GROWTH FACTORS IN DRUG INDUCED GINGIVAL OVERGROWTH

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Three groups of drugs induce gingival overgrowth. They are: (1) phenytoin (PHT), an anticonvulsant; (2) cyclosporin (CS), an immunosuppressant; and (3) nifedipine (Procardia R) and related calcium channel blockers used for the treatment of cardiovascular disorders. Gingival overgrowth is both disfiguring and dysfunctional for a large number of patients of all age groups. The number is likely to increase because no drug is foreseen to replace PHT and the use of CS and nifedipine is increasing. This presents a significant problem in the US where all three of these drugs are widely used. Only PHT and CS will be investigated in the proposed pilot study. The goal of this research proposal is to provide a foundation for investigations into the mechanisms whereby certain drugs, such as PHT and CS induce excessive growth of the gingiva. The working hypothesis is that these drugs stimulate certain cells of the gingival connective tissue to synthesize and secrete excessive amounts of growth factors normally used in the repair of gingival attrition and wounds. The hypothesis will be tested by the following specific aims: 1. To determine the levels of three growth factors in normal human gingiva; 2. To determine whether or not the levels of these three growth factors are elevated in PHT and CS-induced gingival overgrowth; and 3. To determine if PHT and CS stimulate the synthesis and secretion of these three growth factors by human connective tissue cells in the controlled environment of cell culture. The growth factors to be studied are: platelet-derived growth factor, transforming growth factor beta1 and interleukin-1beta. The methods of analysis will include: (1) RNA reverse transcription-polymerase chain reaction analysis to quantify the mRNA for each growth factor in drug- exposed cells in culture, normal gingiva and in gingiva overgrowth; and (2) radioimmunoassay of the secreted growth factors by drug-exposed cells in culture, normal gingiva and drug-induced gingival overgrowth. Data derived from this pilot study will provide a basis for future studies on the cellular mechanisms involved in this drug-related phenomenon.