RRC ID 56621
Author Inoko K, Hiraoka K, Inagaki A, Takahashi M, Kushibiki T, Hontani K, Takano H, Sato S, Takeuchi S, Nakamura T, Tsuchikawa T, Shichinohe T, Gruber HE, Jolly DJ, Kasahara N, Hirano S.
Title Therapeutic activity of retroviral replicating vector-mediated prodrug activator gene therapy for pancreatic cancer.
Journal Cancer Gene Ther
Abstract Toca 511, a retroviral replicating vector (RRV) encoding the yeast cytosine deaminase (yCD) prodrug activator gene, which mediates conversion of the prodrug 5-fluorocytosine (5-FC) to the anticancer drug 5-fluorouracil (5-FU), is currently being evaluated in Phase II/III clinical trials for glioma, and showing highly promising evidence of therapeutic activity. Here we evaluated RRV-mediated prodrug activator gene therapy as a new therapeutic approach for pancreatic ductal adenocarcinoma (PDAC). RRV spread rapidly and conferred significant cytotoxicity with prodrug in a panel of PDAC cells. Efficient intratumoral replication and complete inhibition of tumor growth upon 5-FC administration were observed in both immunodeficient and immunocompetent subcutaneous PDAC models. Biodistribution of RRV was highly restricted in normal tissues, especially in immunocompetent hosts. Tumor growth inhibition by Toca 511 followed by 5-FC was also confirmed in the orthotopic PDAC model. This study provides the first proof-of-concept for application of Toca 511 and Toca FC (extended release 5-FC) to the treatment of human PDAC, and provided support for inclusion of PDAC in a Phase I study evaluating Toca 511 in various systemic malignancies, (NCT02576665), which has recently been initiated.
Volume 25(7-8)
Pages 184-195
Published 2018-8-1
DOI 10.1038/s41417-018-0020-7
PII 10.1038/s41417-018-0020-7
PMID 29735994
MeSH Cell Line, Tumor Cytosine Deaminase* / biosynthesis Cytosine Deaminase* / genetics Fluorouracil / pharmacokinetics Fluorouracil / pharmacology* Genetic Therapy / methods* Genetic Vectors* Humans Pancreatic Neoplasms* / genetics Pancreatic Neoplasms* / metabolism Pancreatic Neoplasms* / pathology Pancreatic Neoplasms* / therapy Prodrugs / pharmacokinetics Prodrugs / pharmacology* Retroviridae* Saccharomyces cerevisiae / genetics Saccharomyces cerevisiae Proteins* / biosynthesis Saccharomyces cerevisiae Proteins* / genetics
IF 4.681
Times Cited 2
Human and Animal Cells PANC-1(RCB2095)