The effect of gefitinib (Iressa, ZD1839) in combination with oxaliplatin is schedule-dependent in colon cancer cell lines

Background: Clinical trials of gefitinib (Iressa, ZD1839) in combination with cytotoxic agents have been carried out or are ongoing in several varieties of tumor. To provide a rationale for future clinical trials, the effects of combining gefitinib with oxaliplatin in different sequences of administration and different dose ratios in two colon cancer cell lines were evaluated. Materials and methods: The colon cancer cell lines HT-29 and LoVo were used. The methods consisted of median effect and combination index analysis, Western blot, mass spectrometry, and a cell death ELISA. Results: In vitro analysis demonstrated that the combination effects of the two agents were sequence-dependent. Changing the sequence of administration from gefitinib first to gefitinib last changed the combination effect from antagonism to synergy. The dose ratio between the two agents affected the combination effects. When equiactive doses of the two agents were used with the sequence gefitinib following oxaliplatin, the greatest level of synergism was obtained (CI = 0.6 ± 0.2, P = 0.032). Further evaluation revealed that gefitinib significantly inhibited removal of Pt-DNA adducts (P <0.05), providing a potential explanation for the sequence-dependent synergy observed with gefitinib following oxaliplatin. However, this effect was not dose-dependent. Additional studies demonstrated that gefitinib enhanced the effects of oxaliplatin by maintaining oxaliplatin-induced apoptosis, and equiactive dose of gefitinib following oxaliplatin induced prominent enhancement of apoptosis. Conclusions: Oxaliplatin followed by an equiactive relative dose of gefitinib is an appropriate combination for evaluation in colon cancer.