Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.1 (cytosine deaminase)
 747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of tumors with Toca 511, a gamma retroviral replicating vector encoding cytosine deaminase, followed by 5-fluorocytosine (5-FC) kills tumors by local production of 5-fluorouracil (5-FU). In brain tumor models, this treatment induces systemic anti-tumor immune responses and long-term immune-mediated survival. Phase 1 Toca 511 and Toca FC (extended-release 5-FC) clinical trials in patients with recurrent high-grade glioma show durable complete responses and promising survival data compared to historic controls. The work described herein served to expand on our earlier findings in two models of metastatic colorectal carcinoma (mCRC). Intravenous (i.v.) delivery of Toca 511 resulted in substantial tumor-selective uptake of vector into metastatic lesions. Subsequent treatment with 5-FC resulted in tumor shrinkage, improved survival, and immune memory against future rechallenge with the same CT26 CRC cell line. Similar results were seen in a brain metastasis model of mCRC. Of note, 5-FC treatment resulted in a significant decrease in myeloid-derived suppressor cells (MDSCs) in mCRC tumors in both the liver and brain. These results support the development of Toca 511 and Toca FC as a novel immunotherapeutic approach for patients with mCRC. A phase 1 study of i.v. Toca 511 and Toca FC in solid tumors, including mCRC, is currently underway (NCT02576665).
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PMID:A Retroviral Replicating Vector Encoding Cytosine Deaminase and 5-FC Induces Immune Memory in Metastatic Colorectal Cancer Models. 2932 91

Uveal melanoma (UM) is the most common intraocular tumor in adults and has a high incidence of metastases. Possible treatments remain limited in UM with enucleation and radiation, leading to poor prognosis in this chemo-resistant carcinoma. Thus, urging demand for novel treatment is needed. We examined the antitumor efficacy of a new recombinant oncolytic herpes simplex virus type 1 (oHSV-1) armed with E.coli cytosine deaminase (CD). We determined the efficacy of the oncolytic virus in UM cell lines. In vivo experiments showed that oHSV-CD/5-fluorocytosine (5-FC) treatment reduce tumor volume and prolonged survival. We further demonstrated the molecular mechanisms of oHSV-CD/5-FC treatment. The oncolytic virus down-regulated IL-6 expression and thereby reversed the epithelial-mesenchymal transition (EMT) phenotype. Dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-fluorouracil (5-FU) metabolism, was also down-regulated. Therefore, the efficacy of oHSV-CD/5-FC was synergistically enhanced by DPD down-regulation and EMT inhibition. This study provides solid evidence for the antitumor efficacy of oHSV-CD/5-FC treatment in vitro and in vivo. The molecular mechanisms of this treatment may bring a new therapeutic approach for future treatment of UM.
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PMID:Antitumor efficacy of oncolytic HSV-1 expressing cytosine deaminase is synergistically enhanced by DPD down-regulation and EMT inhibition in uveal melanoma xenograft. 3294 63


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