HIGH-DOSE TOREMIFENE AS A CISPLATIN MODULATOR IN METASTATIC NONSMALL CELL LUNG-CANCER - TARGETED PLASMA-LEVELS ARE ACHIEVABLE CLINICALLY

Purpose: The triphenylethylenes tamoxifen and toremifene have been rep orted to enhance the cytotoxicity of cisplatin by inhibition of protei n kinase C (PKC) signal transduction pathways. However, the concentrat ions of tamoxifen and toremifene required for chemosensitization in pr eclinical models are generally greater than or equal to 5 mu M, at lea st tenfold higher than plasma levels observed in patients receiving th ese agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-sm all-cell lung cancer, plasma concentrations of toremifene and its acti ve metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. Methods: Treatment cons isted of toremifene, 600 mg orally on days 1-7, and cisplatin, 50 mg/m (2) intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay o n days 4 and 11 prior to cisplatin infusion. Results: In the initial 1 4 patients, the mean total plasma concentrations of toremifene plus it s N-desmethyl metabolite on days 4 and 11 were 14.04 (+/- 8.6) mu M an d 9.8 (+/- 4.4) mu M, respectively. Variability in concentrations achi eved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N-desmethyltoremifene were higher on day 11 r elative to toremifene concentrations. Conclusions: We conclude that pl asma levels achieved compare favorably with the levels required for ci splatin chemosensitization and PKC modulation in vitro. Targeted torem ifene levels can be achieved clinically with 600 mg orally daily in co mbination with cisplatin and are well tolerated.