Recombinant DNA Advisory Committee - 3/3-4/94 
Ms. Grossman stated that the "bystander" effect attributed to the present system is 
different from the ''bystander" effect observed in the herpes simplex virus thymidine 
kinase/ganciclovir protocols. The biological mechanism of the latter phenomenon is 
more clearly understood. 
Ms. Grossman said that although Dr. Roth is a reputable physician qualified to conduct 
a study on small-cell lung cancer, there are serious concerns about the molecular biology 
aspects of this proposal. 
Other Comments 
Dr. Post asked whether the sensitivity of the assay for transforming viruses is adequate 
since this issue was a major concern during the previous review. Ms. Grossman asked 
what construct was assayed for transforming virus. Dr. Motulsky asked the investigators 
to clarify exactly what constructs are proposed for the human study. In addition. Dr. 
Post noted that large volumes of vector supernatants will be administered to these 
patients. Will there be any effect of these oncogene and antioncogene vectors on normal 
cells? 
Dr. Parkman inquired about what is the rate of transduction in the animal tumor model. 
How does the rate of transduction relate to the efficacy of suppressing tumor growth in 
animals? Are these data reproducible? Dr. Parkman asked Dr. Roth to address the 
issue of vector structure in the clinical grade supernatants. 
Investigator Response-Dr. Roth 
Responding to Dr. Post's question on the effect of normal human cells upon 
transduction, Dr. Roth said that vectors expressing either the antisense K-ras or the wild- 
type p53 gene demonstrate no appreciable in vitro effect on the proliferation of normal 
fibroblasts unless the p53 gene is expressed at an extremely high level. 
Dr. Roth made a short presentation about his protocol with illustrations in an attempt to 
address several general questions. Dr. Roth said that the eligible patients must have 
bronchial obstruction that is untreatable with conventional therapy and have an expected 
survival of 4 to 6 months. The proposed treatment is intended to slow tumor growth 
rather than be curative. Following a biopsy, a determination will be made as to whether 
the tumor has K-ras or p53 gene mutation. Based on this information, the appropriate 
construct will be administered. Following partial endoscopic resection, the tumor bed 
will be irrigated with vector supernatants daily for 5 days through a bronchoscope. This 
treatment will be repeated monthly. 
Dr. Parkman noted that there is reproducible therapeutic effect in the animal studies. A 
maximal response is obtained at a multiplicity of infection of 5 retroviral particles per 
tumor cell, but the response decreases to one-half when the ratio is decreased to one- 
third. Dr. Parkman asked about the multiplicity of infection that would be expected in 
the clinical protocol. In the animal experiments, all tumor cells are in cycling and are 
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Recombinant DNA Research, Volume 19 
