Molecular and cell biologic studies of a large number of lung cancer cell lines 
of all histologic types have revealed several mechanisms active in the 
pathogenesis of these cells. Small cell lung cancer (also called "oat cell" lung 
cancer) has a deletion involving chromosome region 3p(14-23) that is confirmed 
by DNA restriction fragment length polymorphisms analysis (studies done in 
collaboration with Dr. Susan Naylor). Several lung cancers of both small cell 
and non-small cell type (including adeno- and squamous cell lung cancer) express 
the proto-oncogenes c-, N-, or L-myc, and in some cases more than one of these 
family members. N-myc appears restricted in its expression to the small cell 
lung cancer type while c-myc and L-myc can be expressed in both small cell and 
non-small cell lung cancers. Many lung cancers of all histologic types also 
express large amounts of p53, which are not correlated with the amount or type 
of myc gene product expressed. In small cell lung cancer, high levels of myc 
gene expression are usually associated with gene amplification, and not 
uncommonly there is rearrangement of some of the amplified copies. In non-small 
cell lung cancer, expression without amplification or rearrangement of myc genes 
is seen. In contrast, high level expression of p53 is not associated with gene 
amplification in any lung cancer type. In addition, to these proto-oncogenes 
acting at a presumed nuclear locus, there is increased expression of various ras 
family members and the c-raf-1 proto-oncogene (in collaboration with Dr. Ulf 
Rapp). Lung cancer cells in tissue culture can grow in medium without serum and 
few or no other growth factors added. Thus, it appears that lung cancer cells 
can produce their own growth factors which can act in an "autocrine" fashion. 
The best characterized example of this is gastrin releasing peptide (GRP, also 
called bombesin) produced by small cell lung cancer. In at least some small cell 
lung cancers, interference with GRP action by specific monoclonal antibodies 
results in inhibition of tumor cell growth in culture and in nude mouse 
xenografts. Thus, constitutively expressed GRP gene may function as a cellular 
oncogene under certain circumstances in small cell lung cancer. Based on these 
observations we are proposing to test monoclonal anti-GRP antibodies in 
patients.