88 R. Patel, et al. carcinogenic under certain experimental conditions while some other agent(s) have been observed to be protective in one organ and enhance the risk in another organ [31]. Based on several of these observations, multi-organ model(s) for evaluation of chemopreventive activity of environmental agent(s) have been proposed where multi- organ carcinogenesis is initiated using multiple organ- specific carcinogens along with exposure to chemopreventive test compound prior, during and after carcinogen exposure to evaluate its chemopreventive effects against different carcinogens in different organs. In few, such studies it was observed that certain chemopreventive agents might promote carcinogenesis in animals challenged with more than one carcinogen as compared to animals challenged with only one specific carcinogen. Caution needs to be exercised while executing and analyzing such experimental data since over burdening animals with number of carcinogens at optimum carcinogenic doses might render certain organs like liver under excess stress which might be one of the reasons of promoting carcinogenesis [31]. Such drawbacks can be dealt with by subjecting the animals to sub-carcinogenic doses of different carcinogens and analyzing molecular markers instead of frank tumors as the end point. However, rodents differ from humans in many ways that are relevant to cancer such as oncogenic signaling, length of telomeres, extent of karyotypic abnormalities, basal metabolic rate and non-epithelial origin of murine malignancies as compared to epithelial origin of human malignancies. These suggest rodent models may not accurately reflect the cellular carcinogenesis and may require caution in extrapolating data from murine neoplasia studies directly to humans. Nonetheless, animal studies are of prime importance not only as confirmatory studies employing various models with different dose regimes but also for better understanding of molecular pathways. Chemoprevention: Current Status and Future Per- spectives After establishment of pre-clinical efficacy of an agent, it further undergoes phase I, II and III clinical trials to test their safety, and efficacy in human situation [25]. Being relatively less toxic, dietary agents have advantage over other synthetic agents. But inspite of this most of the agents, that have emerged highly promising after pre-clinical safety and efficacy studies, have failed in human trials [32]. These failures broadly can be grouped into two distinct outcomes viz., adverse effects or effect. The failure of the beta carotene trial for prevention of lung cancer in high risk population has chanalized rest of the preclinical studies on putative chemopreventive agents towards mechanistic aspects of the observed anticarcinogenic effects rather than focusing only on end points. The advent of more sensitive assays like expressional arrays enables a bird’s eye view of effect of particular chemopreventive agent at cellular, organ and entire organism level which will not only impart better understanding of the safety but also aid in identifying appropriate biomarker. The effects of potential chemo- preventive agents in clinical trials can be attributed to number of issues, which need increased attention. One such issue is individual differences in host susceptibility which in turn are governed by genetic constitution. Certain families of genes associated with xenobiotic metabolism, DNA repair etc. have functional single nucleotide polymorphisms, which may influence carcinogenesis and hence even chemo- prevention [32]. The choice of target population for chemo- prevention is another such issue as considering risk to benefit ratio, most logical population as target for chemoprevention would be high risk individuals. However, identification of such individuals for most cancers, such as oral cancer, is highly challenging due to diverse complexities of individual variations and gene-environment interactions. Moreover, anti-oxidants used as chemopreventive agents depending on the cellular milieu, can also act as pro-oxidants [32]. Choice of dietary chemopreventive agents as active compounds or whole plant extracts, dose, duration and mode of application for particular target population against specific cancers is also very critical. Use of dietary agents for chemoprevention also emphasizes nutritional studies, which encompass certain aspects like interactions of chemopreventive supplements with normal diet and host factors. Thus, clinical evaluation based on mechanistic studies, gene-environment interactions and complementing nutritional studies constitute the major thrust areas in chemoprevention research [33–35]. Acknowledgments The authors thank the Indian Council of Medical Research (ICMR) and National Tea Research Foundation (NTRF) for their partial financial support to their research project(s) and to Lady Tata Memorial Trust for the award of senior scholarship to Ms. Rachana Patel and to the Council for Scientific and Industrial Research (CSIR) for the award of senior research fellowships to Ms. Suvarna Erande and Ms. Rachana Garg. References [1] Harris, C.C.: Concluding remarks: role of carcinogens, co- carcinogens and host factors in cancer risk, in Human Carcinogenesis, eds. By Harris, C.C. and Autrup, H., Academic Press, New York, pp. 941–970, 1983. [2] Tsao, A.S., Kim, E.S., and Hong, W.K.: Chemoprevention of cancer. CA. Cancer J. Clin., 54, 150–180, 2004. [3] Smith, J.J., Tully, P., and Padberg, R.M.: Chemoprevention: a primary cancer prevention strategy. Semin. Oncol. Nurs., 21, J. Clin. Biochem. Nutr.