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Article Dans Une Revue Molecular Cancer Therapeutics Année : 2016

Proteoglycans as Target for an Innovative Therapeutic Approach in Chondrosarcoma: Preclinical Proof of Concept

A. Voissiere
  • Fonction : Auteur
A. Maisonial-Besset
  • Fonction : Auteur
A. Vidal
  • Fonction : Auteur
Philippe Auzeloux
Vincent Gaumet
M. Borel
  • Fonction : Auteur
M. Dauplat
  • Fonction : Auteur
Mercedes Quintana
Françoise Degoul
  • Fonction : Auteur
F. Redini
  • Fonction : Auteur
Jean-Michel Chezal

Résumé

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 chon-drosarcoma 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 mel-phalan (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 chondrosar-coma, 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 [ 3 H]-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 vivo 99m Tc-NTP 15-5 scinti-graphic imaging of PGs, 1 H-HRMAS NMR spectroscopy, and histology. The conjugation of a QA function to Mel did not hamper its in vivo efficiency and strongly improved the toler-ability 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.

Dates et versions

hal-01636341 , version 1 (16-11-2017)

Identifiants

Citer

Caroline Peyrode, Valérie Weber, A. Voissiere, A. Maisonial-Besset, A. Vidal, et al.. Proteoglycans as Target for an Innovative Therapeutic Approach in Chondrosarcoma: Preclinical Proof of Concept. Molecular Cancer Therapeutics, 2016, 15 (11), pp.2575 - 2585. ⟨10.1158/1535-7163.MCT-16-0003⟩. ⟨hal-01636341⟩
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