title: Convection-enhanced delivery improves distribution and efficacy of tumor-selective retroviral replicating vectors in a rodent brain tumor model.
abstract: In the present study, we compared the therapeutic effect of tumor-selective retroviral replicating vectors (RRV) expressing the yeast cytosine deaminase (CD) delivered by convection-enhanced delivery (CED) or simple injection, followed by systemic administration of the pro-drug, 5-fluorocytosine (5-FC). Treatment with RRV-CD and systemic 5-FC significantly increased survival in rodent U87MG glioma model in comparison with controls (P<0.01). Interestingly, CED of RRV-CD followed by 5-FC further enhanced survival in this animal model in comparison with intra-tumoral injection of RRV-CD, followed by systemic 5-FC (P<0.05). High expression levels of Ki-67 were found in untreated tumors compared with treated. Untreated tumors were also much larger than treated. CED resulted in excellent distribution of RRV while only partial distribution of RRV was obtained after injection. Furthermore, RRV-CD and CD were also found in tumors from treated rats at study end points. These results demonstrated that RRV vectors may efficiently transduce and stably propagate in malignant human glioma, thereby achieving a significant in situ amplification effect after initial administration. We conclude that delivery of RRV into the glioma by CED provides much wider vector distribution than simple injection, and this correlated with better therapeutic outcomes.
authors.affiliation: Department of Neurosurgery, University of California San Francisco, San Francisco, CA 94103, USA.
authors.forename: D
authors.initials: D
authors.lastname: Yin
authors.forename: Y
authors.initials: Y
authors.lastname: Zhai
authors.forename: H E
authors.initials: HE
authors.lastname: Gruber
authors.forename: C E
authors.initials: CE
authors.lastname: Ibanez
authors.forename: J M
authors.initials: JM
authors.lastname: Robbins
authors.forename: A P
authors.initials: AP
authors.lastname: Kells
authors.forename: N
authors.initials: N
authors.lastname: Kasahara
authors.forename: J
authors.initials: J
authors.lastname: Forsayeth
authors.forename: D J
authors.initials: DJ
authors.lastname: Jolly
authors.forename: K S
authors.initials: KS
authors.lastname: Bankiewicz
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018481:Convection; D043525:Cytosine Deaminase / Q000008:administration & dosage* / Q000235:genetics; D016503:Drug Delivery Systems; D005437:Flucytosine / Q000008:administration & dosage*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D051381:Rats; D012190:Retroviridae
chemical_list: D019394:Ki-67 Antigen; D005437:Flucytosine; D043525:Cytosine Deaminase