Tumors arising in the brain 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 disease is devastating, due to its 
debilitating neurologic consequences and rapid termination in death. The patients often 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. While there is some variation in the course of the disease 
with the type of brain tumor, no one survives glioblastomas and only a few patients are long-term 
survivors of anaplastic astrocytoma. Conventional brain tumor therapies are not successful because 
they do not distinguish tumor cells from normal cells. Creation of "artificial* differences in 
biochemical behavior of the tumor cells is an attractive option. This proposal seeks to make brain 
tumor cells sensitive to the drug ganciclovir. This will be achieved by directly injecting a virus which 
carries a gene for Herpes virus thymidine kinase. This gene when activated in the tumor cell will 
convert the relatively non-toxic drug ganciclovir to a toxic form and subsequently kill the tumor cell. 
In this phase I study, patients with recurrent brain tumors will receive 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 tu/nor, and intravenous ganciclovir will be continued for additional 14 days. Patients will 
be enrolled in groups of three, with each group receiving successively larger doses of adenovirus. This 
study will determine the toxicity of this therapy, provide evidence as to what portion of the tumor 
expresses the new gene, and determine the extent of virus induced injury. 
II. Background 
II. A. Clinical Aspects of Malignant Brain Tumors 
Malignant brain tumors are diagnosed in approximately 8,000 adults Americans yearly, and account for 
about 2.5 percent of deaths from cancer [1]. In adults, the primary brain tumors are most often 
malignant gliomas. There are some less common types of primary malignant tumors, such as 
lymphomas or sarcomas, as well as benign tumors such as meningiomas. The gliomas are classified as 
astrocytoma (generally benign, usually found in children), anaplastic astrocytoma, and glioblastoma 
multiforme. Occasionally, mixed tumors of intermediate grade are seen, such as the oligodendroglioma 
with anaplastic astrocytoma. The cell of origin for these malignancies is the astrocyte, a supporting cell 
in the brain. Therefore, the tumors arise in white matter, and can be found in any location, although 
about 90 percent are in the cerebrum. The gliomas spread locally, compressing and infiltrating normal 
brain. Growth into ventricles or meninges is uncommon, and metastases via blood stream or lymphatics 
is extremely rare[2j. Frontal lobe tumors may cross to the opposite side of the brain through the 
corpus callosum. However, the spread is contiguous and multifocal disease is not often seen. Autopsy 
studies show that the tumors usually remain localized throughout their course [3, 4]. After surgery or 
radiation therapy, the recurrences are close to the original tumor bed. 
The population affected by gliomas consists of all ages and races, and there is only a slight male 
predominance. Most of the patients are older than 50 years [5]. In the younger age group, anaplastic 
astrocytomas are more common, but in patients over age 50, most of the tumors are glioblastoma. 
There is no known cause or means of prevention. The disease is devastating, due to its debilitating 
neurologic consequences and rapid termination in death. No one survives glioblastoma; only a few 
patients are long-term survivors of anaplastic astrocytoma. 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, 
Recombinant DNA Research, Volume 20 
[353] 
