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

OBJECTIVE

We assessed the effects of cyclosporine A and nifedipine on the in vitro incorporation of [(35)S]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.

METHODS

Gingival fibroblasts were isolated from responder and nonresponder subjects and maintained in vitro. Prior to cell harvest, gingival interleukin-1beta 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 [(3)H]proline or [(35)S]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 [(35)S]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-1beta than gingiva from nonresponders (p < 0.01). The cell cultures derived from responders incorporated significantly more [(35)S]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 [(35)S]sulfate into the cultures.

CONCLUSIONS

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.