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Effect of Altering Dietary -6/-3 Fatty Acid Ratios on Prostate Cancer Membrane Composition, Cyclooxygenase-2, and Prostaglandin E₂

Authors' Affiliations: Departments of ¹ Urology and ² Biostatistics, Division of ³ Clinical Nutrition and ⁴ Hematology-Oncology, Department of Medicine, ⁵ Division of Pediatric Endocrinology, Department of Pediatrics, Department of Pathology, University of California, Los Angeles School of Medicine, Departments of ⁶ Physiological Sciences and ⁷ Pathology, University of California, Los Angeles; ⁸ Urology Section, Department of Surgery, Veterans Administration, Greater Los Angeles Healthcare System, Los Angeles, California; ⁹ Boston University School of Medicine, Boston, Massachusetts; ¹⁰ Department of Surgery, Veterans Administration Medical Center; ¹¹ Urology Section, Department of Surgery, Duke University School of Medicine, Durham, North Carolina; and ¹² Department of Cardiology, School of Medicine, University of California School of Medicine, Los Angeles, California

Requests for reprints: William J. Aronson, Department of Urology, University of California at Los Angeles, 66-124 Center for the Health Sciences, Box 951738, Los Angeles, CA 90095-1738. Phone: 310-268-3446; Fax: 310-268-4858; E-mail: waronson{at}ucla.edu.

Purpose: To determine whether altering the dietary content of -6 (n-6) and -3 (n-3) polyunsaturated fatty acids affects the growth of androgen-sensitive prostate cancer xenografts, tumor membrane fatty acid composition, and tumor cyclooxygenase-2 and prostaglandin E₂ (PGE₂) levels.

Experimental Design: Individually caged male severe combined immunodeficiency mice were fed isocaloric 20% kcal fat diets with the fat derived either primarily from n-6 fatty acids (n-6 group) or with the fat consisting of n-6 and n-3 fatty acids in a ratio of 1:1 (n-3 group), and injected s.c. with Los Angeles Prostate Cancer 4 (LAPC-4) cells. Tumor volumes and mouse weights were measured weekly, caloric intake was measured 3 days per week, and tumors and serum were harvested at 8 weeks postinjection.

Results: Tumor growth rates, final tumor volumes, and serum prostate-specific antigen levels were reduced in the n-3 group relative to the n-6 group. The n-3 group tumors had decreased proliferation (Ki67 staining) and increased apoptosis (terminal nucleotidyl transferase–mediated nick end labeling staining). In vitro proliferation of LAPC-4 cells in medium containing n-3 group serum was reduced by 22% relative to LAPC-4 cells cultured in medium containing serum from the n-6 group. The n-6/n-3 fatty acid ratios in serum and tumor membranes were lower in the n-3 group relative to the n-6 group. In addition, n-3 group tumors had decreased cyclooxygenase-2 protein and mRNA levels, an 83% reduction in PGE₂ levels, and decreased vascular endothelial growth factor expression.

Conclusion: These results provide a sound basis for clinical trials evaluating the effect of dietary n-3 fatty acids from fish oil on tumor PGE₂ and membrane fatty acid composition, and serum and tumor biomarkers of progression in men with prostate cancer.

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