The unique signal transduction pathways that distinguish non-small cell lung 
carcinoma (NSCLC) from small cell lung carcinoma (SCLC) are poorly understood. 
We investigated the ability of edelfosine, an inhibitor of 
phosphatidylinositol-specific phospholipase C (PLC) to inhibit cell viability 
among four NSCLC cell lines and four SCLC cell lines. The differential 
sensitivity of cells to edelfosine's cytostatic and cytotoxic effects has been 
attributed to edelfosine-induced changes in the activities of many enzymes, 
including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated 
kinases (ERK), p38 kinase, and poly(ADP-ribose) polymerase (PARP). To 
investigate the role of these enzymes in edelfosine-induced cytotoxicity, we 
correlated edelfosine-induced changes in enzyme activity and cell viability 
among the different NSCLC and SCLC cell lines. We found that NSCLC cells are 
much more susceptible to the cytotoxic effects of this drug than are SCLC cells. 
Three out of the four edelfosine-sensitive NSCLC cell lines (NCI-H157, NCI-H520, 
NCI-H522) exhibit G2/M arrest, significant apoptosis and some degree of JNK 
activation in response to drug treatment. In contrast, none of the SCLC cell 
lines exhibit edelfosine-induced G2/M arrest or significant apoptosis. A 
comparison of the edelfosine-induced effects among the sensitive and resistant 
lung cancer lines indicates that there is little correlation between 
edelfosine-induced cytotoxicity and altered activities of JNK, ERK, p38, or 
cleavage of PARP. These results demonstrate that edelfosine-induced changes in 
JNK, ERK, p38, or PARP are not good predictors of cell susceptibility to 
edelfosine-induced cytotoxicity. Thus, edelfosine-induced inactivation of PLC 
may disrupt signaling cascades downstream of PLC that are unique to individual 
cellular environments. These findings also identify edelfosine as one of the few 
potential chemotherapeutic agents that has a greater cytotoxic effect against 
NSCLC cells than SCLC cells.