Recombinant DNA Advisory Committee - 09/14-15/92 
called for a vote. The motion passed by a vote of 17 in favor, 0 opposed, and 4 
abstentions. 
Discussion 
Ms. Buc addressed the issue of RAC review and approval of multiple versions of similar 
protocols. It is not undesirable to repeat the early stages of experiments in which the 
outcome will answer a scientifically important question. Dr. Parkman noted that in the 
case of the various leukemia studies, numerous protocols are necessary to answer the 
important issues. Data cannot be extrapolated from one disease to another. Dr. 
Deisseroth added that scientific method, especially in the clinical setting, depends on the 
reproducibility of any finding. There is a need to proceed, not in a sequential fashion 
with one investigator addressing one item, but for multiple investigators to address 
important questions in parallel that resolve current scientific dilemmas. It is important 
that each protocol should be viewed as a new step in the evolving field of gene therapy. 
X. ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING A HUMAN 
GENE TRANSFER PROTOCOL ENTITLED: CLINICAL PROTOCOL FOR 
MODIFICATION OF ONCOGENE AND TUMOR SUPPRESSOR GENE EXPRESSION 
IN NON-SMALL CELL LUNG CANCER (NSCLC) /DR. ROTH 
Review-Dr. D. Miller 
Dr. Murray called on Dr. D. Miller to present his primary review of the protocol 
submitted by Dr. Jack Roth of MD Anderson Cancer Center, University of Texas, 
Houston, Texas. Dr. D. Miller presented an overview of this protocol designed to 
reverse the transformation of cancer cells by introduction of the tumor suppressor gene, 
p53, and the antisense Kirsten-ras (K-ras) gene to inhibit transformation. Dr. Roth has 
presented data demonstrating that cells that have reverted back to a normal phenotype 
exhibit a bystander effect that converts other cancer cells to a more normal state. 
Dr. D. Miller had concerns regarding the proposed retroviral vectors. These vectors are 
basically derived from the standard LNSX vector which contains a long terminal repeat 
(LTR) driving the neo R gene plus an SV40 promoter for the expression of the second 
gene. The K-ras vector contains a (J-actin promoter with the K-ras gene in reverse 
orientation. Therefore, (J-actin would drive K-ras in a counter clockwise direction. An 
SV40 early promoter drives the K-ras in the positive direction which could result in K-ras 
protein. An LTR in the 5' end drives neo R that could make an antisense message to the 
K-ras antisense message; therefore, creating a sense message. There is the potential for 
hybridization of these various messages and the vector. In addition, the K-ras could 
mutate to an oncogene. The mutation rate of retroviruses is probably in the order of 1 
in 10 4 base pairs per generation. The issue of whether K-ras is capable of mutating to 
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