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1.
Arch Gynecol Obstet ; 287(3): 563-70, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23135210

ABSTRACT

OBJECTIVE: To determine the prognostic value of the immunohistochemical evaluation of the multidrug resistance-associated protein 2 (MRP2) expression, together with its subcellular localization in primary fallopian tube carcinomas (PFTCs). METHODS: The immunohistochemical analysis was performed using samples originating from 70 patients with PFTCs. RESULTS: (1) We documented that MRP2 can be localized in the plasma membrane (MRP2c), as well as in the nuclear envelope (MRP2n) of the PFTC cells. (2) Patients with more advanced stage, with progression of the disease and patients who died, showed significantly higher expression of the MRP2n. (3) Univariate and multivariate analyses showed that MRP2n is an unfavorable prognostic factor in PFTCs. (4) The analysis of the classic clinicopathological data revealed that only the FIGO stage had prognostic value, both in the univariate, as well as in multivariate analysis. CONCLUSIONS: (1) This study suggests that MRP2n is a new disadvantageous prognostic factor in PFTCs and (2) that expression in nuclear envelope can be associated with lower differentiation of cancer cells and their resistance to the cisplatin. (3) We have also confirmed independent prognostic value of FIGO stage in PFTCs.


Subject(s)
Carcinoma/metabolism , Fallopian Tube Neoplasms/metabolism , Multidrug Resistance-Associated Proteins/metabolism , Neoplasm Proteins/metabolism , Nuclear Envelope/metabolism , Adenocarcinoma, Clear Cell/diagnosis , Adenocarcinoma, Clear Cell/metabolism , Carcinoma/diagnosis , Carcinoma, Endometrioid/diagnosis , Carcinoma, Endometrioid/metabolism , Carcinoma, Transitional Cell/diagnosis , Carcinoma, Transitional Cell/metabolism , Drug Resistance, Neoplasm , Fallopian Tube Neoplasms/diagnosis , Female , Humans , Immunohistochemistry , Middle Aged , Multidrug Resistance-Associated Protein 2 , Prognosis , Retrospective Studies
2.
Anticancer Res ; 31(9): 2963-70, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21868545

ABSTRACT

BACKGROUND: Y-Box-binding protein-1 (YB-1) acts as a transcription factor for multiple genes and is linked to DNA replication and repair, cell proliferation and resistance to cytostatic drugs. PATIENTS AND METHODS: The prognostic value of YB-1 expression in primarily untreated malignant non-Hodgkin's lymphomas (NHLs) was examined using immunohistochemistry. RESULTS: Expression of YB-1 was detected in 48 out of 56 NHLs, and the immunohistochemical reaction was localized exclusively in the cytoplasm. Expression of YB-1 did not correlate with clinicopathological variables. Patients with higher YB-1 expression had shorter progression-free survival during the entire period of observation (p=0.0434), as well as in the course of 30 months' observation (p=0.0253). Additionally, in the course of 50 months' observation, patients with higher expression of YB-1 demonstrated a shorter overall survival time (p=0.0383) and a shorter progression-free survival (p=0.0309). CONCLUSION: Elevated YB-1 expression may represent a new unfavorable prognostic factor.


Subject(s)
Lymphoma, Non-Hodgkin/metabolism , Y-Box-Binding Protein 1/metabolism , Adult , Disease-Free Survival , Female , Humans , Immunohistochemistry , Lymphoma, Non-Hodgkin/pathology , Male , Middle Aged , Prognosis
3.
Pathol Oncol Res ; 17(3): 511-8, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21207255

ABSTRACT

Estrogen as a potential factor of ovarian carcinogenesis, acts via two nuclear receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERß), but the cellular signal pathways involved are not completely clear so far. In this study we have described the expression of ERα, detected by immunocytochemistry in 11 ovarian carcinoma cell lines and by immunohistochemistry in 43 Federation Internationale des Gyneacologistes et Obstetristes stage III ovarian carcinoma specimens prepared before and after treatment with cisplatin-based schemes. For cisplatin resistance is a major obstacle in the treatment of ovarian carcinoma, analysis of cisplatin sensitivity in 11 ovarian carcinoma cell line was also performed. The strong nuclear ERα expression was only shown in the single A2780P cell line. Expression of ERα in tissue specimens did not reveal any correlations between histopathological parameters (histologic type and grading). We demonstrated a significant association with ERα expression in specimens from primary laparotomies (PL) and cause-specific survival. In the cases terminated by death of the patient, overall immunoreactivity score of ERα expression at PL was significantly lower than in surviving patients. In addition, Kaplan-Meier analysis revealed significantly shorter overall survival time and progression-free time in cases with lower immunoreactivity score of ERα expression at PL. Our findings support the hypothesis that aberrant hormone activity, by way of altered receptor expression, might be an important factor in the malignant transformation of ovarian cancer.


Subject(s)
Biomarkers, Tumor/metabolism , Estrogen Receptor alpha/metabolism , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/mortality , Cystadenocarcinoma, Serous/metabolism , Cystadenocarcinoma, Serous/mortality , Cystadenocarcinoma, Serous/therapy , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/mortality , Endometrial Neoplasms/therapy , Female , Follow-Up Studies , Humans , Immunoenzyme Techniques , Middle Aged , Ovarian Neoplasms/therapy , Prognosis , Retrospective Studies , Tumor Cells, Cultured
4.
Oncol Rep ; 22(6): 1315-23, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19885582

ABSTRACT

One of the leading causes of chemotherapy failure in non-Hodgkin's lymphomas (NHLs) is multidrug resistance (MDR). MDR can be associated with expression of members of the family of ABC-transporters. Since a correlation between expression of cyclooxygenase-2 (COX-2) and MDR in various cancer cells was described, the expression of COX-2 and the ABC-transporters MDR1/P-glycoprotein (P-gp), MRP1, MRP2 and BCRP was examined in 56 previously non-treated patients by immunohistochemistry. The data show that: i) P-gp is not expressed in non-treated NHLs; ii) MRP2 can be localized in the nuclear membranes of NHL cells; iii) expression of MRP2 in the cytoplasm membrane correlates with clinical response; iv) elevated expression of BCRP is typical for the patients, who did not respond to primary chemotherapy and for cases with shorter progression-free survival time in a 30 months follow-up; and v) there is a strong correlation between COX-2 and MRP1, MRP2 and BCRP. It can be concluded that: i) BCRP may be a crucial factor involved in primary resistance of NHLs, thus it may be useful for prediction of chemotherapeutic treatment and risk of relapse; and ii) since there is strong correlation between COX-2 expression and MDR in NHLs, the application of COX-2 inhibitors may be considered for chemosensitization.


Subject(s)
ATP-Binding Cassette Transporters/biosynthesis , Cyclooxygenase 2/biosynthesis , Gene Expression Regulation, Neoplastic , Lymphoma, Non-Hodgkin/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2 , Aged , Antineoplastic Agents/pharmacology , Disease-Free Survival , Female , Humans , Immunohistochemistry/methods , Male , Middle Aged , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/biosynthesis , Neoplasm Proteins/biosynthesis
5.
Mol Med Rep ; 2(4): 543-8, 2009.
Article in English | MEDLINE | ID: mdl-21475863

ABSTRACT

Betulinic acid is a triterpene isolated from the bark of many plants that exhibits cytotoxicity in several cancer cell lines and is capable of inducing apoptosis. In this study, we examined the cytotoxic activity and apoptotic ability of betulinic acid in the drug-sensitive (MeWo) and drug-resistant melanoma MeWo CIS (cisplatin), MeWo ETO (etoposide), MeWo VIN (vinblastin) and MeWo FOTE (fotemusine) cell lines, as well as in the normal melanocyte NHEM-neo cell line. The results show that betulinic acid exhibited significant cytotoxicity on all the cell lines. However, a sulphorhodamine B cell proliferation assay and immunocytochemical analysis of Ki67 expression revealed the strongest cytotoxicity on the normal melanocyte cell line, NHEM-neo. Flow cytometry and immunocytochemical analysis of caspase 3 expression was used to confirm cell death by apoptosis. In conclusion, betulinic acid is a potential candidate for anticancer research, and may also have an application in the cosmetics industry.

6.
Histol Histopathol ; 23(5): 531-8, 2008 05.
Article in English | MEDLINE | ID: mdl-18283637

ABSTRACT

Decreased expression of p16 may result from hypermethylation of the promoter or from deletion of the gene. It can lead to intensified proliferation of neoplastic cells and to cytostatic drug resistance. The study was aimed at the examination of prognostic value of p16 expression in relation to Ki67 and caspase-3 in ovarian cancers using immunohistochemistry. The immunohistochemical studies were performed on 73 paraffin-embedded samples of ovarian cancers from 43 patients and samples from 6 healthy ovaries. We have used monoclonal antibodies against p16. ABC method and DAB were used for antigens visualisation. The intensity of the immunohistochemical reactions was appraised using the semi-quantitative IRS scale. In healthy ovaries we have shown strong reaction in the nuclei of surface epithelium. In the case of studied ovarian cancers, the reaction of a nuclear and cytoplasmic localization was obtained. The mean overall immunoreactivity score of nuclear p16 expression amounted to 5.30+/-3.44 SD in primary laparotomy material and 6.61+/-4.34 SD in secondary cytoreduction material. Statistical analysis demonstrated that lower p16 expression was typical of the younger patients and the patients who died. Kaplan-Meier's analysis proved that lower expression of p16 was characteristic of cases with shorter overall survival. In the present study we have demonstrated that lowered p16 expression represented an unfavourable prognostic index in ovarian cancer. Lowered p16 expression was also typical for chemotherapy-resistant ceases (cases of lower caspase-3 and higher Ki67 at secondary cytoreduction expression).


Subject(s)
Adenocarcinoma/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Ovarian Neoplasms/metabolism , Ovary/metabolism , Adenocarcinoma/mortality , Adenocarcinoma/secondary , Adenocarcinoma/therapy , Biomarkers, Tumor/metabolism , Caspase 9/metabolism , Cell Nucleus/metabolism , Cell Nucleus/pathology , Combined Modality Therapy , Cytoplasm/metabolism , Cytoplasm/pathology , Female , Fluorescent Antibody Technique, Indirect , Humans , Immunoenzyme Techniques , Ki-67 Antigen/metabolism , Middle Aged , Neoplasm Recurrence, Local , Neoplasm Staging , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Ovarian Neoplasms/therapy , Ovary/pathology , Retrospective Studies , Survival Rate
7.
Anticancer Res ; 27(4C): 2917-24, 2007.
Article in English | MEDLINE | ID: mdl-17695471

ABSTRACT

BACKGROUND: Numerous experimental studies have described the capacity of myofibroblasts to stimulate mammary cancer cells in a paracrine manner. Until now, the prognostic significance of myofibroblasts present in breast cancer has not been examined. PATIENTS AND METHODS: In paraffin sections, originating from 45 patients with primary invasive breast cancer, immunohistochemical reactions were performed using antibodies directed against smooth muscle actin, Ki-67, VEGF, bFGF and UPA. RESULTS: The cases with higher content of myofibroblasts in the tumour tissue manifested higher grade, more pronounced expression of Ki-67, VEGF and bFGF and shorter overall survival and relapse-free survival. CONCLUSION: The present study for the first time documents the unfavourable prognostic significance of myofibroblasts in tissues of invasive ductal mammary carcinomas.


Subject(s)
Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Myoblasts/pathology , Actins/biosynthesis , Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/metabolism , Female , Fibroblast Growth Factor 2/biosynthesis , Humans , Immunohistochemistry , Ki-67 Antigen/biosynthesis , Middle Aged , Myoblasts/metabolism , Retrospective Studies , Stromal Cells/metabolism , Stromal Cells/pathology , Urokinase-Type Plasminogen Activator/biosynthesis , Vascular Endothelial Growth Factor A/biosynthesis
8.
Oncol Rep ; 17(3): 505-16, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17273726

ABSTRACT

A major obstacle in treatment of ovarian cancer is intrinsic or acquired drug resistance causing failure of chemotherapy followed by a poor clinical outcome. Drug resistance of ovarian carcinoma can be caused by dysregulation of cellular factors involved in regulation of apoptosis and DNA repair pathways. In this study, 73 ovarian carcinoma specimens obtained before and after chemotherapy were analysed by immunohistochemistry for expression of seven proteins playing an important role in regulation of DNA mismatch repair and apoptosis. The prognostic significance of these proteins in the meaning of overall and progression-free survival was evaluated in univariate and multivariate analysis. Bcl-xL, hMSH2, caspase-3, p21 and p53 displayed prognostic importance in univariate analysis. Furthermore, it was demonstrated that caspase-3 and p21 were also independent prognostic markers for both, overall and progression-free survival. In conclusion, these data indicate that analysis of proteins involved in DNA mismatch repair and apoptosis can be useful for prediction of clinical outcome in ovarian carcinoma patients.


Subject(s)
Apoptosis/physiology , Biomarkers, Tumor/analysis , DNA Mismatch Repair , Ovarian Neoplasms/metabolism , Adaptor Proteins, Signal Transducing , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carrier Proteins/biosynthesis , Caspase 3/biosynthesis , Cyclin-Dependent Kinase Inhibitor p21/biosynthesis , Drug Resistance, Neoplasm/physiology , Female , Humans , Immunohistochemistry , Membrane Proteins/biosynthesis , Middle Aged , MutL Protein Homolog 1 , MutS Homolog 2 Protein/biosynthesis , Nuclear Proteins/biosynthesis , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/mortality , Platinum Compounds/therapeutic use , Prognosis , Survival Analysis , Tumor Suppressor Protein p53/biosynthesis , bcl-X Protein/biosynthesis
9.
Virchows Arch ; 450(2): 187-94, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17216190

ABSTRACT

An obstacle in chemotherapy of ovarian cancer is the development of drug resistance. Taxol (paclitaxel)-resistance-associated gene-3 (TRAG-3/CSAG2) was found to be overexpressed in a paclitaxel-resistant ovarian carcinoma cell line. However, clinical impact of TRAG-3 in ovarian carcinoma has not been demonstrated previously. For demonstration of potential clinical impact of TRAG-3, immunohistochemistry was applied to determine TRAG-3 protein expression in specimens obtained from ovarian carcinoma patients (n=37) who received a paclitaxel-based chemotherapy at two different time points, initial laparotomy before chemotherapy, and secondary cytoreduction after chemotherapy. The TRAG-3-specific immunohistochemical staining was correlated with clinical outcome. In ovarian carcinoma specimens obtained at the initial laparotomy, an advantage in overall (P < 0.001) and progression-free (P = 0.003) survival for patients with weak TRAG-3 expression could be demonstrated. Tumor specimens excised at secondary cytoreduction procedure were not predictive for clinical outcome. In summary, TRAG-3 was found to be a prognostic factor for the prediction of clinical outcome after the application of paclitaxel-based chemotherapy.


Subject(s)
Neoplasm Proteins/analysis , Ovarian Neoplasms/chemistry , Adult , Aged , Female , Humans , Immunohistochemistry , Middle Aged , Neoplasm Proteins/genetics , Ovarian Neoplasms/mortality , Survival Rate
10.
Virchows Arch ; 450(3): 279-85, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17235562

ABSTRACT

Elevated metallothionein (MT) expression in ovarian cancers treated with cisplatin-based schemes represents an unfavorable prognostic index. MT expression is significantly higher in tumor samples obtained after chemotherapy. The present study aimed at examining MT expression in ovarian carcinoma cells sensitive (A2780) or resistant (A2780RCIS) against platinum drug treatment as well as examining effects of exposure to cisplatin on MT expression. Subcellular expression of MT was evaluated also in samples originating from 73 ovarian tumors. Cisplatin-resistant A2780RCIS cells were exposed to increasing cisplatin concentrations, and the subcellular expression of MT was determined by immunocytochemistry. The studies demonstrated that cisplatin-resistant A2780RCIS cells exposed to cisplatin typically manifested a nuclear MT expression. The study demonstrated also that exposure to cisplatin was paralleled by growing MT expression in cell nuclei. The nuclear expression of MT was also found to be specific for ovarian cancers of poor clinical outcome. No relationship could be demonstrated between cytoplasmic expression of MT and clinical variables. Nuclear MT expression is induced by cisplatin and seems to protect DNA in the cells from toxic effects of the drug.


Subject(s)
Adenocarcinoma/metabolism , Antineoplastic Agents/pharmacology , Cell Nucleus/metabolism , Cisplatin/pharmacology , Drug Resistance, Neoplasm/drug effects , Metallothionein/metabolism , Ovarian Neoplasms/metabolism , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Cell Line, Tumor , Cell Nucleus/pathology , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Female , Humans , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Prognosis , Survival Rate
11.
Clin Cancer Res ; 12(23): 7149-58, 2006 Dec 01.
Article in English | MEDLINE | ID: mdl-17145840

ABSTRACT

PURPOSE: Cisplatin resistance is a major obstacle in the treatment of ovarian carcinoma. ABCC2 is commonly localized in apical cell membranes and could confer cisplatin resistance. Here, we show that ABCC2 can be localized in the cytoplasmic membrane as well as in the nuclear membrane of various human tissues including ovarian carcinoma cells. EXPERIMENTAL DESIGN: For the subcellular detection of ABCC2, immunohistochemistry was done using 41 Federation Internationale des Gynaecologistes et Obstetristes stage III ovarian carcinoma specimens prepared before treatment with cisplatin-based schemes and 35 specimens from the same group after chemotherapy. Furthermore, 11 ovarian carcinoma cell lines as well as tissue microarrays consisting of various human tissues were analyzed. RESULTS: Nuclear membranous localization of ABCC2 was associated with response to first-line chemotherapy at primary (P = 0.0013) and secondary surgery (P = 0.0060). Cases with relapse showed higher nuclear membrane expression at primary (P = 0.0003) and secondary surgery (P = 0.0024). Kaplan-Meier analyses showed that weak nuclear membrane ABCC2 expression before treatment was associated with significantly longer overall (P = 0.04) and progression-free survival (P = 0.001); following chemotherapy, it correlated with significantly longer progression-free survival (P = 0.038). Tissue microarrays confirmed nuclear membranous localization of ABCC2, in particular, in poorly differentiated cells. In ovarian carcinoma cells, it correlated with resistance against cisplatin, whereas localization in the cytoplasmic membrane did not. CONCLUSIONS: ABCC2 confers resistance to cisplatin of ovarian carcinoma in cell culture systems and in clinics when expressed in the nuclear membrane. Thus, ABCC2 localization can predict platinum therapy outcome. Furthermore, expression of ABCC2 in nuclear membranes in human tissues is specific for poorly differentiated cells including stem cells.


Subject(s)
Antineoplastic Agents/therapeutic use , Cell Membrane/metabolism , Cell Nucleus/metabolism , Cisplatin/therapeutic use , Membrane Transport Proteins/metabolism , Multidrug Resistance-Associated Proteins/metabolism , Ovarian Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Line, Tumor , Disease-Free Survival , Drug Resistance, Neoplasm , Female , Follow-Up Studies , Gene Expression Profiling , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Membrane Transport Proteins/drug effects , Membrane Transport Proteins/genetics , Middle Aged , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/drug effects , Multidrug Resistance-Associated Proteins/genetics , Neoplasm Staging , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/metabolism , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Recurrence , Reverse Transcriptase Polymerase Chain Reaction , Structure-Activity Relationship , Survival Rate , Treatment Outcome
12.
Oligonucleotides ; 16(3): 263-74, 2006.
Article in English | MEDLINE | ID: mdl-16978089

ABSTRACT

In the chemotherapeutic treatment of patients with disseminated neoplasms, multidrug resistance (MDR) is a major obstacle. ABCG2 (BCRP/MXR), a member of the superfamily of adenosine triphosphate-binding cassette (ABC) transporters, was demonstrated to be associated with "atypical" forms of multidrug-resistant phenotypes of cancer cells. To overcome the ABCG2-depending MDR, two specific anti-ABCG2 small interfering RNAs (siRNAs) were designed for transient triggering of the gene-silencing RNA interference (RNAi) pathway in the human gastric carcinoma cell line EPG85-257RNOV, exhibiting an atypical MDR phenotype. Because both siRNAs showed biological activity, for stable inhibition of ABCG2 corresponding short hairpin RNA (shRNA) expression vectors were constructed. By treatment of EPG85-257RNOV cells with these constructs, expression of the targeted ABCG2-encoding mRNA and transport protein was inhibited completely. Furthermore, anti-ABCG2 shRNA-treated cells increased cellular drug accumulation to the same level measured in drug-sensitive parental cells. These effects were accompanied by complete reversal of the drug-resistant phenotype. Thus, the data indicate that siRNA- and shRNA-mediated RNAi-based gene therapy may be applicable in preventing and reversing ABCG2-depending atypical MDR.


Subject(s)
ATP-Binding Cassette Transporters/physiology , Carcinoma/metabolism , Drug Resistance, Neoplasm/genetics , Neoplasm Proteins/physiology , RNA Interference/physiology , RNA, Small Interfering/physiology , Stomach Neoplasms/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/antagonists & inhibitors , ATP-Binding Cassette Transporters/genetics , Cell Line, Tumor , Humans , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , RNA, Messenger/antagonists & inhibitors , Tumor Cells, Cultured
13.
Biochem Biophys Res Commun ; 348(1): 153-7, 2006 Sep 15.
Article in English | MEDLINE | ID: mdl-16876126

ABSTRACT

The adenosine triphosphate binding cassette (ABC)-transporter ABCC2 (MRP2/cMOAT) can mediate resistance against the commonly used anticancer drugs cisplatin and paclitaxel. To overcome the ABCC2-depending drug resistance, two specific anti-ABCC2 small interfering RNAs (siRNAs) were designed for transient triggering of the gene-silencing RNA interference (RNAi) pathway in the cisplatin-resistant human ovarian carcinoma cell line A2780RCIS. Since both siRNAs showed biological activity, for stable inhibition of ABCC2 a corresponding short hairpin RNA (shRNA)-encoding expression vector was designed. By treatment of A2780RCIS cells with this construct, the expressions of the targeted ABCC2 encoding mRNA and transport protein were inhibited. These effects were accompanied by reversal of resistance against cisplatin and paclitaxel. Thus, the data demonstrate the utility of the analyzed RNAs as powerful laboratory tools and indicate that siRNA- and shRNA-mediated RNAi-based gene therapeutic approaches may be applicable in preventing and reversing ABCC2-depending drug resistance.


Subject(s)
Cisplatin/pharmacology , Drug Resistance, Neoplasm/genetics , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Ovarian Neoplasms/genetics , RNA, Small Interfering/genetics , Cell Line, Tumor , Cisplatin/therapeutic use , Female , Gene Expression Regulation , Humans , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/genetics , Multidrug Resistance-Associated Proteins/metabolism , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , RNA Interference , RNA, Messenger/genetics , RNA, Small Interfering/therapeutic use
14.
Anticancer Res ; 26(1B): 629-34, 2006.
Article in English | MEDLINE | ID: mdl-16739331

ABSTRACT

BACKGROUND: In breast cancer, the expression of CD24 represents a poorly recognised unfavourable prognostic factor. CD24 has been described to be potentially down-regulated by estrogen receptor alpha (ER). The present study was aimed at examining the predictive value of CD24 expression in tamoxifen-treated breast cancer cases. MATERIALS AND METHODS: Sixty patients with primary invasive ductal breast cancers with post-operative tamoxifen treatment were enrolled in the study. Immmunohistochemical reactions were performed using monoclonal antibodies directed against CD24 and ER. RESULTS: Cases demonstrating cytoplasmic-membranous expression of CD24 (CD24c-m) proved to be characterised by a significantly lower expression of ER as compared to CD24c-m-negative cases. A multivariate progression analysis based on the Cox proportional hazard model demonstrated that CD24c-m expression is an independent prognostic factor for poor overall survival. CONCLUSION: The data from the present study suggested that CD24c-m expression is specific for tamoxifen-resistant breast cancer cases. CD24 should be subjected to comprehensive studies as a marker of resistance to tamoxifen treatment.


Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , CD24 Antigen/biosynthesis , Carcinoma, Ductal, Breast/drug therapy , Carcinoma, Ductal, Breast/metabolism , Tamoxifen/pharmacology , Biomarkers, Tumor/biosynthesis , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Drug Resistance, Neoplasm , Female , Humans , Immunohistochemistry , Middle Aged , Predictive Value of Tests , Receptors, Estrogen/biosynthesis
15.
Int J Gynecol Pathol ; 25(2): 131-9, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16633061

ABSTRACT

High cytoplasmic expression of maspin was described in ovarian cancers of shorter survival rates. Until now, no relationship has been described between expression of maspin and sensitivity to cisplatin in ovarian cancers. This study aimed at examining the relationship between expression of maspin, detected by immunohistochemistry and clinical response to cisplatin in ovarian cancer cases as well as the in vitro sensitivity to cisplatin of 11 ovarian cancer cell lines. The analyzes were performed on 73 samples of ovarian cancer and on A2780P, A2780RCIS, CAOV-3, EFO 21, EFO 27, ES-2, Mdah 2774, OAW 42, OVCAR-3, PA-1, and SKOV-3 ovarian cancer cells. Cytoplasmic maspin expression in studied cells significantly correlated with cisplatin sensitivity. A significantly shorter overall survival and progression-free survival was associated with lower cytoplasmic maspin expression at first-look laparotomies and nuclear maspin expression and secondary cytoreductions. Higher nuclear maspin at first-look laparotomies expression was specific for cases of complete response. In the study, the elevated expression of maspin was shown to be typical for cisplatin-sensitive ovarian cancers.


Subject(s)
Antineoplastic Agents/therapeutic use , Cisplatin/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Serpins/metabolism , Aged , Cell Nucleus/metabolism , Cytoplasm/metabolism , Female , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , Humans , Immunohistochemistry , Middle Aged , Ovarian Neoplasms/genetics , Ovarian Neoplasms/mortality , Ovary/drug effects , Ovary/metabolism , Ovary/pathology , Serpins/genetics , Survival Rate
16.
Melanoma Res ; 16(2): 147-55, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16567970

ABSTRACT

Resistance to various antineoplastic agents is common in the clinical management of malignant melanoma. The biological mechanisms conferring these different drug-resistant phenotypes are still unclear. To identify potential factors mediating drug resistance to melanoma cells, the mRNA expression profiles of the parental drug-sensitive human melanoma cell line MeWo and four derived drug-resistant sublines with acquired resistance against four commonly used drugs for melanoma treatment (cisplatin, etoposide, fotemustine and vindesine) were analysed. We investigated cDNA arrays with 43,000 cDNA clones ( approximately 30,000 unique genes) to study the expression patterns of these cell lines. We were able to simultaneously extract new candidate genes associated with drug resistance in malignant melanoma and to correlate the present findings with previously described resistance-associated genes. Using hierarchical clustering and analysing the overlap of genes with altered expression, we detected similarities between the expression signatures related to cisplatin and fotemustine resistance. The resistance against vindesine required a minimal set of changes in gene expression relative to the parental MeWo cell line. Our study provides new data that may be used to obtain further insight into the resistance characteristics of malignant melanoma.


Subject(s)
Drug Resistance, Neoplasm/genetics , Gene Expression , Melanoma/genetics , Cell Line, Tumor , Gene Expression Profiling , Humans , In Situ Hybridization , Oligonucleotide Array Sequence Analysis , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction
17.
Cancer Lett ; 235(2): 272-80, 2006 Apr 28.
Article in English | MEDLINE | ID: mdl-15970376

ABSTRACT

Immunohistochemical analysis of prognostic significance of COX-2 and P-gp expression in ovarian cancers was performed on samples originating from 73 tumors. COX-2-positive cases were shown to demonstrate higher expression of P-gp. The studies demonstrated also that, higher P-gp expression was typical for cases which responded poorly to chemotherapy and for cases with shorter progression-free time. Expression of COX-2 predisposed to a more rapid disease progression. The study documented a relationship between COX-2 and P-gp suggesting that COX-2 inhibitors might investigated in clinical trials as a treatment supplementary to chemotherapy of ovarian cancers.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/analysis , Cyclooxygenase 2/analysis , Ovarian Neoplasms/chemistry , Cyclooxygenase 2/physiology , Cyclooxygenase 2 Inhibitors/therapeutic use , Dinoprostone/biosynthesis , Female , Humans , Immunohistochemistry , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/mortality
18.
Anticancer Res ; 26(6C): 4943-8, 2006.
Article in English | MEDLINE | ID: mdl-17214367

ABSTRACT

BACKGROUND: The membrane cofactor protein CD46 represents a complement inhibitor, which protects autologous cells from complement - mediated cytotoxicity. CD46 may exhibit the potential to protect tumor cells from the immune responses of the host. The present study aimed to evaluate the prognostic significance of CD46 expression in ovarian cancers. MATERIALS AND METHODS: The analyses were performed on 73 ovarian cancer samples. Immunohistochemical reactions were performed on paraffin sections of tumors using monoclonal antibodies directed against CD46. The immunohistochemical reactions and the clinical observations results were subjected to statistical analysis. RESULTS: Expression of CD46 was demonstrated in 60% of primary laparotomy cases and in 70% secondary cytoreduction cases. Kaplan-Meier analysis showed that a significantly shorter revival-free time was linked to cases with CD46 expression at PL (p= 0.01). CONCLUSION: Ovarian cancers manifest CD46 expression that is linked to a less favourable prognosis.


Subject(s)
Membrane Cofactor Protein/biosynthesis , Ovarian Neoplasms/immunology , Female , Humans , Immunohistochemistry , Middle Aged , Paraffin Embedding , Prognosis , Retrospective Studies
19.
Breast Cancer Res ; 7(5): R862-70, 2005.
Article in English | MEDLINE | ID: mdl-16168133

ABSTRACT

INTRODUCTION: Recent reports suggest that expression of the cyclooxygenase 2 (COX-2) enzyme may up-regulate expression of MDR1/P-glycoprotein (MDR1/P-gp), an exponent of resistance to cytostatic drugs. The present study aimed at examining the relationship between the expression of COX-2 and of MDR1/P-gp in a group of breast cancer cases. METHODS: Immunohistochemical reactions were performed using monoclonal antibodies against COX-2 and MDR1/P-gp on samples originating from 104 cases of primary invasive breast cancer. RESULTS: COX-2-positive cases were shown to demonstrate higher expression of MDR1/P-gp (P < 0.0001). The studies also demonstrate that COX-2 expression was typical for cases of a higher grade (P = 0.01), a shorter overall survival time (P < 0.0001) and a shorter progression-free time (P < 0.0001). In the case of MDR1/P-gp, its higher expression characterised cases of a higher grade (P < 0001), with lymph node involvement (P < 0001), and shorter overall survival (P < 0.0001) and progression-free time (P < 0.0001). CONCLUSION: Our studies confirmed the unfavourable prognostic significance of COX-2 and MDR1/P-gp. We also document a relationship between COX-2 and MDR1/P-gp, which suggests that COX-2 inhibitors should be investigated in trials as a treatment supplementary to chemotherapy of breast cancers.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Breast Neoplasms/pathology , Cyclooxygenase 2/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/enzymology , Breast Neoplasms/mortality , Disease Progression , Female , Humans , Immunohistochemistry , Prognosis , Survival Analysis , Time Factors
20.
Pol J Pathol ; 56(2): 69-74, 2005.
Article in English | MEDLINE | ID: mdl-16092668

ABSTRACT

CD24 is a small membranous protein which may participate in invasion of tumor cells. Present study aimed at evaluation of prognostic significance linked to immunohistochemical demonstration of CD24 expression and the proliferation index, Ki67 expression in ovarian cancers. The immunohistochemical reactions with monoclonal CD24- and Ki67-specific antibodies were performed in paraffin sections originating from 30 patients with ovarian cancer treated using cisplatin and paclitaxel. Results of the reactions and analysis of the clinical course of the patients were subjected to statistical analysis. Cases with cytoplasmic-membranous expression of CD24 (CD24c-m) were found to exhibit significantly shorter overall survival time (P = 0.0002) and progression-free period (P = 0.0005). Cases with membranous expression of CD24 (CD24m) manifested a longer overall survival time (P = 0.022). No relationship was disclosed between expression of Ki67 on the one hand and survival time and CD24 expression on the other. As documented using chi square test, expression of CD24c-m predisposed to relapses (P = 0.012), progression (P = 0.0362) and to death (P = 0.0034). Deaths were encountered significantly less frequently in cases with CD24m expression (P = 0.0465). The studies demonstrated that CD24c-m represented a strongly unfavorable prognostic indicator. The antigen represents an interesting target in the search for novel therapeutic methods. The more aggressive course of cases with CD24c-m expression was not linked to more intense proliferation of the tumor cells.


Subject(s)
Antigens, CD/metabolism , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/analysis , Cisplatin/therapeutic use , Membrane Glycoproteins/metabolism , Ovarian Neoplasms/drug therapy , Paclitaxel/therapeutic use , CD24 Antigen , Female , Humans , Immunohistochemistry , Ki-67 Antigen/metabolism , Middle Aged , Ovarian Neoplasms/mortality , Prognosis
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