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In vitro evaluation of the effects of gefitinib on the cytotoxic activity of selected anticancer agents in a panel of human endometrial cancer cell lines

Department of Gynecologic Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

Judith K Wolf, MD

Department of Gynecologic Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

Jubilee Brown, MD

Department of Gynecologic Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

Lois M Ramondetta, MD

Department of Gynecologic Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

Judith A Smith, PharmD FCCP BCOP

Department of Gynecologic Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, jasmith{at}mdanderson.org, Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas, Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Health Science Center at Houston Medical School at Houston

Purpose. This study was conducted to determine the in vitro optimal combination of selected anticancer agents with gefitinib and evaluate its effect on the expression of correlative biological targets in the cell-signaling pathway. In addition, the effect of gefitinib on the expression of ATP-binding cassette (ABC) transport proteins was evaluated.

Methods. Growth inhibition assays were conducted in six human endometrial cancer cell lines to evaluate the activity of selected anticancer agents with gefitinib compared to each alone. Enzyme linked immunosorbant assay (ELISA) assessed the presence of pEGFR in treated and untreated cells. Evaluation of the suppression of correlative biological targets in the cell-signaling pathway was completed by immunoblotting. RT-PCR was used to characterize the expression of MRP and ABC transport proteins.

Results. This in vitro study gefitinib did not observe cytotoxic activity as a single agent. However, the activity of gefitinib as EGFR inhibitor was confirmed. The combination of gefitinib with paclitaxel and docetaxel exhibited improved in vitro cytotoxic activity compared to each antineoplastic agent alone. Suppression of pAKT and p27 in the human endometrial cancer cells treated with selected combinations of chemotherapeutic drugs and gefitinib was observed.

Conclusion. These data suggest that EGFRinhibitors, such as gefitinib, have the potential to modulate common mechanisms of drug resistance and may have a role in optimizing antineoplastic regimens for the treatment of recurrent endometrial cancer. This may represent a promising option for this class of agents in the treatment of endometrial cancer. J Oncol Pharm Practice (2009) 15: 35—44.

Key Words: endometrial cancer • getitinib • drug resistance • MDR • modulation

This version was published on March 1, 2009

Journal of Oncology Pharmacy Practice, Vol. 15, No. 1, 35-44 (2009)
DOI: 10.1177/1078155208095141


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