High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer: Targeted plasma levels are achievable clinically

Primo N. Lara, David R. Gandara, Gregory T. Wurz, Derick Lau, Margaret Uhrich, Corinne Turrell, James Raschko, Martin J. Edelman, Timothy Synold, James Doroshow, Franco Muggia, Edith A. Perez, Mike DeGregorio

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Purpose: The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally ≤5 μM, at least tenfold higher than plasma levels observed in patients receiving these 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-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. Methods: Treatment consisted of toremifene, 600 mg orally on days 1-7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion. Results: In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (± 8.6) μM and 9.8 (± 4.4) μM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N- desmethyltoremifene were higher on day 11 relative to toremifene concentrations. Conclusions: We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.

Original languageEnglish (US)
Pages (from-to)504-508
Number of pages5
JournalCancer chemotherapy and pharmacology
Issue number6
StatePublished - 1998


  • Cisplatin
  • Lung cancer
  • Phase II trial
  • Protein kinase C
  • Toremifene

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)


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