Determination of the mechanism of gemcitabine modulation of cisplatin drug resistance in panel of human endometrial cancer cell lines.
OBJECTIVE
The primary objective of this study was to determine the mechanism(s) of cisplatin drug resistance in endometrial cancer cell lines. To evaluate the mechanism that gemcitabine modulates cisplatin drug resistance in endometrial cancer cell lines.


METHODS
Combination treatment was completed in panel of four human endometrial cancer cell lines. Growth inhibition assays were conducted in each cell line evaluating combinations of the Ic25, Ic50, and Ic90 to determine optimal dosing for the combination of gemcitabine plus cisplatin. Evaluation of the correlative biological targets for modulation of platinum drug resistance was completed by the respective immunohistochemistry assays.


RESULTS
Downregulation of glutathione-S-transferase (GST) activity by 11% to 100% was observed with an associated 78.6% to 100% decrease in intracellular glutathione (GSH) concentrations. In the gemcitabine plus cisplatin treatment arm compared to either alone, there was also downregulation of MSH2, p53, and ERCC1 expression. No changes observed in the pro-apoptotic proteins, BAX or BAD, expression, AKT activation, or MDR1/PGP expression regardless of treatment with combination of gemcitabine plus cisplatin or either agent alone.


CONCLUSIONS
There is likely more than one mechanism contributing to the increase synergistic in vitro platinum-resistant cell lines and increase clinical activity that has been observed in patients with platinum-resistant tumors. In this in vitro study, we determined the downregulation of intracellular GST activity and GSH concentration were the predominant mechanisms involved in the modulation of platinum resistance. Downregulation of MSH2, p53 and ERCC1 expression may also contribute to increase cytotoxic activity compared to cisplatin alone.
Smith
Judith A
JA
Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX 77230-1439, USA. jasmith@mdanderson.org
Gaikwad
Anjali
A
Ramondetta
Lois M
LM
Wolf
Judith K
JK
Brown
Jubilee
J
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D000093542:Gemcitabine
D003841:Deoxycytidine; D005978:Glutathione; D002945:Cisplatin; D000093542:Gemcitabine