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Multidrug Resistance Proteins in Gastrointestinal Stromal Tumors: Site-Dependent Expression and Initial Response to Imatinib

Authors' Affiliations: ¹ Pharmacy and ² Biochemistry Departments, Paul Brousse Hospital; ³ Institut National de la Sante et de la Recherche Medicale U602; ⁴ Oncology Department, Institut Gustave Roussy, Villejuif, France; ⁵ Unité Propre de l'Enseignement Supérieur 2706, Faculty of Pharmacy, Université Paris XI; ⁶ Pathology Department, Lariboisière Hospital; ⁷ Pathology Department, Tenon Hospital, Paris, France; ⁸ Pathology and ⁹ Public Health and Medical Information Departments, Ambroise Paré Hospital, Boulogne, France; and ¹⁰ Faculty of Medicine, Paris-Ile de France Ouest, Garches, France

Requests for reprints: Jean-François Emile, Service d'anatomie pathologique, Hôpital Ambroise Paré, 9 Av. Ch. de Gaulle, 92104, Boulogne Cedex, France. Phone: 33-1-49-09-57-25; Fax: 33-1-49-09-58-72; E-mail: jean-francois.emile{at}apr.aphp.fr.

Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the digestive tract and respond poorly to chemotherapy. A tyrosine kinase inhibitor treatment, imatinib mesylate, was recently shown to have antitumor effects in metastatic patients. However, this drug is a substrate for multidrug resistance (MDR) proteins. Therefore, we investigated the expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and ABCG2 (BCRP) by Western blotting in 21 GISTs and 3 leiomyosarcomas. All the GISTs were positive for either ABCB1 (86% of cases) or ABCC1 expression (62%), but negative for ABCG2. ABCB1 was expressed in all gastric GISTs, but in only 67% of nongastric GISTs. By contrast, ABCC1 expression was more common in nongastric tumors (78% versus 42%). The levels of these MDR proteins in gastric GISTs were higher for ABCB1 (P = 0.007) and lower for ABCC1 (P = 0.004) compared with nongastric GISTs. We found no correlation between MDR protein expression and the risk assessment. None of the six patients treated with imatinib was resistant, although all were positive for at least one MDR protein. These results confirm that gastric and nongastric GISTs have different biological characteristics and suggest that MDR proteins do not impair the initial response of the tumor to imatinib.

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