal studies and in vitro investigation, there are potential questions of relevance to the human situation. In epidemiological studies, generalizability, confounding, and other biases may be a question, but there are also other issues. Mechanistic considerations often manifest themselves epidemiologically in terms of interactions or effects in subgroups (e.g. associations varying by genotype, initial hormone level, or nutrient status). In these circumstances, data dredging and measurement error may be prominent problems. Clinical trials may have clear advantages for these observational limitations. For example, for nutrients, measurement error may cloud observational analyses, but be only a minor issue in clinical trials because they give a precise 'dose' of the agent. This may be particularly true for nutrients, since their intake may be difficult to measure precisely, and their effects are likely to be modest. Thus the identification of preventive interventions is best approached through a sophisticated multidisciplinary approach. None of the available assessment approaches is appreciably better than the others when used appropriately. For mechanistic understanding, particularly of nutrients, clinical trials may be particularly valuable." "Diet in the etiology and prevention of progression to cancer: Some lessons from Barrett's esophagus", presented by Alan R. Kristal, Fred Hutchinson Cancer Research Center, Seattle, WA. "One approach to understanding the role of diet in cancer is to study how dietary factors affect the process of neoplastic progression. Preneoplastic conditions are well characterized for many cancers, including prostate, cervix, breast, skin and esophagus, and longitudinal studies of persons with these conditions can give insight into the possible mechanisms underlying associations of these cancers with diet. Studies in persons with these preneoplastic conditions can also be useful for clinical care, because dietary change could be used as a primary or adjunct treatment to prevent progression to cancer. Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.