B. Potential Complications Specific to Adenovirus Injection 
In addition to surgical complications, there may be complications that are associated 
with virus treatment. The magnitude of these complications is unknown. Based upon 
animal studies potential complications may include: 
1. Vasogenic edema: Studies in non-human primates demonstrated that injection of 
10 ml of a PBS solution containing 1.5 x 10 9 particles of ADV/RSV-tk into a 
single site into normal brain tissue (centrum semiovale) caused vasogenic 
edema that was visible by MRI at 3 and 6 weeks post-injection. (Appendix A) 
Injection of ADV/RSV-tk into tumors may also cause vasogenic edema in 
surrounding tissue as well as in the tumor. If clinical signs indicate the presence 
of edema, steroids may be administered to alleviate this phenomenon. 
2. Tissue destruction: Studies in rodents and non-human primates demonstrated that 
single site injections of ADV/RSV-tk at doses ranging from 1.5 x 10 9 to 3.0 x 10 10 
particles caused tissue destruction in the presence and absence of GCV. 
(Appendix A) At the higher doses (1.2 x 10 9 particles for rats and 3.0 x 10 10 
particles for baboons) destruction was grossly visible. At lower doses (1 .5 x 10 9 
in baboons) cellular cytopathology was visible at microscopic examination. 
3. Dissemination of ADV/RSV-tk - Intracranial: Studies in rodents using a similar 
vector containing the bacterial marking gene b-galactosidase have shown that 
the vector is transported to areas of the brain distant from the injection site. 
(Appendix A) Routes of dissemination appear to be vascular, ventricular, and 
axonal transport. Hence, there is the potential that a portion of the vector will be 
disseminated throughout the brain. Studies in non-human primates using 
ADV/RSV-tk have not revealed adverse reactions away from to the injection site. 
4. Dissemination of ADV/RSV-tk - Systemic: There is the potential that ADV/RSV-tk 
virus may escape the tumor bed and be disseminated via the blood supply to 
transduce other sites in the patient's body. Studies in non-human primates 
indicate that if this happens it does not cause observable damage. (Appendix A) 
5. Immune reaction to adenovirus: There is a potential that an inflammatory reaction 
may be raised either intracranially or systemically as a result of antibodies to 
adenovirus present in the patient. Immunological screens will be performed to 
identify patients with high titers of antibodies to adenovirae and such patients will 
be excluded. Standard clinical therapy will be used, if warranted, in the event 
that an inflammatory response is mounted to the virus injection. 
6. Recombination with wild type adenovirus: It is theoretically possible that 
recombination with an adenovirus harbored by the patient could reintroduce the 
El a region back into the virus. Such an recombinant virus that contained the 
RSV and/or HSV-tk genes and the regained El sequence would be too large for 
packaging in the viral protein coat and would not be recoverable. No viral 
product of this type has been documented in animals receiving this type of 
vector, nor has it been seen in cultured 293 cells which contain the El region. A 
recombinant virus which did not retain the RSV and HSV-tk genes would 
resemble a wild type virus which would cause a viral meningitis if formed in the 
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Recombinant DNA Research, Volume 20 
