The fibroblast growth factor (FGF) axis is an important mitogenic stimulus in prostate carcinogenesis. We have previously reported that transcript level of human similar expression to FGF (hSef), a key regulator of this pathway, is downregulated in clinical prostate cancer. In this study we further analysed the role of hSef in prostate cancer. METHODS: hSef function was studied in in vitro and in vivo prostate cancer models using stable over-expression clones. Protein expression of hSef was studied in a comprehensive tissue microarray. RESULTS: Stable over-expression of hSef resulted in reduced in vitro cancer cell proliferation, migration and invasive potential. In an in vivo xenograft model, the expression of hSef significantly retarded prostate tumour growth as compared with empty vector (P ¼ 0.03) and non-transfected (P ¼ 0.0001) controls. Histological examination further showed a less invasive tumour phenotype and reduced numbers of proliferating cells (P ¼ 0.0002). In signalling studies, hSef inhibited FGF-induced ERK phosphorylation, migration to the nucleus and activation of a reporter gene. Constitutively active Ras, however, was able to reverse these effects, suggesting that hSef exerts an effect either above or at the level of Ras in prostate cancer cells. In a large tissue microarray, we observed a significant loss of hSef protein in high-grade (Po0.0001) and metastatic (Po0.0001) prostate cancer. CONCLUSION: Considered together, the role of hSef in attenuating FGF signalling and evidence of downregulation in advanced tumours argue strongly for a tumour suppressor function in human prostate cancer.

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Summary The tolerability, anti-tumour activity and pharmacokinetic interaction of high-dose intravenous cyclosporin combined with intravenous etoposide was evaluated in children. Eighteen patients with recurrent or refractory tumours, all of whom had previously received etoposide, were treated with a combination of high-dose cyclosporin and etoposide. In 13, cyclosporin was given as a continuous infusion (15 mg kg-' per 24 h for 60 h) and in five a short 3-hour infusion of 30 mg kg-' day-' on three consecutive days. Pharmacokinetic profiles of etoposide were determined with and without cyclosporin. Cyclosporin levels ranged from 1359 to 4835 ng ml-' and cyclosporin increased the median area under the concentration time for etoposide curve from 7.2 to 12.5 mg ml-' min. The major toxicity was acute with varying forms of hypersensitivity reactions.In four cases this was severe. Hyperbilirubinaemia was present in 25 of 32 courses but was of short duration. In 14 courses, creatinine and/or urea was elevated, but was also transient. Significant hypertension was seen in six courses. Four of 17 patients evaluable for response obtained a partial response and one showed stable disease. It is concluded that in children given the combination of high-dose cyclosporin and etoposide, the etoposide dose should be halved in order to achieve an area under the drug concentration-time curve similar to that with etoposide alone. A continuous infusion schedule of cyclosporin is better tolerated during the period of administration but is associated with similar hepatic and renal dysfunction to a short schedule. The 24% response rate in children who had previously received etoposide suggests that this may be an effective method of enhancing drug sensitivity and further phase 11 evaluation is justified.

Co-administration of Cereport with carboplatin may result in a greater than predicted AUC. The mechanism of this possible interaction remains to be determined, although this did not result in any increased toxicity. Thus, the clinical potential of this combination in the treatment of brain tumours warrants further investigation.

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