boundaries of LD disease. LD stage SCLC accounts for approximately 1/3 of all SCLC. Although 
initial chemotherapy in ED produces a 65-85% overall response and a 15-30% complete response, 
median survival is short (7-11 months) and two year survival is < 5% (46-50). Because of the rapid 
pace and brief duration of response to therapy, ED patients will not be well enough, long enough to 
allow generation and therapy with gene transfected cells. We will therefore include only patients with 
LD on this study. Initial chemotherapy produces an overall response of 80-95% in patients with LD 
and a complete remission rate of 40-70% (46,51-54). The median survival is 12-16 months, two year 
survival, 10-25%, and 5 year survival, <10% (47). A range of chemotherapy regimens have been 
employed in therapy, most commonly cyclophosphamide, adriamycin and vincristine (CAV) or etoposide 
and cis-platinum (EP) (46). Neither regimen used alone or together is superior (50). 
Although the addition to chemotherapy of radiation therapy to the primary site of disease in the lung 
increases the complete remission rate, median and long-term survival is probably not improved (46). 
Moreover, in one study, delayed radiation therapy was better than early, concurrent radiation therapy 
(56). The results of studies using cyclophosphamide, adriamycin and etoposide as we use here showed 
comparable results without primary radiation therapy (55). Similarly, although prophylactic cranial 
irradiation reduces the chances of later symptomatic brain metastases, survival is not improved (46). 
Because long-term outcome is unaltered and to avoid suppression of the immunologic response, radiation 
therapy will not be used in the initial therapy of these patients, prior to gene therapy. 
1.5 Establishment of primary lung tumor cell cultures from patients 
The development of techniques to grow SCLC cell lines has been greatly improved. At present over 
50 SCLC cell lines have been established and studied (56-61) The success rate in growing SCLC is 
approximately 70-80%. Based on the appearance of the cell culture, SCLC cell lines can be classified 
into two major groups (62,63). The so-called "classical small cell lung cancer" will grow as spherical 
or dense aggregate (-80%). These cell lines express properties of APUD cells and contain high levels 
of the neurone specific enolase and L-dopadecarboxylase. Generally, the "classical" SCLC cell lines 
have been established from specimens of patients who had the usual course of disease with response to 
chemotherapy. The other "variant" of SCLC is usually associated with a more malignant course and 
poor prognosis. These cells tend to grow loosely aggregated or attach as monolayer and do not secrete 
peptide hormones. They also tend to have amplification of certain oncogenes, such as C-myc or N-myc. 
In vitro, drug sensitivity testing using SCLC lines established from patients has demonstrated a good 
correlation with the patients’ clinical response and survival (64-66). These observations suggest the 
exploration of innovative treatments in this disease. Established cell lines retain the genetic 
characteristics of SCLC tumor samples, such as deletion and/or LOH on chromosome 3p, abnormalities 
in structure and expression of the Rb gene (13% in primary tumor and 18% in SCLC lines) and 
mutation of p53 (67-69). 
The ability of SCLC to grow in vitro has been shown not to correlate with the prognosis of the 
patient (70); in contrast the ability to establish non SCLC (NSCLC) lines correlates with decreased 
survival (71). Therefore, there will be no bias in SCLC for patients with poor prognosis. All these 
considerations have led us to choose SCLC as a model for this trial. Although the median survival of 
SCLC is relatively short (8 months), patients usually respond to chemotherapy. We estimate from our 
experience that a 4 month period is required to establish cells and to transfect and select them, which 
should suffice for those patients who are responsive to chemotherapy. 
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