In vitro evaluation of the effects of gefitinib on the modulation of cytotoxic activity of selected anticancer agents in a panel of human ovarian cancer cell lines.
OBJECTIVE
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 five human ovarian cancer cell lines to evaluate the activity of selected anticancer agents in combination with gefitinib compared to each alone. Enzyme linked immunosorbant assay (ELISA) assessed the presence of pEGFR in treated and untreated cells. Expression of correlative biological targets in the cell-signaling pathway was completed by immunoblotting. RT-PCR was used to characterize the expression ABC transport proteins.


RESULTS
This in vitro study confirmed gefitinib did not have significant cytotoxic activity, the combination of gefitinib with other chemotherapy drugs demonstrated improved in vitro cytotoxic activity in platinum sensitive ovarian cancer cell lines. Suppression of pAKT and p-erk activation in cells treated with combination of cisplatin and gefitinib was observed and suggests the role of gefitinib inhibition of proliferative cell signaling pathway.


CONCLUSIONS
This data suggests that EGFR-inhibitors, such as gefitinib, have the potential to modulate common mechanisms of drug resistance and may have a role in optimizing chemotherapy regimens for the treatment of ovarian cancer.
Smith
Judith A
JA
Department of Gynecologic Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, P.O. Box 301439-UNIT 1362, Houston, TX 77230-1439, USA. jasmith@mdanderson.org
Gaikwad
Anjali
A
Yu
Jiang
J
Wolf
Judith K
JK
Brown
Jubilee
J
Ramondetta
Lois M
LM
Stewart
Clinton F
CF
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007202:Indicators and Reagents; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D012313:RNA; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D012996:Solutions
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D011799:Quinazolines; C034477:RNA primers; D012334:RNA, Neoplasm; D012996:Solutions; D012313:RNA; D000077156:Gefitinib