Synergism between nifedipine and cyclosporine A on the incorporation of [35S]sulfate into human gingival fibroblast cultures in vitro

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Abstract

Background and Objective

We assessed the effects of cyclosporine A and nifedipine on the in vitro incorporation of [35S]sulfate into gingival fibroblast cell cultures derived from responder and nonresponder subjects who had received an organ transplant followed by a therapeutic regimen using a combination of those drugs.

Material and Methods

Gingival fibroblasts were isolated from responder and nonresponder subjects and maintained in vitro. Prior to cell harvest, gingival interleukin-1β concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Cells were untreated or exposed to either 10−7−10−10 M nifedipine or 100–500 ng/ml cyclosporine A. Incorporation of [3H]proline or [35S]sulfate into the cell cultures was determined by liquid scintillation analysis. In addition, the effects of 400 ng/ml cyclosporine A + 10−7 M nifedipine and 400 ng/ml cyclosporine A + 10−10 M nifedipine on incorporation of [35S]sulfate into the cell cultures was determined. Data were compared by factorial analysis of variance (ANOVA) and a posthoc Tukey's test.

Results

Gingiva from responders contained significantly more interleukin-1β than gingiva from nonresponders (p < 0.01). The cell cultures derived from responders incorporated significantly more [35S]sulfate than those derived from nonresponders following exposure to either cyclosporine A or 10−7 M nifedipine. In addition, the exposure of fibroblasts derived from gingival overgrowth to either 400 ng/ml cyclosporine A + 10−7 M nifedipine or 400 ng/ml cyclosporine A + 10−10 M nifedipine significantly increased or decreased, respectively, the incorporation of [35S]sulfate into the cultures.

Conclusion

The therapeutic combination of cyclosporine A and nifedipine could be a significant risk factor for gingival overgrowth in subjects susceptible to either agent. The mechanism for overgrowth could include edema secondary to increased sulfated-glycosaminoglycan (sGAG) synthesis by fibroblasts, but further investigation is required.

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