genes in cancer cells. 
Preliminary data on transfection of an antisense K-ras expression vector 
indicated that inhibition of expression of a single oncogene reduced the growth 
rate of cancer cells and tumorigenicity in nu/nu mice. However, transfected 
cells retained viability, as did cells with no endogenous K-ras mutation that were 
also transfected with the construct. The wtp53 appears dominant over the 
mutant gene and will select against proliferation when transfected into cells with 
the mutant gene 16,18 . Normal expression of the transfected wtp53 does not 
affect the growth of cells with endogenous wtp53. Thus, such constructs might 
be taken up by normal cells without adverse effects. This protocol focuses 
regional delivery of the two gene constructs, antisense K-ras and wtp53, to lung 
cancer cells in patients with unresectable obstructing endobronchial cancers. 
The efficiency of delivery and gene expression will be evaluated both in lung 
cancer cells and in normal cells in vivo . This is of importance for the design of 
constructs that may be useful therapeutically. The effects of these constructs on 
clinical progression of the cancer will be studied. 
These approaches may lead to cancer therapy based on direct alteration of 
gene expression in cancer cells. Current therapy relies on attempts to kill or 
remove the last cancer cell. However, tumor cell dormancy is an established 
phenomenon making effective killing highly unlikely. Although inhibition of 
expression of some oncogenes may be lethal to the cancer cell, in some cases 
cell replication will slow or cease, thus rendering these cancers clinically 
dormant. Even if absolute specificity is not achieved, single oncogenes may 
still be important targets, because it is likely that adverse effects to normal cells 
will be minimal. 
2.2 Natural history of locally unresectable NSCLC 
Patients with NSCLC will die of their cancer in 86% of cases. Regional delivery 
of gene constructs to areas at risk for development of cancer has important 
implications for both prevention and therapy. Failure of therapy at the primary 
tumor site is a significant problem 19 - 20 . Of the 161,000 patients newly 
diagnosed with lung cancer in 1991, 45,080 will undergo surgical resection. 
Local recurrence as the first site of failure will occur in 9,000 of those patients. 
Of the remaining patients, 52% will have localized tumors. However, 38% of 
these patients will have local failures following radiation therapy (22,900). Thus, 
31,900 patients per year could benefit from improved local-regional therapy. 
Patients with unresectable obstructing NSCLC that is resistant to radiation 
therapy or who have coexisting metastases have a median survival of 6 months 
or less 21 . The Department of Thoracic Surgery at the University of Texas M. D. 
Anderson Cancer Center has extensive experience in the treatment of lung 
cancer. Over 1200 patients with lung cancer are seen yearly and over 200 of 
these patients undergo resection. 
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Recombinant DNA Research, Volume 16 
