Protocol THS 94-002 
REVISED 3/28/94 
Page 1 
Clinical Protocol Modification of Tumor Suppressor 
Gene Expression and Induction of Apoptosis in 
Non-Small Cell Lung Cancer (NSCLC) with an Adenovirus 
Vector Expressing Wildtype p53 and Cisplatin* 
1.0 OBJECTIVES 
1.1 To determine the maximum tolerated dose of the wild-type p53 adenovirus vector given with and 
without cisplatin in patients with refractory non-small cell lung cancer. 
1.2 To determine the qualitative and quantitative toxicity and reversibility of toxicity of this treatment 
approach. 
1.3 To document observed antitumor activity of this treatment approach. 
2.0 BACKGROUND AND RATIONALE 
2.1 Molecular events in NSCLC 
Lung cancer remains the leading cause of cancer deaths in the United States where it kills more 
than 1 40,000 people annually. Recently, age-adjusted mortality from lung cancer has surpassed that 
from breast cancer in women. Although implementation of smoking-reduction programs has 
decreased the prevalence of smoking, lung cancer mortality rates will remain high well Into the 21st 
century[1]. Unfortunately, all current treatment modalities, including radiation therapy, surgery, and 
chemotherapy, have limited effectiveness. The rational development of new therapies for lung cancer 
will depend on an understanding of the biology of lung cancer at the molecular level. Research in 
our laboratory has identified critical molecular events leading to NSCLC development and 
progression. The goal of this research is to directly modify the cancer cell to eliminate the 
expression of gene products which are responsible for the maintenance or progression of the 
malignant phenotype or to restore In normal form deleted or mutated gene products that suppress 
the characteristics of the malignant phenotype. 
The purpose of this protocol Is to Investigate molecular mechanisms that may influence the growth 
and progression of human lung cancer; our goal is development of therapeutic agents specifically 
targeted at the molecular level. The most common lung cancer histologies (80%) are grouped under 
the term non-small-cell lung cancer (NSCLC) and indude squamous, adenocarcinoma, and large- 
cell undifferentiated. Many of the current data on the molecular biology of lung cancer come from 
the study of the more uncommon small-cell lung cancer (SCLC). SCLC can be distinguished from 
NSCLC by the neuroendocrine features of the cells; SCLC is very responsive to chemotherapy but 
recurs rapidly after treatment. NSCLC also may serve as a modd for other carcinogen-induced 
raalignancies. The approaches and observations developed in this study may be applicable to other 
types of epithelial cancers. 
Abundant evidence has accumulated that the process of malignant transformation is mediated by a 
genetic paradigm(21. The major lesions detected in cancer cells occur In dominant oncogenes and 
tumor suppressor genes. Dominant oncogenes have alterations in a class of genes called proto- 
oncogenes, which participate In critical normal cell functions. Including signal transduction and 
transcription. Primary modifications In the dominant oncogenes that confer the ability to transform 
Include point mutations, translocations, rearrangements, and amplification. Tumor suppressor genes 
appear to require homozygous loss of function, by mutation, deletion, or a combination of these for 
transformation to occur. Some tumor suppressor genes appear to play a role In the governance of. 
proliferation by regulation of transcription. It Is possible that modification of the expression of 
dominant and tumor suppressor oncogenes may influence certain characteristics of cells that 
contribute to the malignant phenotype. 
Despite increasing knowledge of the mechanisms Involved in oncogene-mediated transformation. 
Recombinant DNA Research, Volume 19 
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