دورية أكاديمية
Fast Track Adaptation of Oncolytic Coxsackie B3 Virus to Resistant Colorectal Cancer Cells - a Method to Personalize Virotherapy
| العنوان: | Fast Track Adaptation of Oncolytic Coxsackie B3 Virus to Resistant Colorectal Cancer Cells - a Method to Personalize Virotherapy |
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| المؤلفون: | Leslie Elsner, Lisanne Heimann, Anja Geisler, Babette Dieringer, Klaus-Peter Knoch, Luisa Hinze, Karin Klingel, Michel Solimena, Jens Kurreck, Henry Fechner |
| المصدر: | Biological Procedures Online, Vol 26, Iss 1, Pp 1-16 (2024) |
| بيانات النشر: | BMC, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Medicine (General) LCC:Biology (General) |
| مصطلحات موضوعية: | Cancer Therapy, Oncolytic Virus, Personalized Therapy, Colorectal Carcinoma, Direct Virus Evolution, Coxsackievirus B3, Medicine (General), R5-920, Biology (General), QH301-705.5 |
| الوصف: | Abstract Background The efficacy of oncolytic viruses (OV) in cancer treatment depends on their ability to successfully infect and destroy tumor cells. However, patients’ tumors vary, and in the case of individual insensitivity to an OV, therapeutic efficacy is limited. Here, we present a protocol for rapid generation of tumor cell-specific adapted oncolytic coxsackievirus B3 (CVB3) with enhanced oncolytic potential and a satisfactory safety profile. This is achieved by combining directed viral evolution (DVE) with genetic modification of the viral genome and the use of a microRNA-dependent regulatory tool. Methods The oncolytic CVB3 variant PD-H was adapted to the refractory colorectal carcinoma cell line Colo320 through serial passaging. XTT assays and virus plaque assays were used to determine virus cytotoxicity and virus replication in vitro. Recombinant PD-H variants were generated through virus mutagenesis. Apoptosis was detected by Western blots, Caspase 3/7 assays, and DAPI staining. The therapeutic efficacy and safety of the adapted recombinant OV PD-SK-375TS were assessed in vivo using a subcutaneous Colo320 xenograft mouse model. Results PD-H was adapted to the colorectal cancer cell line Colo320 within 10 passages. Sequencing of passage 10 virus P-10 revealed a heterogenous virus population with five nucleotide mutations resulting in amino acid substitutions. The genotypically homogeneous OV PD-SK was generated by inserting the five detected mutations of P-10 into the genome of PD-H. PD-SK showed significantly stronger replication and cytotoxicity than PD-H in Colo320 cells, but not in other colorectal carcinoma cell lines. Increase of apoptosis induction was detected as key mechanisms of Colo320 cell-specific adaptation of PD-SK. For in vivo safety PD-SK was engineered with target sites of the miR-375 (miR-375TS) to exclude virus replication in normal tissues. PD-SK-375TS, unlike the PD-H-375TS not adapted homolog suppressed the growth of subcutaneous Colo320 tumors in nude mice without causing any side effects. Conclusion Taken together, here we present an optimized protocol for the rapid generation of tumor cell-specific adapted oncolytic CVB3 based on the oncolytic CVB3 strain PD-H. The protocol is promising for the generation of personalized OV for tumor therapy and has the potential to be applied to other OV. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1480-9222 |
| Relation: | https://doaj.org/toc/1480-9222 |
| DOI: | 10.1186/s12575-024-00237-2 |
| URL الوصول: | https://doaj.org/article/12073503249b4b00bb4d7853be5b2933 |
| رقم الأكسشن: | edsdoj.12073503249b4b00bb4d7853be5b2933 |
| قاعدة البيانات: | Directory of Open Access Journals |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 14809222 |
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| DOI: | 10.1186/s12575-024-00237-2 |