title: Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types.
abstract: Toca 511 is a modified retroviral replicating vector based on Moloney γ-retrovirus with an amphotropic envelope. As an investigational cancer treatment, Toca 511 preferentially infects cancer cells without direct cell lysis and encodes an enhanced yeast cytosine deaminase that converts the antifungal drug 5-fluorocytosine to the anticancer drug, 5-fluorouracil. A panel of established human cancer cell lines, derived from glioblastoma, colon, and breast cancer tissue, was used to evaluate parameters critical for effective anticancer activity. Gene transfer, cytosine deaminase production, conversion of 5-fluorocytosine to 5-fluorouracil, and subsequent cell killing occurred in all lines tested. We observed >50% infection within 25 days in all lines and 5-fluorocytosine LD50 values between 0.02 and 6 μg/ml. Although we did not identify a small number of key criteria, these studies do provide a straightforward approach to rapidly gauge the probability of a Toca 511 and 5-fluorocytosine treatment effect in various cancer indications: a single MTS assay of maximally infected cancer cell lines to determine 5-fluorocytosine LD50. The data suggest that, although there can be variation in susceptibility to Toca 511 and 5-fluorocytosine because of multiple mechanistic factors, this therapy may be applicable to a broad range of cancer types and individuals.
authors.affiliation: Tocagen, Inc. , San Diego, California.
authors.forename: Chris G
authors.initials: CG
authors.lastname: Twitty
authors.affiliation: Tocagen, Inc. , San Diego, California.
authors.forename: Oscar R
authors.initials: OR
authors.lastname: Diago
authors.affiliation: Tocagen, Inc. , San Diego, California.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hogan
authors.affiliation: Tocagen, Inc. , San Diego, California.
authors.forename: Cindy
authors.initials: C
authors.lastname: Burrascano
authors.affiliation: Tocagen, Inc. , San Diego, California.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Ibanez
authors.affiliation: Tocagen, Inc. , San Diego, California.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Jolly
authors.affiliation: Tocagen, Inc. , San Diego, California.
authors.forename: Derek
authors.initials: D
authors.lastname: Ostertag
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D043525:Cytosine Deaminase / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D012333:RNA, Messenger / Q000235:genetics; D012190:Retroviridae / Q000235:genetics*; D014161:Transduction, Genetic; D019076:Transgenes; D016662:Virus Integration; D014779:Virus Replication
chemical_list: D012333:RNA, Messenger; D043525:Cytosine Deaminase; D005472:Fluorouracil