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

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Abstract
Background: Preclinical studies have suggested antitumor activity of an epidermal growth factor (EGF)-receptor targeted therapy with selective tyrosine kinase inhibitors alone or in combination with conventional cytostatic drugs. However, in non-small cell lung cancer (NSCLC), addition of ZD1839 (Iressa?) to combination chemotherapy did not improve the therapeutic outcome. Thus, further work is necessary to define factors predicting outcome of combination therapy. Materials and Methods: In the present study, the activity 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 all other cell lines. The single agent activity of ZD1839 was highest in cell line A431. In the other cell lines, it was lower and appeared to be independent of EGF-receptor expression levels. The relative antitumor activity (RAA) was low (RAA = 1). Combined exposure to oxaliplatin and ZD1839 (IC30) resulted in significant synergy in 4 out of 6 colorectal cancer (CRC) cell lines and significant antagonism in 4 out of 6 non-colorectal cancer cell lines. Continuous exposure to ZD1839 (IC30) induced a marked G1-phase arrest and dephosphorylation of EGF-receptor in A431, whereas no significant cell cycle perturbation could be detected in the low-expression cell lines. Other factors than cell cycle perturbation seem to determine the mode of drug interaction between oxaliplatin and ZD1839. Conclusion: Based on RAA, the single agent activity of ZD1839 in the investigated cell line panel appeared to be low. Combined exposure to ZD1839 and oxaliplatin exerted synergy in colorectal cancer cell lines, warranting further evaluation in this type of cancer. However, based on the observed antagonism in non-colorectal cancer cell lines, combined treatment with ZD1839 and oxaliplatin is not recommended for other types of cancer. Further research is necessary to identify factors which determine the nature of drug interaction in different tumor types including CRC and lung cancer.