title: Widespread intratumoral virus distribution with fractionated injection enables local control of large human rhabdomyosarcoma xenografts by oncolytic herpes simplex viruses.
abstract: Novel methods of local control for sarcomas are needed. We investigated the antitumor effect of two related herpes simplex virus (HSV) mutants, NV1020 and NV1066, on human rhabdomyosracoma cells and xenografts. Cell death correlated with virus replication and apoptosis in cultured cells and tumors. Complete regression was seen in all tumors <250 mm(3) following a single injection, yet only half of tumors >250 mm(3) showed a complete response. Fractionation of the virus dose into five injection sites did not increase transduction efficiency, transgene expression, or virus production, but did yield more widespread intratumoral distribution. Despite the same total dose of virus, improved control of large tumors was seen using fractionated injections as all large tumors (500-700 mm(3)) had durable, complete regression. Our data suggest that oncolytic HSVs may be useful for local control of bulky rhabdomyosarcoma tumors and that fractionated virus administration results in a more widespread virus infection and better tumor control. Therefore, strategies to maximize intratumoral virus distribution at initial delivery should be sought.
authors.affiliation: Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Currier
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Adams
authors.forename: Yonatan Y
authors.initials: YY
authors.lastname: Mahller
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cripe
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002469:Cell Separation; D005434:Flow Cytometry; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008856:Microscopy, Fluorescence; D009154:Mutation; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000628:therapy; D018139:Simplexvirus / Q000235:genetics*; D013997:Time Factors; D019076:Transgenes; D014779:Virus Replication; D014780:Viruses / Q000235:genetics*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D049452:Green Fluorescent Proteins; D001616:beta-Galactosidase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases