Inhibition of Chondrosarcoma Growth by mTOR Inhibitor in an In Vivo Syngeneic Rat Model
| Autor: | Anthony Besse, Jennifer Perez, Jean Philippe Michot, Anne Valérie Decouvelaere, Thomas Pointecouteau, Aurélie Dutour, Jean Yves Blay, Daniel Pissaloux |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Pathology Proliferation index Cancer Treatment lcsh:Medicine Apoptosis 0302 clinical medicine Antineoplastic Combined Chemotherapy Protocols Bone and Soft Tissue Sarcomas lcsh:Science 0303 health sciences Multidisciplinary Reverse Transcriptase Polymerase Chain Reaction TOR Serine-Threonine Kinases Animal Models 3. Good health Oncology 030220 oncology & carcinogenesis Medicine Oncology Agents Research Article medicine.drug medicine.medical_specialty Blotting Western Chondrosarcoma Bone Neoplasms Real-Time Polymerase Chain Reaction 03 medical and health sciences Model Organisms In vivo medicine Adjuvant therapy Animals Humans Doxorubicin Everolimus RNA Messenger Biology Cell Proliferation 030304 developmental biology Sirolimus business.industry lcsh:R Cancers and Neoplasms Chemotherapy and Drug Treatment medicine.disease Rats Disease Models Animal Tumor progression Cancer research Rat lcsh:Q Neoplasm Recurrence Local business |
| Zdroj: | PLoS ONE, Vol 7, Iss 6, p e32458 (2012) PLoS ONE BASE-Bielefeld Academic Search Engine PLoS ONE; Vol 7 |
| ISSN: | 1932-6203 |
| Popis: | Background Chondrosarcomas are the second most frequent primary malignant type of bone tumor. No effective systemic treatment has been identified in advanced or adjuvant phases for chondrosarcoma. The aim of the present study was to determine the antitumor effects of doxorubicin and everolimus, an mTOR inhibitor on chondrosarcoma progression. Methods and Findings Doxorubin and/or everolimus were tested in vivo as single agent or in combination in the rat orthotopic Schwarm chondrosarcoma model, in macroscopic phase, as well as with microscopic residual disease. Response to everolimus and/or doxorubicin was evaluated using chondrosarcoma volume evolution (MRI). Histological response was evaluated with % of tumor necrosis, tumor proliferation index, metabolism quantification analysis between the treated and control groups. Statistical analyses were performed using chi square, Fishers exact test. Doxorubicin single agent has no effect of tumor growth as compared to no treatment; conversely, everolimus single agent significantly inhibited tumor progression in macroscopic tumors with no synergistic additive effect with doxorubicin. Everolimus inhibited chondrosarcoma proliferation as evaluated by Ki67 expression did not induce the apoptosis of tumor cells; everolimus reduced Glut1 and 4EBP1 expression. Importantly when given in rats with microscopic residual diseases, in a pseudo neoadjuvant setting, following R1 resection of the implanted tumor, everolimus significantly delayed or prevented tumor recurrence. Conclusions MTOR inhibitor everolimus blocks cell proliferation, Glut1 expression and HIF1a expression, and prevents in vivo chondrosarcoma tumor progression in both macroscopic and in adjuvant phase post R1 resection. Taken together, our preclinical data indicate that mTOR inhibitor may be effective as a single agent in treating chondrosarcoma patients. A clinical trial evaluating mTOr inhibitor as neo-adjuvant and adjuvant therapy in chondrosarcoma patients is being constructed. |
| Databáze: | OpenAIRE |
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