{"corpus_id":89666956,"paper_sha":"88a9e989b1211c3d11de0c743073c881754066f7","doi":"10.1016/S1525-0016(16)34140-5","arxiv_id":null,"pmid":null,"pmcid":null,"mag_id":2562197410,"dblp_id":null,"acl_id":null,"title":"531. Intravenous Delivery of Toca 511 Gene Therapy in Combination with 5-Fluorocytosine for Intratumoral Production of 5-Fluorouracil in a Colon Cancer Metastasis Model","year":2015,"publication_date":"2015-05-01","venue":"","journal":{"name":"Molecular Therapy","pages":null,"volume":"23"},"journal_issn":null,"journal_title":null,"publication_types":[],"pubmed_pub_types":null,"s2_fields_of_study":["Biology","Medicine"],"reference_count":0,"citation_count":5,"influential_citation_count":0,"is_open_access":false,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":null,"chemicals":null,"comments_corrections":null,"source_flags":1,"s2_open_access_pdf_url":null,"s2_open_access_landing_url":null,"s2_open_access_license":null,"s2_open_access_status":null,"pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"Despite advances in screening, colorectal cancer (CRC) remains the fourth most commonly diagnosed cancer and the second leading cause of cancer death for both men and women in the US. Approximately one half of patients with CRC develop liver metastases (mCRC). The standard treatment for mCRC is 5-fluorouracil (5-FU) based combination chemotherapy. 5-FU combination chemotherapy has extended the median survival of these patients from 6 to >20 months.We are pursuing a unique investigational approach to treat cancer via in situ production of 5-FU. Toca 511 (vocimagene amiretrorepvec), a retroviral replicating vector (RRV), selectively replicates and spreads in malignant cells and encodes an optimized yeast cytosine deaminase (CD) gene. Within infected cells, the CD enzyme is expressed and converts 5-FC (flucytosine, an orally available anti-fungal drug) to the anti-cancer drug 5-FU. Both a direct cytotoxic effect and an extended immunotherapeutic effect have been reported using this approach.Toca 511, in conjunction with subsequent oral extended-release 5-fluorocytosine (Toca FC), is currently under investigation in patients with recurrent high grade glioma. In these studies, Toca 511 is delivered either intratumorally (NCT01156584), by injection into the surgical resection bed (NCT01470794), or intravenously (NCT01985256) in subjects scheduled for subsequent resection. We tested the suitability of the intravenous approach for the treatment of mCRC in a mouse syngeneic liver metastasis model. CT-26-luciferase colon carcinoma cells were delivered via intrasplenic injection producing multiple tumor foci within the liver. Intravenous delivery of RRV resulted in expression of the vector encoded transgene in tumor foci but not in adjacent normal liver tissue. Intravenous delivery of Toca 511 followed by courses of 5-FC resulted in shrinkage or elimination of tumor foci and improved survival in this model of mCRC. The data is supportive of future clinical trials of intravenous Toca 511 followed by cycles of Toca FC in metastatic CRC.","claims":[{"public_id":"cl_c106d6c98005c50e4104ecdbca5b3bb1","status":"active","text":"Intravenous delivery of Toca 511 followed by 5-fluorocytosine improved survival in the mouse model of metastatic colorectal cancer.","confidence":0.97,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_c106d6c98005c50e4104ecdbca5b3bb1"},{"public_id":"cl_e03745d5a1e177eaaeb6b192194df409","status":"active","text":"Intravenous delivery of Toca 511 followed by courses of 5-fluorocytosine caused shrinkage or elimination of tumor foci in the mouse metastasis model.","confidence":0.96,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous 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(12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_5fa7f1fca08000909139e870e8170f96"}],"concepts":[{"public_id":"co_2228376c2f3e7e965dd02a5c649b6ade","status":"active","name":"liver metastasis model","description":"A mouse syngeneic model in which colon carcinoma cells form multiple tumor foci in the liver.","types":["animal model","disease model"],"aliases":["mouse syngeneic liver metastasis model"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_2228376c2f3e7e965dd02a5c649b6ade"},{"public_id":"co_43b7795d5278baa18b1405c8fa5961cb","status":"active","name":"metastatic colorectal cancer","description":"Colorectal cancer that has spread to distant sites, including liver metastases.","types":["cancer 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