title: Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate cancer cells.
abstract: Genetically engineered oncolytic herpes simplex virus-1 (HSV-1) vectors selectively replicate in tumor cells causing direct killing whereas sparing normal cells. One clinical limitation of using oncolytic HSV vectors is their attenuated growth. We hypothesized that the appropriately chosen chemotherapeutic agent combined with an oncolytic HSV could be an effective means to promote augmented prostate cancer cell killing both in vitro and in vivo. Here we have identified that G47Delta synergizes with the microtubule-stabilizing taxane agents docetaxel and paclitaxel to enhance the in vitro killing of prostate cancer cells. In vivo efficacy studies show that when combined with docetaxel, G47Delta could be reduced at least 10-fold. Immunoblot analysis revealed that docetaxel-induced accumulation of the phospho-specific mitotic markers op18/stathmin or histone-H3 was markedly reduced by G47Delta, which correlated with enhanced apoptosis and required active viral replication. Furthermore, cell-cycle analysis demonstrated that in the presence of G47Delta, the majority of 4N cells arrested in mitosis were MPM-2-negative, indicative of cells exiting mitosis prematurely. These findings suggest that G47Delta may act in part, on mitotically blocked cells to enhance cell death, which may account for the enhanced antitumor efficacy observed in vivo.
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. bpasser@partners.org
authors.forename: B J
authors.initials: BJ
authors.lastname: Passer
authors.forename: P
authors.initials: P
authors.lastname: Castelo-Branco
authors.forename: J S
authors.initials: JS
authors.lastname: Buhrman
authors.forename: S
authors.initials: S
authors.lastname: Varghese
authors.forename: S D
authors.initials: SD
authors.lastname: Rabkin
authors.forename: R L
authors.initials: RL
authors.lastname: Martuza
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D050130:Oncolytic Virotherapy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000628:therapy*; D018139:Simplexvirus / Q000235:genetics / Q000502:physiology; D043823:Taxoids / Q000627:therapeutic use*; D014779:Virus Replication
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids