Due to a lack of curative chemotherapy for many solid tumors, alternative therapeutic approaches have received considerable attention. One such approach has been attempts to generate non-cytotoxic induction of differentiation. Most agents utilized for this approach have not been clinically successful partly because the agents used are not effective inducers of differentiation unless they are used at concentrations which are marginally toxic. Therefore, the objective of the original proposal for this renewal application, was the identification of key differentiation signals in tumor cells which might be elicited by non-toxic agents. Key signals that were identified included repression of the competence gene c-myc and the induction of extracellular matrix (ECM) related components. Furthermore, it was found that the transforming growth factor-beta's (TGF-beta's) could induce these signals in colon carcinoma cells in the complete absence of toxicity. However, TGF-beta's themselves are limited as potential therapeutic products because of the need of continuous target cell exposure, rapid clearance from the blood and the prohibitive expense of pharmaceutical development of protein based therapy. However, if the expression of TGF's can be controlled or their effects mimicked by other non-toxic agents, systemic therapy could be circumvented. Therefore, it is important to determine relationships among the TGF-beta's, differentiation control and the mechanisms which control TGF-beta activity and expression. There is evidence for an autoregulatory role for TGF-beta's in regulation of proliferation and differentiation suggesting that nontoxic control of expression of TGF-beta's would be therapeutically important. Therefore, the objectives of the renewal application are to provide an understanding of the autoregulatory mechanisms involved by: 1. Determination of the autocrine function of the various TGF-beta's in human colon carcinoma cell lines and its potential revelance to differentiation. 2. Characterization of the molecular basis for control of TGF-beta expression in human colon carcinoma cell lines. 3. Determination of the molecular basis of TGF-beta action and the basis for the failure of some subtypes of colon carcinoma cells to respond to TGF-beta's.
Showing the most recent 10 out of 63 publications
