Schedule-dependent interaction between epidermal growth factor inhibitors (EGFRI) and G2/M blocking chemotherapeutic agents (G2/MB) on human NSCLC cell lines in vitro
2004; Lippincott Williams & Wilkins; Volume: 22; Issue: 14_suppl Linguagem: Inglês
10.1200/jco.2004.22.14_suppl.7028
ISSN1527-7755
AutoresBilal Piperdi, Y.-H. Ling, Glenn S. Kroog, Román Pérez-Soler,
Tópico(s)HER2/EGFR in Cancer Research
Resumo7028 Background: EGFRI have shown clinical activity in NSCLC patients. Despite single agent activity, addition of EGFRI to chemotherapy has so far failed to improve outcome. EGFRI cause G1 cell cycle arrest. Cytotoxic chemotherapies act on dividing cells. G2/MB such as taxanes are essential part of standard chemotherapy. We examined the effects of combining EGFRI with G2/MB on human NSCLC cells in vitro using different schedules. Methods: H322 and our strain of A549 cells were used based on their differential sensitivity to EGFRI, erlotinib. The following G2/MB were used: paclitaxel, vinblastine and bortezomib. The cells were treated with the EGFRI alone, G2/MB alone, or a combination of two given together or sequentially 24-hrs apart. Cell cycle analysis and apoptotic fractions were determined by flow cytometry after staining with PI at 48-hr after exposure. Cytotoxicity was determined using a MTT assay. Results: The IC50s of erlotinib for H322 and A549 are 1.04 uM and >20 uM respectively. The cell cycle effects of EGFRI and G2/MB are as expected. The concomitant and the sequential treatment of G2/MB followed by EGFRI result in accumulation of cells in both G1 and G2/M. However, pre-treatment with erlotinib causes G1 arrest and effectively abrogates the action of G2/MB. This antagonistic effect is seen in both H322 and A549, although more prominent in H322 cells. This is accompanied by increase in cell survival and decrease in apoptosis. Similar effects are obtained with cetuximab, indicating the general effect of EGFRI. Conclusions: Sequential therapy using EGFRI followed by G2/MB antagonized cell cycle effects of G2/MB and reduced their efficacy. Since studies of the combination of EGFRI with standard chemotherapy utilized schedules involving continuous exposure to EGFRI, our results suggest that their failure may be (in part) due to choice of schedule. Possibly, continuous exposure to EGFRI, by causing G1 arrest, may decrease the effectiveness of chemotherapy in subsequent cycles. Further in vivo studies will be required to further evaluate this hypothesis. Supported by NIH CA 91784 and OSIP. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI Pharmaceuticals OSI Pharmaceuticals OSI Pharmaceuticals OSI Pharmaceuticals
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