PMID: 8431976Jan 1, 1993Paper

Targeting chemosensitizing doses of toremifene based on protein binding

Cancer Chemotherapy and Pharmacology
G WurzV Wiebe

Abstract

Toremifene is currently being evaluated as a chemosensitizing agent in doxorubicin-resistant patients. Although concentrations of > 2 microM reverse resistance in vitro, target concentrations required to reverse multidrug resistance (MDR) in vivo may be highly influenced by variables such as protein binding in serum. We examined the effects of high serum concentrations on the cellular accumulation of toremifene in an MDR MDA-MB-A-1 human breast-cancer cell line. We then examined the cellular accumulation of doxorubicin at various toremifene concentrations in 5% - 100% serum. We also measured the concentrations of toremifene and its major metabolites in plasma specimens obtained from two patients receiving 360 mg/day for 5 days in a phase I study. Our results show that (1) high serum concentrations decrease toremifene accumulation, (2) toremifene concentrations of < or = 2.5 microM enhance doxorubicin accumulation, and (3) patients achieve plasma toremifene concentrations of 10-15 microM following doses of 360 mg/day x 5 days. Our findings suggest that in vivo toremifene concentrations well above those used to reverse resistance in vitro are required to overcome the effect of high serum-protein binding.

References

Jan 1, 1990·Cancer Chemotherapy and Pharmacology·V J WiebeM DeGregorio
Sep 1, 1989·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·M DeGregorioV Wiebe
Apr 1, 1989·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·M M Gottesman, I Pastan
Jun 21, 1989·Journal of the National Cancer Institute·B A Chabner, A T Fojo
Jul 1, 1988·Pharmacology & Toxicology·H SipiläT Halme
Jan 13, 1984·Biochemical and Biophysical Research Communications·H Y Lam
Dec 1, 1982·Cancer Chemotherapy and Pharmacology·M DeGregorioJ R Wilbur

Citations

Jul 26, 2008·Breast Cancer : the Journal of the Japanese Breast Cancer Society·Shigehira Saji, Katsumasa Kuroi
Dec 1, 1996·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·E R SalomaaJ Komi
Dec 7, 2000·Clinical Pharmacokinetics·T L TarasM DeGregorio
Oct 17, 1998·Cancer Investigation·D L Fairclough

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