Protocol THS 94-002 
REVISED 3/28/94 
Page 3 
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 kiiiing 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 or tumor suppressor genes may still be important 
targets, because it is likely that adverse effects to normal cells will be minimal. 
Programmed cell death, also known as apoptosis, shows a characteristic pattern of DMA 
fragmentation resulting from cleavage of nuclear DMA and is considered to be a selective process of 
physiologic cell deletion. It has recently been reported that the wt-p53 gene is involved in mediating 
programmed cell death of some types of tumor cells including human lung cancer cells[14-16]. The 
loss of p53 function may contribute to resistance to a variety of chemotherapeutic agents[17]. Our 
studies showed that H358a cells, which have a homozygous p53 deletion, were resistant to cisplatin 
in vitro. Recombinant adenovirus-mediated wt-p53 gene transfer into monolayer cultures or 
multicellular tumor spheroids of H358a resulted in a marked increase in cellular sensitivity to 
cisplatin. The dying p53-transduced cells showed apoptosis with specific DMA fragmentation. Direct 
Injection of p53 adenovirus Into H358a tumors subcutaneously implanted in nu/nu mice, followed by 
Intraperitoneal administration of cisplatin, induces massive apoptotic destruction of established 
tumors. These results support the use of this strategy in a clinical trial. 
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[18,19]. 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[20]. The Department of Thoracic 
and Cardiovascular 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 yeariy and 
over 200 of these patients undergo resection. 
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, reduction in 
measurable endobronchial tumor or measurable tumor mass, or reduction in the volume of 
pleural effusion with clearing of malignant cells. 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 administration of the adenovirus constructs with cisplatin 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, reduce- 
the growth rate or cause regression of locally extensive cancers and pleural effusions and 
therefore prolong the patient’s survival and relieve symptoms. 
2.2.3 Alternative therapies 
Patients with unresectable endobronchial turpor recurrence that is partially or completely 
Recombinant DNA Research, Volume 19 
