Gene therapy of malignant brain tumors: a rat glioma line bearing the herpes simplex virus

Fisher rats were implanted intracranially with wild-type 9L glioma cells, subsequently injected with C6tk cells at the same brain coordinate, and thereafter treated with GCV or saline. The in vivo experiments were performed in five adult patients who had failed standard therapy and were expected to survive only a few weeks. We report the following: (a) all five mutant HSVs were avirulent in experimental animals but were cytotoxic for human tumor cells in vitro and in vivo; (b) the gamma(1)34.5- HSV replicated in human glioma cells almost as efficiently as wild-type HSV-1(F) based on replication assays, in situ hybridization for viral DNA, and expression of infected cell protein 27; (c) capacity of mutant HSVs to kill human cells derived from glioblastoma multiforme (CH-235MG, D-37MG, D-54MG, D-65MG, U-251MG, U-373MG, and SK-MG-1), anaplastic astrocytoma (Hs-683), anaplastic glioma (U-87MG and U-138MG), gliosarcoma (D-32GS), or normal human astrocytes demonstrated that glioma cells varied in their susceptibility to HSV-mediated cytotoxicity and that cultured astrocytes were two to three orders of magnitude less susceptible to killing than were malignant glia; and (d) scid mice, which received 0.5 or 5 x 10(6) plaque-forming units of R4009, either were coinoculated at the time of intracranial transplantation with 106 U251MG or D-54MG human glioma cells or received the cells intratumorally 5 days after tumor induction and experienced significant increases in median survivals, with no histopathological indication of an infectious encephalitic process. In culture, C6VIKWT cells were 300-fold more sensitive to the toxicity of ganciclovir than were C6VIK cells, suggesting that the presence of wild type retrovirus contributed to the toxicity. For in vivo experiments, intracerebral tumors were induced in rats by stereotactic injection of 10(4) HSV-tk-modified C6 cells. Another promising new approach has been the engineering of novel oncolytic HSV vectors that retain wildtype replication, but are targeted to tumor cells through a variety of mechanisms. Despite intervention by brain tumor experts, Sen.

In an attempt to improve this grim prognosis of patients with malignant brain tumors (both primary tumors and secondary metastasis from systemic cancer such as melanoma, lung and breast cancer), we have developed a novel approach to the therapy of brain tumors. 5(-)) alone or with a virus expressing IL-10. In culture, C6VIKWT cells were 300-fold more sensitive to the toxicity of ganciclovir than were C6VIK cells, suggesting that the presence of wild type retrovirus contributed to the toxicity. To evaluate these findings, samples of 40 gliomas, 31 meningiomas, and 6 acoustic neurinomas (ACNs) were analyzed for the presence of HCMV macromolecules using polymerase chain reaction (PCR) and immunohistochemistry. The altered genes have been demonstrated to be responsible for the induction of malignant transformation in cell cultures or in animals. The in vivo experiments were performed in five adult patients who had failed standard therapy and were expected to survive only a few weeks. It is also the hardest to treat.

tumors elicited cytotoxic T-cell responses not only to HSV but also to a tumor antigen; however, only a limited antitumor effect was observed on metastatic brain tumors. The “moving wall” represents the time period between the last issue available in JSTOR and the most recently published issue of a journal. You can also find other documents related to your research within ProQuest. You can view the entire episode (along with some extras!) here. In situ hybridization for HSV-TK demonstrated survival of vector-producing cells (VPCs) at 7 days but indicated limited gene transfer to tumors, suggesting that indirect, “bystander,” mechanisms provide local antitumor activity in human tumors. In situ hybridization for HSV-TK demonstrated survival of vector-producing cells (VPCs) at 7 days but indicated limited gene transfer to tumors, suggesting that indirect, “bystander,” mechanisms provide local antitumor activity in human tumors. He treats patients at The Alabama Center for Childhood Cancer and Blood Disorders at Children’s of Alabama and is an associate professor of pediatrics at the University of Alabama at Birmingham (UAB) and a scientist in the Neuro–Oncology Program at the UAB Comprehensive Cancer Center.

The “moving wall” represents the time period between the last issue available in JSTOR and the most recently published issue of a journal. E. You can also find other documents related to your research within ProQuest. Starting on day 3 after vector administration, animals were treated by intraperitoneal injection of 60 mg/kg/day ganciclovir (GCV) or placebo. The “moving wall” represents the time period between the last issue available in JSTOR and the most recently published issue of a journal. G207 was injected directly into the tumors, which were surgically removed several days later. You can also find other documents related to your research within ProQuest.

Our findings raise the potential importance of HSV-1 latent infection and reactivation in the brain. Mesenchymal stem cells (MSC) engineered to co-express the prodrug converting enzyme, herpes simplex virus thymidine kinase (HSV-TK) and a potent and secretable variant of tumor necrosis factor apoptosis-inducing ligand (S-TRAIL) induced caspase-mediated GBM cell death and showed selective MSC sensitization to the prodrug ganciclovir (GCV).