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local or regional delivery of wtp53 to HNSCC patients with unresectable regionally metastatic 
squamous cell carcinomas, unresectable local cancers, or advanced local and/or regional HNSCC that 
have failed prior treatment which included radiation therapy but remains locally and regionally 
resectable. The efficiency of delivery and gene expression will be evaluated both in head and neck 
cancer cells and in nor mal cells in vivo . This is of importance for tne design of constructs that may be 
useful therapeutically. The effects of these constructs on clinical progression of the cancer will also 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. Nevertheless, the chosen delivery 
method of adenovirus vectors addresses this dormancy issue since transduction by the vector is cell 
cycle independent. 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 as well as transient with the transient adenovirus vector chosen. 
Programmed cell death, also known as apoptosis, shows a characteristic pattern of DNA fragmentation 
resulting from cleavage of nuclear DNA and is considered to be a selective process of physiologic cell 
deletion. It has recently been reported that the wtp53gene is involved in mediating programmed cell 
death of some types of tumor cells 1 . 4 - 16 . Our studies have shown that independent of the 
endogenous p53 status (homozygous mutated or wild-type), HNSCC cells transduced with 
recombinant adenovirus-mediated wtp53gene exhibit histologic alterations both by light field and 
electron microscopy that are consistent with apoptosis. Similarly, in vitro infection with the same 
vector induces specific DNA fragmentation consistent with this mechanistic hypothesis. 
Nevertheless, this is in contrast to normal cells with wildtype p53 which are unaffected by wildtype 
p53. Direct injection of adenovirus p53 into subcutaneously established and microscopic HNSCC 
tumors in nu/nu mice induces apoptosis and dose response destruction and inhibition of tumor 
development and growth.(Clayman, unpublished data, Appendix D) These changes occur 
independent of the HNSCC tumor cell line endogenous p53 status (wildtype or mutated). These 
results support the use of this strategy in a clinical trial. 
2.2 Natural history of locally unresectable HNSCC and M.D. Anderson Patient Patterns 
Patients with HNSCC die of their cancer in approximately 55% of cases and failure of therapy at the 
primary or regional tumor site is a significant problem 16 - 1 ^ Of the 45,000 patients newly diagnosed 
with head and neck cancer in 1991 , nearly half underwent surgical resection with or without radiation 
therapy. Local and or regional recurrence as the first site of failure will occur in approximately 22,000 
of all of those patients independent of the treatment modality chosen (surgery, radiation therapy, 
chemotherapy or combinations thereof). Thus, nearly 22,000 patients per year could benefit from 
improved local-regional therapy. Patients with local/ regionally unresectable HNSCC, that has failed 
radiation therapy, have a median survival of approximately 6 months and no known systemic 
chemotherapy has shown significant survival benefit among these patients. The Department of Head 
and Neck Surgery at the University of Texas M. D. Anderson Cancer Center has extensive experience 
in the treatment of patients afflicted with squamous carcinoma of the upper aerodigestive tract. Over 
1200 patients with head and neck cancer are seen yearly and over 600 of these patients undergo 
resections. From September 1992 to August 1993, 469 patients with local/regional squamous cell of 
the upper aerodigestive tract (no evidence of distant metastasis) were referred to the Department of 
Head and Neck Surgery at M. D. Anderson Cancer Center; 1 13 had prior radiation therapy ( 52 
radiation therapy only, 40 surgery and radiation therapy, 13 chemotherapy and radiation therapy, and 
8 chemotherapy + radiation therapy + surgery). Of these 1 13, 84 had local/regional squamous cell 
carcinoma without distant metastasis. 
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 
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Recombinant DNA Research, Volume 20 
