The responsiveness of human gingival fibroblast populations to cyclosporin A (CsA) and its principal metabolite, hydroxycyclosporine (M17), was evaluated in cell culture. Gingival fibroblasts exhibited a dose‐dependent accumulation and bell‐shaped distribution of dansylated CsA. A 100‐fold excess of non‐labeled CsA prevented the accumulation of the fluorescent probe in the fibroblasts. Both CsA (400 ng/ml) and M17 (100 ng/ml) stimulated mean gingival fibroblast cell number to 23.2% and 36.7% above controls, and reduced mean collagen production by 37.7% and 37.4% below controls, respectively; however, neither CsA nor M17 affected mean protean production in comparison to control cultures. Analyses of responses to CsA and M17 by ligand‐accumulating and non‐accumulating fibroblasts sorted out from the parent cultures did not provide consistent interstrain responses either by cells representing the upper quartile of fluorescence or cells representing the bottom quartiles of fluorescence. These data demonstrate that CsA is accumulated by gingival fibroblasts and that CsA and M17 are potent modulators of gingival fibroblast phenotype.

This phase II study evaluated the activity and toxicity of gemcitabine plus cisplatin as first-line treatment of patients with advanced ovarian cancer. Chemonaive patients >/=60-year-old with FIGO stage IIIC or IV epithelial ovarian carcinoma were enrolled. Patients received cisplatin 75 mg /m2 on day 1 and gemcitabine 1250 mg /m2 on day 1 (before cisplatin) and day 8 of a 21-day cycle. Of 44 female patients (median age, 70 years), 72.7% had stage IIIC disease and 67.4% had a Karnofsky performance status >/=80. Of the 37 response-evaluable patients (35 with measurable lesion[s] >/=2 cm), there were seven (18.9%) pathologic complete responses, two (5.4%) pathologic partial responses, two (5.4%) clinical complete responses, and 12 (32.4%) clinical partial responses, for an overall response rate of 62.2% (95% CI, 44.8%-77.5%), and a pathologic response rate of 24.3% (95% CI, 11.8%-41.2%). Median survival was 27.7 months (95% CI, 14.3-40.8 months). Grade 3/4 neutropenia and thrombocytopenia occurred in 59.5% and 30.2% of patients, respectively, with neutropenic fever in one patient. Grade 3 nausea /vomiting and alopecia occurred in 25.6% and 9.5% of patients, respectively. We conclude that gemcitabine plus cisplatin is active and feasible as first-line treatment of advanced epithelial ovarian cancer in patients >/=60 years. Further clinical trials adding gemcitabine to current standard, first-line treatment seem warranted in younger as well as older patients.

The effects of cyclosporine A (CsA) and one of its immunologically inactive structural analogues, cyclosporine A acetate (CsA-A) on lipopolysaccharide (LPS)-, interleukin-1 (IL-1)-, 1,25 dihydroxyvitamin D3 (1,25 D3)- and parathyroid hormone (PTH)-stimulated bone resorption were tested in mouse calvaria cultures. The release of calcium and a lysosomal enzyme, N-acetylglycosaminidase (NAG) was determined after 3 days of culture. All bone resorbing agents potently stimulated calcium and NAG release. At therapeutic concentration levels of 0.1 and 1.0 micrograms/ml, the immunologically active CsA was significantly more potent than the inactive CsA-A against LPS- and 1,25 D3-induced calcium and NAG release. The inhibition by both cyclosporines of IL-1 and PTH stimulated calcium release was not significantly different. CsA was however more potent than CsA-A against IL-1 stimulated NAG release. PTH-stimulated NAG release was not inhibited by CsA or CsA-A. These findings suggest that both cyclosporines interfere with more than one mechanism of activation of bone resorption. The specific effect of CsA against LPS and 1,25 D3 may be related to its known inhibition of immune cell derived cytokine expression.