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 vivo 99mTc-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.
Highlights
One of the key problems in chondrosarcoma, the second most common type of skeletal malignancy after osteosarcoma, is the lack of response to both chemotherapy and radiotherapy, giving rise to poor patient outcomes and leaving surgery as the only effective curative treatment
We developed a therapeutic approach with a quaternary ammonium (QA) derivative of melphalan (Mel-QA), an alkylating agent, that showed promising results from in vitro and in vivo preclinical experiments [13]
Evaluation of the QA binding to PGs by surface plasmon resonance (SPR) Studies were performed for Mel and its QA derivative (Mel-QA), respectively, to Mel injected in increasing concentrations (0–2 mmol/L)
Summary
One of the key problems in chondrosarcoma, the second most common type of skeletal malignancy after osteosarcoma, is the lack of response to both chemotherapy and radiotherapy, giving rise to poor patient outcomes and leaving surgery as the only effective curative treatment. The type of required surgical procedure may vary according to the grade, the initial location, and the extent of the disease. Large en bloc dramatic resection or amputation, often necessary to allow the local control of the tumor and to avoid metastases, are at the origin of strong disability and morbidity [1]. Wide resection is not always possible in large tumors and critical anatomic locations such as pelvis, axial. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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