Cisplatin is a widely used chemotherapeutic agent for treatment of ovarian, testicular, lung, and stomach cancers. The initial response to the drug is robust; however, tumor cells commonly develop resistance to cisplatin, which complicates treatment. Recently, overexpression of the Cu-ATPase ATP7B in ovary cells was linked to the increased cellular resistance to cisplatin; and the role for Cu-ATPases in the export of cisplatin from cells was proposed. Our results support functional interactions between cisplatin and ATP7B but argue against the active transport through the copper translocation pathway as a mechanism of drug resistance. In hepatocytes, we observed no correlation between the levels of endogenous ATP7B and the resistance of cells to cisplatin. Unlike copper, cisplatin does not induce trafficking of ATP7B in hepatoma cells, neither does it compete with copper in a transport assay. However, cisplatin binds to ATP7B and stimulates catalytic phosphorylation with EC 50 similar to that of copper. Mutations of the first five N-terminal copper-binding sites of ATP7B do not inhibit the cisplatin-induced phosphorylation of ATP7B. In contrast, the deletion of the first four copper-binding sites abolishes the effect of cisplatin on the ATP7B activity. Thus, cisplatin binding to ATP7B and/or general changes in cellular copper homeostasis are likely contributors to the increased resistance to the drug. The link between changes in copper homeostasis and cisplatin resistance was confirmed by treating the Huh7 cells with copper chelator and increasing their resistance to cisplatin. Cisplatin, cis-diamminedichloroplatinum (DDP),3 is a common anti-tumor agent that is used to treat many types of cancer. It is especially prescribed for testicular, ovarian, bladder, liver, lung, and stomach cancers (1-5). DDP mediates its cytotoxic effects by binding to DNA, forming the intrastrand crosslinks and thus causing an inhibition of DNA synthesis and repair with eventual cell death (6, 7). The initial tumor response to the treatment with DDP is robust; however, the efficacy of treatment decreases with longer and repetitive therapy cycles. The resistance arises rapidly and is sufficient to cause a failure of DDP therapy (8). The mechanisms by which cells develop resistance to DDP are not fully understood. Detoxification of DDP, enhanced repair and tolerance of DNA adducts, inhibition of apoptosis, impaired uptake and increased efflux of the drug may contribute to the acquired resistance of cells (9 -13).Recently, an unexpected connection was discovered between the resistance of cells to DDP and cellular copper metabolism (14 -16). Either down-regulation of CTR1 (49), a transporter responsible for the uptake of copper, and/or up-regulation of the copper-transporting ATPases (Cu-ATPases) responsible for copper efflux were found to increase cells resistance to DDP, although correlation between the levels of CTR1 and resistance were not always observed (17). The DDP-resistant cells were shown to have a lower copper content (18), and...

The objective of this study was to evaluate the role of the fimbriated end and nonfimbriated epithelium of fallopian tubes with regard to p53 signature, tubal intraepithelial lesions in transition (TILT), and serous tubal in-situ carcinoma (STIC) in cases of different kinds of serous pelvic cancer. This study immunohistochemically evaluated (by Ki-67 and p53 staining) the presence of p53 signature, TILT lesions, and STIC in 14 consecutive cases of prophylactic salpingo-oophorectomy in women with BRCA-1/2 mutation (bilateral salpingo-oophorectomy), 11 cases of macroscopically inconspicuous adnexae of patients with primary contralateral tubal cancer (TC), 9 cases of primary peritoneal cancer (PPC), and 10 cases of serous ovarian borderline tumors, evaluating the fallopian tubes (using the Sectioning and Extensively Examining the FIMbria protocol), ovarian surface epithelium, and ovarian cortical inclusion cysts. The frequencies of p53 signature, TILT, and STIC were 35.7%, 7.1%, and 0% in cases of prophylactic surgery, 18.2%, 9.1%, and 18.2% in TC, and 11.1%, 0%, and 33.3% in PPC. These precursor lesions were missed during the initial routine screening and were found in the fimbriated end of the fallopian tubes in 94%. In 1 case of PPC, staining for p53 was negative in STIC. The studied adnexal tissue of serous ovarian borderline tumor and ovarian cortical inclusion cysts of all cases showed no alterations according to p53 signature, TILT, or STIC. STIC and p53 signature as precursor lesions of pelvic serous cancer were seen in macroscopically inconspicuous contralateral fallopian tubes in unilateral TC, in patients with elective bilateral salpingo-oophorectomy, and in patients affected by PPC. Therefore, we propose the complete processing of adnexal tissue and the use of step sectioning to establish the correct diagnosis. Immunohistochemistry for p53 and ki-67 may aid in the diagnosis, but is not necessary for routine investigation.

Recent new data in the pathogenesis of serous pelvic cancer and the introduction of serous tubal in situ carcinoma (STIC) and its precursors have raised the question that whether all primary peritoneal cancers (PPC) are in fact of tubal origin. Therefore, the present study evaluates the frequency of STIC and its precursor lesions in cases that were diagnosed as PPC using the morphologic criteria of the most recent WHO classification. The present study evaluates immunohistochemically (Ki-67 and p53 staining) the presence of STIC and its precursor lesions (p53 signature, serous tubal intraepithelial lesion [STIL]) in the completely processed Fallopian tubes of 46 consecutive PPCs. STIC was detected in 10 patients (21.7%) and p53 signature in 9 cases (19.6%). No STIL was observed. All except 1 STIC occurred at the fimbriated end of the Fallopian tube, and a bilateral involvement was detected in 2 cases. These precursor lesions were missed during the initial routine screening. Repeated staining for p53 was negative in STIC in 2 cases. STIC and p53 signature as precursor lesions of pelvic serous cancer are detected in some but not all the cases of primary serous peritoneal cancer. There might be the 2 different carcinogenetic pathways within PPC, and further studies are required to identify the source of serous cancer in cases without an STIC lesion.

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