Expression of Bcl-xL in ovarian carcinoma is associated with chemoresistance and recurrent disease.
OBJECTIVE
The long-term survival of patients with epithelial ovarian cancer is limited by the emergence of tumor cells that are resistant to chemotherapy. We hypothesized that expression of Bcl-x(L), a homologue of Bcl-2 that confers protection from chemotherapy-induced apoptosis, may be predictive of patients' clinical response to treatment, and that treatment with chemotherapy may result in the selection of tumor cells that overexpress this protein.


METHODS
We determined the expression of Bcl-x(L) in epithelial ovarian cancers from 28 patients at the time of initial staging laparotomy and in recurrent tumors in the same patients following treatment with platinum-based chemotherapy. The data were analyzed to determine whether Bcl-x(L) expression was predictive of clinical outcome. A2780 ovarian cancer cells were stably transfected with Bcl-x(L) or control plasmid. Chemotherapy-induced apoptosis in these cell lines was determined in vitro and in a xenograft model.


RESULTS
Bcl-x(L) expression in primary tumors was associated with a significantly shorter disease-free interval as compared to patients whose tumors did not express Bcl-x(L) (1.6 months as compared to 7.7 months). We found that Bcl-x(L) expression conferred resistance to chemotherapy-induced apoptosis resulting from treatment with cisplatin, paclitaxel, topotecan, and gemcitabine in vitro. In a xenograft model, Bcl-x(L) expressing tumors continued to grow following treatment with cisplatin, paclitaxel, topotecan, and gemcitabine, in contrast to control tumors, which disappeared.


CONCLUSIONS
These results portray an important role for Bcl-x(L) as a key factor associated with chemotherapy failure in the treatment of ovarian cancer.
Williams
Jennifer
J
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
Lucas
Peter C
PC
Griffith
Kent A
KA
Choi
Milheon
M
Fogoros
Sarah
S
Hu
Yuan Yuan
YY
Liu
J Rebecca
JR
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000473:pathology; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D019772:Topotecan / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein; D000093542:Gemcitabine
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D003841:Deoxycytidine; D019772:Topotecan; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine