title: Proteoglycans as Target for an Innovative Therapeutic Approach in Chondrosarcoma: Preclinical Proof of Concept.
abstract: To date, surgery remains the only option for the treatment of chondrosarcoma, which is radio- and chemoresistant due in part to its large extracellular matrix (ECM) and poor vascularity. In case of unresectable locally advanced or metastatic diseases with a poor prognosis, improving the management of chondrosarcoma still remains a challenge. Our team developed an attractive approach of improvement of the therapeutic index of chemotherapy by targeting proteoglycan (PG)-rich tissues using a quaternary ammonium (QA) function conjugated to melphalan (Mel). First of all, we demonstrated the crucial role of the QA carrier for binding to aggrecan by surface plasmon resonance. In the orthotopic model of Swarm rat chondrosarcoma, an in vivo biodistribution study of Mel and its QA derivative (Mel-QA), radiolabeled with tritium, showed rapid radioactivity accumulation in healthy cartilaginous tissues and tumor after [3H]-Mel-QA injection. The higher T/M ratio of the QA derivative suggests some advantage of QA-active targeting of chondrosarcoma. The antitumoral effects were characterized by tumor volume assessment, in vivo99mTc-NTP 15-5 scintigraphic imaging of PGs,1H-HRMAS NMR spectroscopy, and histology. The conjugation of a QA function to Mel did not hamper its in vivo efficiency and strongly improved the tolerability of Mel leading to a significant decrease of side effects (hematologic analyses and body weight monitoring). Thus, QA conjugation leads to a significant improvement of the therapeutic index, which is essential in oncology and enable repeated cycles of chemotherapy in patients with chondrosarcoma. Mol Cancer Ther; 15(11); 2575-85. ©2016 AACR.
authors: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France. caroline.peyrode@udamail.fr.|INSERM, UMR990, Clermont-Ferrand, France.
authors: Caroline
authors: C
authors: Peyrode
authors: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.|INSERM, UMR990, Clermont-Ferrand, France.
authors: Valérie
authors: V
authors: Weber
authors: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.|INSERM, UMR990, Clermont-Ferrand, France.
authors: Aurélien
authors: A
authors: Voissière
authors: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.|INSERM, UMR990, Clermont-Ferrand, France.
authors: Aurélie
authors: A
authors: Maisonial-Besset
authors: Arronax, Saint-Herblain, France.
authors: Aurélien
authors: A
authors: Vidal
authors: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.|INSERM, UMR990, Clermont-Ferrand, France.
authors: Philippe
authors: P
authors: Auzeloux
authors: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.|INSERM, UMR990, Clermont-Ferrand, France.
authors: Vincent
authors: V
authors: Gaumet
authors: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.|INSERM, UMR990, Clermont-Ferrand, France.
authors: Michèle
authors: M
authors: Borel
authors: CLCC Jean-Perrin, Clermont-Ferrand, France.
authors: Marie-Mélanie
authors: MM
authors: Dauplat
authors: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.|INSERM, UMR990, Clermont-Ferrand, France.
authors: Mercedes
authors: M
authors: Quintana
authors: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.|INSERM, UMR990, Clermont-Ferrand, France.
authors: Françoise
authors: F
authors: Degoul
authors: INSERM, UMR S957, Nantes Atlantique Université, Nantes, France.
authors: Françoise
authors: F
authors: Rédini
authors: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.|INSERM, UMR990, Clermont-Ferrand, France.
authors: Jean-Michel
authors: JM
authors: Chezal
authors: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.|INSERM, UMR990, Clermont-Ferrand, France.
authors: Elisabeth
authors: E
authors: Miot-Noirault
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D008558:Melphalan / Q000737:chemistry / Q000494:pharmacology; D057054:Molecular Imaging / Q000379:methods; D061848:Optical Imaging / Q000379:methods; D011509:Proteoglycans / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D011509:Proteoglycans; D000644:Quaternary Ammonium Compounds; D008558:Melphalan