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Sensitization by Dietary Docosahexaenoic Acid of Rat Mammary Carcinoma to Anthracycline: A Role for Tumor Vascularization

Authors' Affiliations: ¹ Institut National de la Santé et de la Recherche Médicale, E0211 Nutrition Croissance et Cancer, Tours; IFR 135, Univ. Tours, Tours; ² Institut National de la Santé et de la Recherche Médicale, U619, Tours; IFR 135, Univ. Tours, Tours; and ³ Centre de Recherches Biologiques, Baugy, France

Requests for reprints: Philippe Bougnoux, Institut National de la Sante et de la Recherche Medicale E0211, CHU Bretonneau, 2 bis Boulevard Tonnellé, F-37044 Tours, France. Phone: 33-247-366179; Fax: 33-247-478065 or 33-247-366226; E-mail: bougnoux{at}med.univ-tours.fr.

Purpose: To investigate whether dietary docosahexaenoic acid (DHA), a peroxidizable polyunsaturated -3 fatty acids, sensitizes rat mammary tumors to anthracyclines and whether its action interferes with tumor vascularization, a critical determinant of tumor growth.

Experimental Design: Female Sprague-Dawley rats were initiated by N-methylnitrosourea to develop mammary tumors and then assigned to a control group (n = 18), receiving a supplementation of palm oil, or to a DHA group (n = 54), supplemented with a microalgae-produced oil (DHASCO, 1.5 g/d). The DHA group was equally subdivided into three subgroups with addition of different amounts of -tocopherol. Epirubicin was injected weekly during 6 weeks after the largest tumor reached 1.5 cm², and subsequent changes in the tumor surface were evaluated. Tumor vascularization was assessed by power Doppler sonography before and during chemotherapy.

Results: DHA and -tocopherol were readily absorbed and incorporated into rat tissues. Epirubicin induced a 45% mammary tumor regression in the DHA-supplemented group, whereas no tumor regression was observed in the control group. In the DHA group, before chemotherapy was initiated, tumor vascular density was 43% lower than in the control group and remained lower during chemotherapy. Enhancement of epirubicin efficacy by DHA was abolished in a dose-dependent manner by -tocopherol, and the same trend was observed for DHA-induced reduction in tumor vascular density.

Conclusions: Dietary DHA supplementation led to a reduction in tumor vascularization before the enhancement of any response to anthracyclines, suggesting that DHA chemosensitizes mammary tumors through an inhibition of the host vascular response to the tumor.