2.2.1 Measure of disease activity 
The goal of this therapy is to halt or reverse the manifestations of the 
disease. The efficacy of therapy in this group of patients will be 
measured by determining length of patient survival, length of time the 
affected lobe of the lung remains aerated, and reduction in measurable 
endobronchial tumor. There is no curative therapy for this stage of 
disease and thus the outcome is predictable enough to allow for an 
assessment of the results of gene therapy. The measurements that will 
be used are described in Section 7.0. 
2.2.2 Anticipated effect of protocol treatment 
It is anticipated that the uptake of the retroviral constructs by proliferating 
NSCLC cells will decrease the rate of proliferation of these cells. This 
would increase the length of time the affected lung would remain 
expanded, prevent regrowth of the endobronchial tumor, and prolong the 
patient’s survival. 
2.2.3 Alternative therapies 
Patients with unresectable endobronchial tumor recurrence that is 
partially or completely obstructing the airway and that have failed or are 
unable to receive external beam radiotherapy will be considered for this 
protocol. Existing therapies for this condition offer only short-term 
palliation. Most patients have recurred despite external beam 
radiotherapy. It may be possible to insert a brachytherapy catheter and 
administer additional radiotherapy. Patients receiving this treatment have 
a median survival of 6 months 21 . Patients failing brachytherapy would 
also be eligible to receive gene therapy. Tumor can be removed from 
the airway with the laser or biopsy forceps. This can be done in 
conjunction with injection of the retroviral construct thus decreasing the 
volume that must be injected. The administration of the retroviral 
constructs would not preclude the patient from receiving other palliative 
therapy if the tumor progresses. 
2.3 Structure and characteristics of the biological system 
2.3.1 Downregulation of activated K-ras expression with an antisense construct 
2.3. 1.1 Preliminary studies with plasmid DNA 
The ras p21 gene product plays an important role in the 
intracellular signaling pathway of cells. Dysregulation of this 
pathway because of point mutations in regions critical to ras 
function confer transforming properties to the mutant protein. 
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