Cellular predictive factors for the drug response of lung cancer

The main objective of this study was to analyze which of 31 cellular factor s (resistance proteins, proliferative factors, apoptotic factors, angiogeni c factors, pl oto-oncogenes) most accurately predict the resistance of non- small cell lung carcinomas. To this purpose, we used a short-term in vitro test that measures changes in the rate at which radioactive nucleic acid pr ecursors are incorporated into tumor cells after the addition of doxorubici n to determine the response to doxorubicin in 94 non-small cell lung carcin omas. The results obtained by the short-term test were related to the vario us cellular factors which were in turn determined by immunohistochemistry a nd flow cytometry. A significant correlation was found between the data obt ained by the short-term test and the expression of P-glycoprotein 170 (P=0. 00004), glutathione-S-transferase-pi (P=0.0002), metallothionein (P=0.0008) , thymidylate synthase (P=0.002), O6-methylguanine-DNA-methyltransferase (P =0.008) and lung resistance-related protein (LRP, P=0.03). There was only a weak correlation between hear shock proteins (HSP70) and no correlation be tween the expression of topoisomerase II or catalase and the short-term tes t results. To measure the proliferative activity, the following were determ ined: PCNA, cyclin A, cyclin D and cdk2. Only a weak relationship was found between the expression of cdk2 (P=0.04) and PCNA (P=0.05) and the doxorubi cin response in vitro. Of the investigated pro-apoprotic factors (Fas/CD95, Fas ligand, caspase-3), only Fas/CD95 is significantly associated with the drug response (P=0.007). The apoptotic index also reveals a significant co rrelation (P=0.03). Angiogenesis, as measured by the microvessel density an d the angiogenic factors, is inversely correlated to the resistance of non- small cell lung cancer. Platelet-derived endothelial cell growth factor (PD -ECGF) and vascular endothelial growth factor (VEGF) exhibit a significant relationship to the drug resistance (P=0.0006 and P=0.004, respectively). O f the investigated proto-oncogenes (Fos, Jun, ErbB-1, ErbB-2, Myc, Ras), on ly ErbB-2 is weakly associated with the in vitro short term test. In order to deter-mine whether combining factors can result in improved predictive i nformation, combinations of the factors (pairs, triplets) were analyzed. Th e systematic investigation of these combinations yields an improvement in t he predictive information. With one factor Erp to 76.6% of the tumors, with two factors up to 85.4% and with three factors up to 89.5% of the armors c ould be correctly diagnosed.