Resistance to platinum-containing drugs is a major obstacle in the treatment of ovarian carcinoma. ABCC2 is commonly localized on apical cell membranes and can confer cisplatin or carboplatin resistance to various cancer cell lines including ovarian carcinoma cells. In this study, it could be demonstrated that ABCC2 can be localized in the cytoplasm membrane as well as in the nuclear membrane of ovarian carcinoma cell lines. ABCC2 expression in nuclear membranes correlated with resistance against platinum drugs, whereas localization in the cytoplasm membrane did not correlate with drug resistance. 43 ovarian carcinoma specimens prepared before treatment with cisplatin-based schemes and 36 specimens from the same group after cisplatin treatment were analyzed by immunohistochemistry. A subcellular localization of ABCC2 on the cytoplasm membrane as well as on the nuclear membrane could be demonstrated. Nuclear membrane localization of ABCC2 was associated with response to first-line chemotherapy at primary laparatomy (P=0.0013), and at secondary surgery (P=0.0054). Cases with relapse demonstrated higher nuclear membrane expression of ABCC2 at primary laparatomy (P=0.0003), and at secondary surgery (P=0.002). Kaplan-Meier analyzes demonstrated that weak nuclear membrane ABCC2 expression before treatment was associated with significantly longer overall survival time (P=0.04) and progression-free survival time (P=0.001). Furthermore, weak nuclear membrane ABCC2 expression following cisplatin treatment correlated with significantly longer progression-free survival time (P=0.038). In conclusion, ABCC2 can confer resistance to cisplatin of ovarian carcinoma in vitro and in clinics when expressed on the nuclear membrane. Thus, ABCC2 localization can predict platinum drug therapy outcome and should be considered for chemotherapy of ovarian carcinoma.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]