DELIVERY OF HERPESVIRUS AND ADENOVIRUS TO NUDE RAT INTRACEREBRAL TUMORS AFTER OSMOTIC BLOOD-BRAIN-BARRIER DISRUPTION

The delivery of viral vectors to the brain for treatment of intracereb ral tumors is most commonly accomplished by stereotaxic inoculation di rectly into the tumor. However, the small volume of distribution by in oculation may limit the efficacy of viral therapy of large or dissemin ated tumors. We have investigated mechanisms to increase vector delive ry to intracerebral xenografts of human LX-1 small-cell lung carcinoma tumors in the nude rat. The distribution of Escherichia coli lacZ tra nsgene expression from primary viral infection was assessed after deli very of recombinant virus by intratumor inoculation or intracarotid in fusion with or without osmotic disruption of the blood-brain barrier ( BBB). These studies used replication-compromised herpes simplex virus type 1 (HSV; vector RH105) and replication-defective adenovirus (AdRSV lacZ), which represent two of the most commonly proposed viral vectors for tumor therapy. Transvascular delivery of both viruses to intracer ebral tumor was demonstrated when administered intraarterially (i.a.) after osmotic BBB disruption (n = 9 for adenovirus; n = 7 for HSV), wh ile no virus infection was apparent after i.a. administration without BBB modification (n = 8 for adenovirus; n = 4 for HSV). The thymidine kinase-negative HSV vector infected dumps of tumor cells as a result o f its ability to replicate selectively in dividing cells. Osmotic BBB disruption in combination with i.a. administration of viral vectors ma y offer a method of global delivery to treat disseminated brain tumors .