VPC into the subarachnoid space. Such symptoms are expected to be self-limiting and 
ameliorated with symptomatic care (analgesics). However, such a reaction may be severe 
and could produce severe permanent neurological deficits or death. When indicated, CSF 
sampling may be required to rule out infection. 
Severe edema : Edema secondary to necrosis and destruction of the transduced tumor cells 
may occur. The magnitude of such edema, if it occurs at all, is unknown. As a precaution, 
all patients will be treated with high-dose steroids. If edema around the tumor is not 
responsive to therapy, permanent, significant neurological deficits or death may result. 
Surgical Procedures : The surgical procedures carry a risk for loss of neurological function, 
non-neurological complications and death. The risk depends on the preoperative condition of 
the patient, size and location of the tumor, and associated diseases (e.g. Ischemic heart 
disease, renal failure, COPD etc.). The individual risk will be determined prior to the 
decision on the line of therapy and will be discussed with the patient prior to surgery. 
B. Use of the Ommaya Reservoir. The Ommaya reservoir is a commonly used device in 
neurosurgery. The potential complications resulting from its use are infections and bleeding. 
Every effort will be used to maintain sterility and prevent bleeding. 
C. The development of replication-competent retrovirus. As discussed (Section IV.E.). 
D. Survival of Vector Producer Cells in the Host. The PA317 cells can survive only 7-14 
days in a subcutaneous site in syngeneic (H-2b) mice and only 7-14 days in xenogeneic rat 
brain. Likewise in immunosuppressed monkeys, the producer cells could not be identified > 
14 days after injection. Taken together, these findings suggest that any PA 137 cells that are 
not killed by GCV will not have the ability to survive long term in the human brain. 
E. Dissemination of GlTkSvNa.29 Our MoMLV amphotropic retroviral vectors are directly 
inactivated by human complement without antibody. Therefore, escape of free vector into 
the cerebral spinal fluid or the vascular space should result in immediate inactivation. The 
gene transfer in this direct injection system is most likely due to the intimate contact of the 
tumor and VPC. Any vector particles that are released in the area of injection will be 
quickly bound by the thousands of amphotropic vector receptors on each tumor cell and 
other host cells. Vectors binding to non-dividing cells in the brain will be lost. Even if all 
of the vector particles produced were able to escape direct transfer into adjacent tumor cells 
or binding to non-dividing cells and cross the blood-brain barrier, the number of vector 
particles relative to the number of receptors in any organ would still be very small 
suggesting a minimal risk of injury to proliferating cells in any non-CNS organ. Any direct 
transfer into neurons by cell-to-cell contact will not result in HS-tk gene integration and 
therefore, should not pose a risk for their destruction with GCV treatment. 
F. Transduction of surrounding brain tissue. There is no evidence in our animal model that 
transduction of surrounding normal brain tissue is likely to occur (Section 3.1. A. 2.). 
However, if the HS-tk gene is introduced into a large number of normal dividing cells 
within the CNS (such as endothelial cells and astroglial cells), vasculitis like symptoms 
(headaches, convulsions, bleeding) may develop. Such changes however will be localized to 
the immediate vicinity of the tumor as had been shown in our experiments (3.I.C.2). 
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Recombinant DNA Research, Volume 17 
