Complement Depletion Facilitates the Infection of Multiple Brain Tumors by an Intravascular, Replication-Conditional Herpes Simplex Virus Mutant

摘要: Intravascular routes of administration can provide a means to target gene- and virus-based therapies multiple tumor foci located within an organ, such as the brain. However, we demonstrate here that rodent plasma inhibits cell transduction by replication-conditional (oncolytic) herpes simplex viruses (HSV), replication-defective HSV, adenovirus vectors. In vitro depletion complement with mild heat treatment or in vivo athymic rats cobra venom factor (CVF) partially reverses this effect. Without CVF, inhibition infection HSV is observed at dilution high 1:32, while from CVF-treated animals displays anti-HSV activity lower dilutions (1:8). When applied therapy intracerebral brain tumors, facilitates initial (assayed 2-day time point) intra-arterial cells, three separate distinct human glioma masses. 4-day point, no propagation initially infected cells could be observed. Previously, have shown immunosuppressive agent, cyclophosphamide (CPA), oncolytic delivered intravascularly, masses, both innate elicited neutralizing antibody response (K. Ikeda et al., Nat. Med. 5:881–889, 1999). study, thus show addition CPA CVF results significant increase viral measured period. The concerted action significantly increases life span rodents harboring large xenografts after intravascular, HSV. Southern analysis genomes analyzed PCR reveals presence virus brains, livers, spleens, kidneys, intestine treated animals, although none these tissues evidence HSV-mediated gene expression. light clinical trials for malignant findings suggest antitumor efficacy may limited host humoral responses.