II. NON-TECHNICAL ABSTRACT: 
Non-Technical Abstract 
There are 15,000 new cases of primary brain tumor with 1 1,000 deaths annually in the 
United States, and brain tumors are the second leading cause of cancer death in children and 
young adults. Even with aggressive surgical and radiation therapies many patients with brain 
tumors have survival times of only 9 to 10 months. Hence, the prognosis for this disease is bleak 
and compels investigation of new therapeutic avenues. 
1 
Direct introduction of therapeutic genes into tumor cells may provide an effective treatment 
of brain tumors. One strategy is to confer drug sensitivity to tumor cells by inserting a recombinant 
gene into them. This gene is from the common Herpes virus and it codes for the enzyme thymidine 
kinase (HSV-tk) enzyme. Thymidine kinase converts the anti-viral drug ganciclovir into a form that 
is toxic to rapidly dividing cells such as tumor cells. Non-dividing are not harmed. This approach is 
especially suitable for the treatment of brain tumors since the normal brain tissue is made up largely 
of non-dividing cells. Several techniques have been used to introduce therapeutic genes to tumors. 
Of these, virus-mediated transfer is currently the most efficient method and the most efficient virus 
is the genetically engineered adenovirus. We have demonstrated using two animal models that 
adenovirus-mediated transfer of the HSV-tk gene and ganciclovir treatment resulted in ablation of 
the tumors and significant increases in life spans. 
This phase I study is designed to study the safety and efficacy of gene therapy for patients 
l with brain tumors. Patients with malignant brain tumors refractory to all potentially curative therapy 
will be treated with intra-tumor injections of replication-defective adenovirus vector delivering the 
Herpes Simplex Virus thymidine kinase gene. Initial tests will use a low dose of virus. Ganciclovir 
will then be administered intravenously at 10 mg/kg/day for 14 days. Only one course of therapy will 
be administered. Each patient will be carefully monitored for one month for adverse effects. Five 
patients will be tested with this low dose before another group of patients are treated with a higher 
dose and monitored closely for 1 month. This will be repeated until the target dose is reached or 
significant toxicity is detected. Effectiveness will be monitored by MRI and/or CT scans and by 
comparing survival times to the historical survival times for patients with recurrent brain tumors. The 
primary objective of this initial study is to determine whether the treatment is associated with 
significant toxicity. 
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Recombinant DNA Research, Volume 20 
[709] 
