Preclinical Evaluation of ZD1839 Alone or in Combination with Oxaliplatin in a Panel of Human Tumor Cell Lines – Implications for Clinical Use

Abstract

Background: Preclinical studies have suggested antitumor activityof an epidermal growth factor (EGF)-receptor targeted therapy withselective tyrosine kinase inhibitors alone or in combination withconventional cytostatic drugs. However, in non-small cell lung cancer(NSCLC), addition of ZD1839 (Iressa?) to combinationchemotherapy did not improve the therapeutic outcome. Thus, furtherwork is necessary to define factors predicting outcome of combinationtherapy. Materials and Methods: In the present study, theactivity of ZD1839 alone or in combination with oxaliplatin (Eloxatin?) was evaluated in 12 human cancer cell lines including colon,testicular, anaplastic thyroid and epidermoid carcinoma cells. Results:The EGF-receptor protein was overexpressed in line A431(epidermoid carcinoma) and near the minimum detection limit in allother cell lines. The single agent activity of ZD1839 was highest incell line A431. In the other cell lines, it was lower and appeared tobe independent of EGF-receptor expression levels. The relative antitumoractivity (RAA) was low (RAA = 1). Combined exposure tooxaliplatin and ZD1839 (IC30) resulted in significant synergy in 4 outof 6 colorectal cancer (CRC) cell lines and significant antagonism in4 out of 6 non-colorectal cancer cell lines. Continuous exposure toZD1839 (IC30) induced a marked G1-phase arrest and dephosphorylationof EGF-receptor in A431, whereas no significant cell cycle perturbationcould be detected in the low-expression cell lines. Otherfactors than cell cycle perturbation seem to determine the mode ofdrug interaction between oxaliplatin and ZD1839. Conclusion:Based on RAA, the single agent activity of ZD1839 in the investigatedcell line panel appeared to be low. Combined exposure toZD1839 and oxaliplatin exerted synergy in colorectal cancer celllines, warranting further evaluation in this type of cancer. However,based on the observed antagonism in non-colorectal cancer celllines, combined treatment with ZD1839 and oxaliplatin is not recommendedfor other types of cancer. Further research is necessaryto identify factors which determine the nature of drug interaction indifferent tumor types including CRC and lung cancer.