Scientific Abstract 
Scientific Abstract 
Primary CNS malignancies are responsible for approximately 12,000 deaths annually 
in the United States. There has been little change in the outcome for adults with 
malignant brain tumors over the past few decades, despite improvements in surgical 
techniques and advances in radiation therapy. These tumors are uniformly fatal one to 
two years after diagnosis. The morbidity and mortality of this disease arises from the 
effects of a locally invasive, non-metastasizing lesion. The patients may suffer from 
seizures, paralysis, incoordination, aphasia, confusion, memory loss, sensory deficits 
or visual loss, depending on the regions of the brain affected. In addition, they usually 
require large doses of corticosteroids early and late in their illness, and may experience 
disabling side effects of this treatment, such as edema, proximal myopathy, diabetes, 
fungal infections or deep vein thrombosis. Few patients in the older age group are able 
to work after the diagnosis. Most of the patients are incapable of self-care for several 
months before death. The localized transfer of new genes into cancer cells potentially 
permits the expression of proteins with specific biologic functions that may provide a 
means to alter the biology of tumor growth through a variety of mechanisms including 
increasing tumor immunogenicity, inducing the local expression of toxic agents, and 
sensitization of tumors to chemotherapeutic agents. Gene therapy with the transfer of 
the drug susceptibility gene Herpes virus thymidine kinase (HSV-TK) has shown 
promise in a number of animal models, including CNS tumors. This study will evaluate 
the use of adenovirus-mediated transfer of the HSV-TK gene into primary human brain 
tumors followed by systemic treatment with ganciclovir. The goals of this phase I study 
is to evaluate the overall safety and efficacy of this treatment and to gain insight into the 
parameters that may limit the general applicability of this approach. In this phase I 
study, patients with recurrent gliomas will receive stereotactic-guided injections of the 
virus into the brain tumor, followed by intravenous ganciclovir for 14 days. Patients 
eligible to undergo a palliative debulking procedure will receive the same treatment 
followed by resection on day 7. At the time of resection a second dose of virus will be 
administered intra-operatively into the residual, unresectable portion of the tumor, and 
intravenous ganciclovir will be continued for additional 14 days. Tissue removed at the 
time of resection will be analyzed for evidence of adenovirus infection, thymidine kinase 
expression and signs of inflammation. The size and metabolic activity of all tumors will 
be followed by volumetric MRI scans and Positron Emission Tomography Scans, 
respectively. Patients will be enrolled in groups of three, with each group receiving 
successively larger doses of adenovirus. This study will quantify the toxicity of this 
therapy, and provide evidence as to the duration of transgene expression and virus 
induced inflammation. 
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Recombinant DNA Research, Volume 20 
