Targeting the DNA repair pathway in Ewing sarcoma
| Autor: | Claudia A. Benavente, Lyudmila Tsurkan, Asa Karlstrom, Armita Bahrami, Lyra Griffiths, William Caufield, Nathaniel R. Twarog, Suresh Thiagarajan, Philip M. Potter, M. Jason Hatfield, Burgess B. Freeman, Amos Hong Pheng Loh, Alberto S. Pappo, Cori Bradley, Jianrong Wu, Andras Sablauer, Anang A. Shelat, Abbas Shirinifard, Gregory M. Miller, Michael A. Dyer, Elizabeth Stewart, Brittney Gordon, Scott E. Snyder, Ross Goshorn, Christopher Calabrese |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
DNA Repair
Nude Medical Physiology Piperazines Mice Double-Stranded DNA Breaks Double-Stranded Molecular Targeted Therapy Enzyme Inhibitors lcsh:QH301-705.5 Tumor Cell Death Drug Synergism Sarcoma 3. Good health Dacarbazine Poly(ADP-ribose) Polymerases medicine.drug Mice Nude Sarcoma Ewing Biology Poly(ADP-ribose) Polymerase Inhibitors Irinotecan Article General Biochemistry Genetics and Molecular Biology Cell Line Cell Line Tumor Ewing medicine Temozolomide Animals DNA Breaks DNA Repair Pathway medicine.disease Pediatric cancer Xenograft Model Antitumor Assays lcsh:Biology (General) Localized disease Immunology Cancer research Phthalazines Camptothecin Benzimidazoles Biochemistry and Cell Biology |
| Zdroj: | Stewart, E; Goshorn, R; Bradley, C; Griffiths, LM; Benavente, C; Twarog, NR; et al.(2014). Targeting the DNA repair pathway in Ewing sarcoma. Cell Reports, 9(3), 829-840. doi: 10.1016/j.celrep.2014.09.028. UC Irvine: Retrieved from: http://www.escholarship.org/uc/item/9fn307ds Cell Reports, Vol 9, Iss 3, Pp 829-840 (2014) Cell reports, vol 9, iss 3 |
| Popis: | © 2014 The Authors. Ewing sarcoma (EWS) is a tumor of the bone and soft tissue that primarily affects adolescents and young adults. With current therapies, 70% of patients with localized disease survive, but patients with metastatic or recurrent disease have a poor outcome. We found that EWS cell lines are defective in DNA break repair and are sensitive to PARP inhibitors (PARPis). PARPi-induced cytotoxicity in EWS cells was 10- to 1,000-fold higher after administration of the DNAdamaging agents irinotecan or temozolomide. We developed an orthotopic EWS mouse model and performed pharmacokinetic and pharmacodynamic studies using three different PARPis that are in clinical development for pediatric cancer. Irinotecan administered on a low-dose, protracted schedule previously optimized for pediatric patients was an effective DNA-damaging agent when combined with PARPis; it was also better tolerated than combinations with temozolomide. Combining PARPis with irinotecan and temozolomide gave complete and durable responses in more than 80% of the mice. |
| Databáze: | OpenAIRE |
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