NON ANTIBIOTIC PROPERTIES OF TETRACYCLINES

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This application seeks supplemental support for a new and unique Gordon Research Conference entitled "Non-Antibiotic Properties of Tetracyclines and Other Antibiotics." In 1983, Golub et.al., studying the pathogenesis of periodontal disease, discovered that certain tetracycline (TC) drugs inhibited the action of matrix metalloproteinases, (MMPs) independent of their antimicrobial capacity. This observation regarding the MMPs has since been confirmed in over 25 laboratories. The mechanism(s) include effects on gene expression, activation, and enzymatic activity. Many scientists have subsequently extended our knowledge of the non- antibiotic properties of TCs as well as the potential applications of such agents. TCs are now known to inhibit angiogenesis, to suppress cancer cell invasion and metastasis, to regulate gene expression, to ameliorate diabetes, to restore osteoblast/clast function, and to inhibit expression of iNOS and other genes. TC analogues exist from which the anti-microbial properties of the compound have been deleted with retention of the anti-MMP capacity. These agents, known now as CMTs (chemically modified tetracyclines), have since been shown to have a wide variety of host-modulating actions applicable to many disease processes. In additional to their signature application for periodontal disease, there is now evidence that TCs/CMTs may be useful in cancer, arthritis, eye and skin disease, metabolic bone disease, aneurysm, and atherosclerosis. New mechanisms of action of TCs are under investigation, which may elucidate TC pharmacology, and consequently have important implications in a variety of health issues. This Conference represents the first GRC which will bring together leading researchers in this emerging field, and will focus on the exchange of new information regarding promising biological models for TC investigation, molecular mechanisms of action and pharmacology of TC, with particular emphasis on cancer. This Conference is expected to have a significant impact on this rapidly emerging field by fostering interactive collaborations and establishing a forum for discussions regarding the direction of future research.