Scheduling of paclitaxel and gefitinib to inhibit repopulation for optimal treatment of human cancer cells and xenografts that overexpress the epidermal growth factor receptor

Purpose

In clinical studies, evaluating the combination of chemotherapy and the epidermal growth factor receptor (EGFR) inhibitor gefitinib, treatments were administered concurrently, despite it being counter-intuitive to give a cytostatic agent concurrent with cycle-active chemotherapy. One strategy to enhance efficacy might be to give the agents sequentially, thus allowing selective inhibition of repopulation of cancer cells between doses of chemotherapy. Here, we evaluate the hypothesis that sequential administration might allow inhibition of repopulation by gefitinib, with tumor cells re-entering cycle to allow sensitivity to subsequent chemotherapy.

Methods

Sequential and concurrent administration of paclitaxel and gefitinib were studied in vitro and in xenografts using EGFR over-expressing, EGFR-mutant, and EGFR wild-type human cancer cell lines. We evaluated cell cycle distribution and repopulation during treatment.

Results

The sequential use of gefitinib and paclitaxel to treat EGFR over-expressing A431 cells in vitro decreased repopulation compared to chemotherapy alone, and there was greater cell kill compared to concurrent treatment. In contrast, combined treatment led to greater growth delay than use of gefitinib alone for concurrent but not for sequential treatment of mice bearing A431 xenografts; concurrent treatment had greater effects to reduce functional vasculature in the tumors. Conversely, sequential treatment led to greater growth delay than concurrent treatment of EGFR-mutant HCC-827 xenografts that are sensitive to lower doses of gefitinib.

Conclusions

These studies highlight the importance of considering effects on the cell cycle, and on the solid tumor microenvironment, including tumor vasculature, when scheduling cytostatic and cytotoxic agents in combination.