To date, clinical studies combining the new generation of targeted
therapies and
chemotherapy have had mixed results. Preclinical studies can be used to identify potential antagonism/synergy between certain agents, with the potential to predict the most efficacious combinations for further investigation in the clinical setting. In this study, we investigated the sequence-dependent interactions of
ZD6474 with
oxaliplatin in two human colon cell lines in vitro. We evaluated the in vitro antitumor activity of
ZD6474, an inhibitor of
vascular endothelial growth factor receptor (VEGFR),
epidermal growth factor receptor (EGFR) and RET
tyrosine kinase activity, and
oxaliplatin using three combination schedules:
ZD6474 before
oxaliplatin,
oxaliplatin before
ZD6474, and concurrent exposure. Cell proliferation studies showed that treatment with
oxaliplatin followed by
ZD6474 was highly synergistic, whereas the reverse sequence was clearly antagonistic as was concurrent exposure.
Oxaliplatin induced a G(2)-M arrest, which was antagonized if the cells were previously or concurrently treated with
ZD6474.
ZD6474 enhanced
oxaliplatin-induced apoptosis but only when added after
oxaliplatin. The sequence-dependent antitumor effects appeared, in part, to be based on modulation of compensatory prosurvival pathways. Thus, expression of total and active phosphorylated EGFR, as well as AKT and
extracellular signal-regulated kinase, was markedly increased by
oxaliplatin. This increase was blocked by subsequent treatment with
ZD6474. Furthermore, the synergistic sequence resulted in reduced expression of
insulin-like growth factor-I receptor and a marked reduction in secretion of
vascular endothelial growth factor protein.
ZD6474 in combination with
oxaliplatin has synergistic antiproliferative properties in human
colorectal cancer cell lines in vitro when
oxaliplatin is administered before
ZD6474.