In order to better understand colon cancer, a model system reflecting the heterogenous nature of this disease was developed and used in the development of new cytotoxic and non-cytotoxic therapeutic approaches. A large bank of colon carcinoma cell lines was established from primary human colon carcinomas and grouped based on their tumorigenicity in athymic mice, their growth rates in soft agarose and in tissue culture, and their secreted levels of carcinoembryonic antigen. These cell lines were later characterized based on cell surface proteins and antigens detected with antisera raised against a differentiated colon carcinoma cell line. Although these biochemical markers correlated with the biological classification of these cell lines, there was still extensive heterogeneity within each group in all properties examined. This colon carcinoma cell system was used to study natural vs. selected resistance to the anticancer drug mitomycin C (MMC). The differing IC50 values in vitro were reflected in the inhibition by MMC of xenograft growth in athymic mice. A new, more readily bioactivatable analogue of MMC was tried and shown to be more active in vitro and in vivo, suggesting that rapid efflux of the drug before activation may be important in examining causes of resistance to MMC. Another approach to the treatment of colon cancer is the use of non-cytotoxic agents such as growth factors and differentiation agents to restore normal growth to the malignant cells. We have isolated and characterized two types of polypeptides from colon carcinoma cells and conditioned medium from these cells. The first, transforming growth factors (TGF's) confer a transformed phenotype on non-transformed fibroblasts while the second, tumor inhibitory factors (TIF's), inhibits the anchorage independent growth of transformed cells. The fact that extracts of colon carcinoma cells contain both activities suggests that the heterogeneity of the cell lines could be due to different levels of TGF's and TIF's produced. The effectiveness of differentiation agents to restore normal growth control using a transformed mouse embryo cell line was examined. Treatment of these cells with differentiation agents restored normal growth control to these cells. An increased synthesis of TGF's resulted from these treatments. Therefore, differentiation agents may be useful in non-cytotoxic treatment. The use of this model system for human colon carcinoma will hopefully lead to more effective drugs for the treatment of colon cancer in man.

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The capacity to locate, access, and appraise information is an important skill required for success in dental school and beyond. An interdisciplinary course was implemented to teach first-year dental students at the University of Texas Health Science Center at Houston Dental Branch about evidence-based dentistry, search strategies, critical appraisal of the literature, and dental informatics. Students learned to develop a clinical question, conduct a search to find answers to that question, and critically appraise one of the retrieved resources. Over a period of four years, a total of 259 dental students completed a questionnaire that requested their assessment of this course. Seventy-five percent of the respondents agreed or strongly agreed that they learned to effectively search databases such as the Cochrane Collaboration and PubMed and to critically appraise websites and journal articles and that the information on evidence-based dentistry and critical thinking skills was valuable.In response to open-ended questions, approximately 35 percent of the respondents mentioned the importance of learning to search PubMed and Cochrane databases. Approximately 20 percent of the respondents felt the course did not contain new information. These results indicated the effectiveness of the course in familiarizing the students with the capacity of online resources to help them locate, access, and appraise information pertinent to oral health issues and the practice of dentistry. A future goal is to integrate information and skills associated with evidence-based practice into other courses in the dental curriculum.Dr. Levine is Associate Professor,

The human colon carcinoma cell line, HCT 116, can be grown in chemically defined media in the absence of exogenous growth factors. The addition of transferrin and insulin will significantly stimulate growth. The interaction of these growth factors with their receptors was studied to determine whether the synergistic action of insulin and transferrin on growth involved alterations in the growth-factor receptors. Redistribution of the transferrin receptor occurred in the presence of transferrin or transferrin plus insulin. The presence of insulin in the growth media resulted in occupation of cell-surface insulin receptors without a reduction in total insulin binding. Addition of transferrin with insulin resulted in a decrease in insulin binding to its receptor, with no alteration in receptor affinity. It appears that transferrin plays a role in regulating the insulin receptor and that this may contribute to the synergistic effect of insulin and transferrin on growth.

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