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Imatinib Mesylate Enhances Therapeutic Effects of Gemcitabine in Human Malignant Mesothelioma Xenografts

Authors' Affiliations: ¹ Department of Chemical, Food, Pharmaceutical and Pharmacological Sciences and Drug and Food Biotechnology Center, University of Piemonte Orientale "A. Avogadro," Novara, Italy; ² Animal Model Facility, National Cancer Institute and ³ Laboratory of Experimental Pharmacology, National Cancer Institute, Genoa, Italy; ⁴ Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico/San Matteo University Hospital, Pavia, Italy; and ⁵ Department of Medicine, Local Health Unit 11, Piemonte, Italy

Requests for reprints: Giovanni Gaudino, Department of Chemical, Food, Pharmaceutical and Pharmacological Sciences and Drug and Food Biotechnology Center, University of Piemonte Orientale "A. Avogadro," Via Bovio 6, 28100 Novara, Italy. Phone: 39-0321-375815; Fax: 39-0321-375821; E-mail: giovanni.gaudino{at}unipmn.it.

Purpose: Platelet-derived growth factor receptor β (PDGFRβ), frequently activated in malignant mesothelioma, is a promising cancer therapeutic target. Imatinib mesylate (STI571; Glivec) is a selective inhibitor of tyrosine kinases as bcr-abl, c-kit, c-fms, and PDGFRβ and enhances tumor drug uptake by reducing the interstitial fluid pressure. We previously showed that imatinib mesylate synergizes with gemcitabine and pemetrexed in PDGFRβ-positive mesothelioma cells. Here, we aimed at investigating these combined treatments in a novel mesothelioma model.

Experimental Design: REN mesothelioma cells, infected with a lentiviral vector carrying the luciferase gene, were injected in the peritoneum of severe combined immunodeficient mice. This model allowed imaging of live animals treated with pemetrexed or gemcitabine chemotherapeutics, or with imatinib mesylate alone, as well as with a combination of gemcitabine and imatinib mesylate.

Results: We show here that, consistent with our previous in vitro studies, gemcitabine inhibited tumor growth, whereas pemetrexed was ineffective, even at the highest dosage tested. Compared with monotreatment, the combination of gemcitabine with imatinib mesylate led to a further tumor growth inhibition and improved mice survival, by a decrease rate of tumor cell proliferation and an increase in number of apoptotic tumor cells.

Conclusions: Imatinib mesylate enhances the therapeutic response to gemcitabine, in accordance with our previous in vitro data. These in vivo results validate imatinib mesylate and gemcitabine as a combination treatment of malignant mesothelioma, also in view of its known positive effects on tumor drug uptake. These evidences provide the rationale for the currently ongoing clinical trials.