X-ray on chip: Quantifying therapeutic synergies between radiotherapy and anticancer drugs using soft tissue sarcoma tumor spheroids
| Autor: | Elena Refet-Mollof, Philip Wong, Y Kamio, Thomas Gervais, Maeva Bavoux, Julie Lafontaine, Ouafa Najyb, Jean-François Carrier, Emmanuelle Vigneux-Foley |
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| Rok vydání: | 2021 |
| Předmět: |
Radiosensitizer
medicine.medical_treatment Antineoplastic Agents Soft Tissue Neoplasms 030218 nuclear medicine & medical imaging Pazopanib 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Spheroids Cellular Radioresistance Tumor Microenvironment medicine Humans Talazoparib Radiology Nuclear Medicine and imaging Clonogenic assay business.industry X-Rays Soft tissue sarcoma Cancer Sarcoma Hematology medicine.disease Radiation therapy Oncology chemistry 030220 oncology & carcinogenesis Cancer research business medicine.drug |
| Zdroj: | Radiotherapy and Oncology. 157:175-181 |
| ISSN: | 0167-8140 |
| Popis: | Purpose Radioresistance, tumor microenvironment, and normal tissue toxicity from radiation limit the efficacy of radiotherapy in treating cancers. These challenges can be tackled by the discovery of new radiosensitizing and radioprotecting agents aimed at increasing the therapeutic efficacy of radiotherapy. The goal of this work was to develop a miniaturized microfluidic platform for the discovery of drugs that could be used in combination with radiotherapy. The microfluidic system will allow the toxicity testing of cancer spheroids to different combinations of radiotherapy and molecular agents. Materials and methods An orthovoltage-based technique was used to expose the devices to multiple X-ray radiation doses simultaneously. Radiation dose-dependent DNA double-strand breaks in soft tissue sarcoma (STS) spheroids were quantified using comet assays. Analysis of proliferative death using clonogenic assays was also performed, and synergy between treatments with Talazoparib, Pazopanib, AZD7762, and radiotherapy was quantified using dedicated statistical tests. Results The developed microfluidic system with simple magnetic valves was capable of growing 336 homogeneous STS spheroids. The irradiation of the microfluidic system with an orthovoltage-based technique enabled the screening of sixteen drug-radiotherapy combinations with minimal reagent consumption. Using this framework, we predicted a therapeutic synergy between a novel anticancer drug Talazoparib and radiotherapy for STS. No synergy was found between RT and either Pazopanib or AZD7762, as the combinations were found to be additive. Conclusion This methodology lays the basis for the systemic search for molecular agent/radiotherapy synergies among preexisting pharmaceutical compounds libraries, in the hope to identify failed drug candidates in monotherapy that, in the presence of radiotherapy, would make it through clinical trials. |
| Databáze: | OpenAIRE |
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