5243

ABCB1

ATP-binding cassette, sub-family B (MDR/TAP), member 1;ABCB1;ATP-binding cassette, sub-family B (MDR/TAP), member 1

P-glycoprotein 1|colchicin sensitivity|doxorubicin resistance|multidrug resistance protein 1

7q21.12

protein-coding

Despite intensive high-dose chemotherapy and autologous hematopoietic stem cell transplantation, disseminated neuroblastoma (NB) frequently proves to be chemosensitive but not chemocurable, and more often so in NB-presenting MYCN amplification. To assess the direct relationship between the MYCN oncogene and chemoresistance acquisition during NB metastatic dissemination, we have studied MYCN and MDR1 genes using the human IGR-N-91 ectopic xenograft metastatic model. This characterized experimental in vitro model includes human neuroblasts derived from a subcutaneous primary tumor xenograft, disseminated blood cells, myocardium, and bone marrow (BM) metastatic cells. All IGR-N-91-derived neuroblasts harbor a consistent MYCN genomic content but, unlike primary tumor xenograft, BM, and myocardium, human neuroblasts elicit a concomitant increase in MYCN and MDR1 transcripts levels, consistent with chemoresistance phenotype and active P-gp. In contrast, no variation of MRP1 transcript level was associated with the metastatic process in this model. Using an MDR1 promoter-CAT construct, we have shown that the MycN protein activates MDR1 transcription both in exogenous transient MYCN-transfected SK-N-SH cells and in endogenous BM metastatic neuroblasts with an increase in the MYCN transcript level. Band-shift experiments indicate that IGR-N-91 cells enriched with the MycN transcription factor do bind to two E-box motifs localized within the MDR1 promoter. Overall, our data indicate that MYCN overexpression increment contributes to the acquired drug resistance that occurs throughout the NB metastatic process.

BACKGROUND & OBJECTIVES: The clinical study showed that the P-glycoprotein(P-gp) expression was closely associated with the chemotherapeutic effect, response rate, prognosis, and survival time. Until now, few clinical papers have reported about metastatic sites and its response to chemotherapy with P-gp expression in metastatic breast carcinoma. The current study was designed to investigate the role of P-gp expression and its clinical value of chemotherapy for the patients with different metastatic sites of this carcinoma. METHODS: P-gp expression in 46 postoperative patients with metastatic breast carcinoma was detected by SABC immunohistochemical method. 43 cases treated with combination regimen: Cyclophosphamide 600 mg/m2 i.v. on day 1, Pirarubicin 60 mg/m2 i.v. on day 1, 5-Fluorouracil 600 mg/m2 i.v. on days 1 and 8. Repeat the cycle every 3 weeks for at least 2 cycles. The correlation between P-gp expression and chemotherapeutic response was analyzed. RESULTS: 1) P-gp expression positive rate was 56.5%, the P-gp expression in the patients with lung or liver viscera metastasis was higher than that in skin or lymph node metastasis (P = 0.049). 2) The overall response rate was 58.1% in 43 patients. The response rate of the P-gp negative group was higher than the P-gp positive group(P < 0.01). 3) The response rate in the patients with skin and lymph node metastasis was higher than the patients with lung and liver metastasis (P < 0.05). 4) The postoperative patients who had received CAF(cyclophosphamide + adriamycin + 5-fluorouracil) or CMF(cyclophosphamide + methotrexate + 5-fluorouracil) regimen adjuvant chemotherapy previously, the response rate of metastatic diseases to chemotherapy had no significant difference (P > 0.05). CONCLUSIONS: P-gp expression may be considered as an index for evaluating multidrug resistance, guiding drug use, and judging prognosis of the patients with metastatic breast carcinoma.

Several reports have suggested that breast cancer patients with elevated serum levels of interleukin-6 (IL-6) have a worse prognosis than patients with lower levels. We have studied IL-6 in breast cancer cell lines and have shown that autocrine production of IL-6 can confer multi-drug resistance in vitro by inducing multidrug resistance gene-1 transcription with subsequent overexpression of P-glycoprotein (PGP). Both IL-6 and PGP expression can be measured in malignant cells using immunohistochemical (IHC) techniques. We hypothesized that patients whose tumors expressed higher amounts of IL-6 or PGP would be less likely to respond to paclitaxel, an agent affected by the PGP pathway. If so, then IL-6 could serve as a predictive factor for paclitaxel sensitivity. Both IL-6 and PGP expression were measured in patients treated in a randomized trial that compared three doses of single agent paclitaxel (175, 210, and 250 mg/m(2) over 3 h every 3 weeks) in 469 women with metastatic breast cancer (CALGB 9342). No difference in complete and partial response was found among the three treatment arms. Tissue blocks in this trial were analyzed for IL-6 (154 patients) and PGP (149 patients) in paraffin-embedded sections from tumor samples; clinical characteristics of these patients were similar to the total sample of 469 patients. There were no significant differences among IL-6 or PGP scores whether measured as continuous or dichotomous variables, or by other scoring, and response to paclitaxel. In multivariate analysis neither IL-6 nor PGP was a significant predictor of time to progression or overall survival. IHC expression of IL-6 and PGP levels in tumor cells is not a predictive marker for response to paclitaxel in women with metastatic breast cancer.

BACKGROUND: ABCB1 is responsible for multidrug resistance, the principal mechanism by which many cancers develop resistance to chemotherapeutic drugs. There is a controversy whether ABCB1 gene polymorphisms correlate with survival and response in cancer patients treated with chemotherapy. We evaluated the association between clinical outcome (safety and efficacy) of paclitaxel monotherapy in metastatic breast cancer patients with ABCB1 gene polymorphisms 2677G>T/A or 3435C>T. PATIENTS AND METHODS: Patients with metastatic breast cancer were treated with 175 mg/m(2) paclitaxel per 3-week cycle. Peripheral blood mononuclear cells from patients were used to genotype ABCB1 2677G>T/A and 3435C>T polymorphisms. Genotypes were investigated for their association with tumor response, survival, toxicity, and chemoresistance. RESULTS: ABCB1 3435 CT showed a significantly lower disease control rate than the CC genotype (P = 0.025). ABCB1 3435 CT was correlated with shorter overall survival (OS) in Cox regression analysis (P = 0.026). The 2677 GG genotype showed a significant association with chemoresistance to paclitaxel and anthracycline (P = 0.04 and 0.04, respectively). None of the ABCB1 genotypes correlated with toxicity. CONCLUSIONS: ABCB1 genotypes may be a predictor of paclitaxel activity as well as a prognostic factor in metastatic breast cancer patients.

OBJECTIVE: The aim of this study was to elucidate clinical implications of ABCB1, FCGR2A, and FCGR3A polymorphisms in patients with HER2-positive metastatic breast cancer (MBC) after taxane plus trastuzumab (TH) chemotherapy. METHODS: Using genomic DNA samples extracted from mononuclear cells of consecutive patients with HER2-positive MBC who received first-line TH, we analyzed five polymorphisms (ABCB1 1236C>T, ABCB1 2677G>T/A, ABCB1 3435C>T, FCGR2A 131H/R, and FCGR3A 158V/F) and then correlated them with the response rate, progression-free survival (PFS), overall survival (OS), and adverse events of patients. RESULTS: A total of 57 women were analyzed. The median age was 46 years (range 27-72). ABCB1 2677T carriers had a longer PFS (p = 0.037) along with a tendency toward a longer OS (p = 0.057). ABCB1 3435CC genotype carriers had a shorter PFS (p = 0.039) along with a tendency toward a shorter OS (p = 0.093). In combined analysis, PFS was significantly longer in ABCB1 1236CC and/or 2677TT carriers compared to the others (p = 0.006). FCGR2A 131H/R and FCGR3A 158V/F polymorphisms were not significantly associated with response rate, PFS, and OS. CONCLUSIONS: Our data support that ABCB1 polymorphisms may predict PFS after first-line TH chemotherapy in patients with HER2-positive MBC. In contrast, FCGR2A 131H/R and FCGR3A 158V/F polymorphisms could not predict treatment outcomes.

BACKGROUND: To evaluate risk factors that predict brain metastasis in epithelial ovarian, fallopian tube, and peritoneal cancer. METHODS: All patients with FIGO stage I to IV who underwent initial cytoreductive surgery between January 1995 and January 2009 were evaluated. The tumor samples were evaluated for 7 markers including multidrug resistance gene (MDR-1), DNA aneuploidity and S-phase fraction, human epidermal growth factor receptor 2, estrogen receptor, progesterone receptor, p53 mutation, epidermal growth factor receptor, and CD31. Biomarker expression was evaluated as a predictor of hematogenous metastasis to the following locations: (i) liver and spleen, (ii) lung, and (iii) brain. RESULTS: There were 309 cases identified during the period. Of those, 5 (1.6%, 95% CI: 0.2%-3.0%) women developed brain metastasis. Time to onset of brain metastasis was significantly longer than that for other recurrent sites (median time to recurrence after initial cytoreduction, brain vs. lung vs. liver, 21.4 vs. 12.6 vs. 11.0 months, P< 0.05). Significantly increased expression of MDR-1 was seen in tumors from women who developed brain metastasis (brain vs. nonbrain sites, 80% vs. 4.2%-24.3%, P= 0.004). In multivariate analysis, MDR-1 was the only significant variable associated with the risk of brain metastasis. MDR-1 expression predicted brain metastasis (receiver-operator-characteristic curve analysis, AUC 0.808, P= 0.018), and with a 10% positive expression of MDR-1 as the cutoff value, sensitivity, specificity, positive predictive value, negative predictive value, accuracy of prediction of brain metastasis were 80%, 86.1%, 15.4%, 99.3%, and 85.9%, respectively (odds ratio: 24.7, 95% CI: 2.64-232, P= 0.002). CONCLUSIONS: Increased expression of MDR-1 in the tumor tissue obtained at initial cytoreduction is associated with increased risk of developing brain metastases in women with epithelial ovarian, fallopian tube, or peritoneal cancer.

metastasis of tumor cells to distant organs is the leading cause of death in melanoma. Yet, the mechanisms of metastasis remain poorly understood. One key question is whether all cells in a primary tumor are equally likely to metastasize or whether subpopulations of cells preferentially give rise to metastases. Here, we identified a subpopulation of uveal melanoma cells expressing the multidrug resistance transporter ABCB1 that are highly metastatic compared to ABCB1(-) bulk tumor cells. ABCB1(+) cells also exhibited enhanced clonogenicity, anchorage-independent growth, tumorigenicity and mitochondrial activity compared to ABCB1(-) cells. A375 cutaneous melanoma cells contained a similar subpopulation of highly metastatic ABCB1(+) cells. These findings suggest that some uveal melanoma cells have greater potential for metastasis than others and that a better understanding of such cells may be necessary for more successful therapies for metastatic melanoma.

Resistance to chemotherapy significantly affects the treatment results in various cancers. Multidrug resistance caused by P-glycoprotein expression is now widely studied in human malignancies. We present the results of P-glycoprotein expression examination in 91 tumor tissue samples obtained from children treated for different malignant tumors in the Dept. of Pediatric Oncology, Prague. The correlation between the level of P-glycoprotein expression and tumor histology, clinical outcome, use of therapy, relapse rate and metastatic disease was made. P-glycoprotein expression was found significantly more frequent in soft tissue sarcomas, neuroblastomas, and hepatoblastomas, and generally in disseminated disease. On the contrary, a high expression of P-glycoprotein was not found in malignant brain tumors and nephroblastomas. The data strongly support the possibility that the percentage of P-glycoprotein expressing cells in selected tumors (soft tissue sarcomas, neuroblastomas), may have a clinical importance.

BACKGROUND & OBJECTIVE: The overexpression of P-glycoprotein (P-gp) plays an important role in the chemoresistance of relapsed lymphoma. It is up-regulated in a cyclooxygenase-2 (COX-2)-dependent manner. This study was to observe the expression and correlation of COX-2 and P-gp in B-cell non-Hodgkin's lymphoma (B-NHL), and to investigate their correlations to clinicopathologic features of B-NHL. METHODS: The expression of COX-2 and P-gp in 43 specimens of naive B-NHL and 27 specimens of relapsed B-NHL were detected by SP immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The positive rates of COX-2 and P-gp were significantly lower in naive B-NHL than in relapsed B-NHL (23.3% vs. 74.1%, 11.6% vs. 70.4%, P<0.01). COX-2 expression was positively correlated to P-gp expression in relapsed B-NHL (r=0.998, P<0.01). The positive rates of COX-2 and P-gp were significantly higher in aggressive B-NHL than in indolent B-NHL (64.3% vs. 10.7%, P=0.002; 52.4% vs. 7.1%, P=0.012). CONCLUSION: COX-2 and P-gp are highly expressed in relapsed B-NHL, and they may play a role in tumor metastasis of B-NHL.

AIM: The multidrug resistance protein 1 (MDR1, P-gp, p-170) is a membrane glycoprotein that acts as an energy-dependent drug efflux pump. In various malignancies its expression is associated with resistance to diverse cytostatic drugs, and therefore predicts resistance to systemic treatment. The aim of this study was to investigate the prognostic value of MDR1 expression in primary tumor tissue to predict necrosis or viable cancer in residual tumor masses after systemic chemotherapy for advanced testicular germ cell cancer. MATERIALS AND METHODS: Out of 77 patients, histopathological characteristics of primary testicular cancer specimens and retroperitoneal lymph node dissection (RPLND) samples following chemotherapy were available from 72 and all 77 patients, respectively. Moreover, MDR1 expression was determined by immunohistochemistry in 47 primary tumors and corresponding 73 RPLND sections. RESULTS: After chemotherapy and subsequent RPLND, the examination of residual tumor masses revealed that mature teratoma and active viable tumor were predominantly found in patients with non-seminoma (NSGCT; p=0.048), especially in those with containing mature teratoma (p=0.001). Moreover, using univariate analysis the expression of MDR1 in the primary testicular tumor predicted viable tumor/teratoma residues in RPLND sections (p=0.003). However, in multivariate analysis including the tumors' histological subtype, MDR1 expression alone failed to reach statistical significance as an independent prognostic marker for residual vital tumor (p>or=0.16). CONCLUSIONS: With the limited number of patients given, the correlation between MDR1 expression in primary testis cancer and active residual retroperitoneal disease after chemotherapy failed to reach statistical significance as in independent marker. Therefore, up to now routine MDR1 staining of testicular germ cell cancer samples should not be performed in clinical practice. However, as there was a clear trend, a larger number of patients suffering from metastatic non-seminomas should be studied, as MDR1 expression might have significant prognostic value in this particular subgroup of patients.

cancer metastasis and anti-cancer drug resistance are the major reason for the failure of clinical cancer treatment. We evaluated CD147, monocarboxylate transporters (MCT1 and MCT4), and multidrug resistance (MDR) markers (MDR1 and MRP2) in 4 epithelial ovarian cancer (EOC) cell lines and primary tumors (n = 120) along with the matched metastatic lesions (n = 40) with immunofluorescence labeling. We correlated CD147 with MCT1, MCT4, MDR1 and MRP2 markers in primary and metastatic cells in cell lines and tissues using confocal microscopy. We also investigated the relationship of expression of CD147, MCT1 and MCT4 with various progression parameters. Our results indicate that the co-expression of CD147 with MCTs or MDR markers was found in primary and metastatic EOC cells and stromal cells; the over-expression of CD147, MCT1 and MCT4 was found in most primary and the matched metastatic lesions of EOC, and was significantly associated with tumor stage, grade, residual disease status and presence of ascites (P < 0.05) but not with histology type (P > 0.05). These results suggest that over-expression of CD147, MCT1 and MCT4 is correlated with EOC progression, and co-expression of CD147 and MCT1/MCT4 is related to drug resistance during EOC metastasis and could be useful therapeutic targets to prevent the development of incurable, recurrent and drug resistance EOC.

BACKGROUND: To evaluate risk factors that predict brain metastasis in epithelial ovarian, fallopian tube, and peritoneal cancer. METHODS: All patients with FIGO stage I to IV who underwent initial cytoreductive surgery between January 1995 and January 2009 were evaluated. The tumor samples were evaluated for 7 markers including multidrug resistance gene (MDR-1), DNA aneuploidity and S-phase fraction, human epidermal growth factor receptor 2, estrogen receptor, progesterone receptor, p53 mutation, epidermal growth factor receptor, and CD31. Biomarker expression was evaluated as a predictor of hematogenous metastasis to the following locations: (i) liver and spleen, (ii) lung, and (iii) brain. RESULTS: There were 309 cases identified during the period. Of those, 5 (1.6%, 95% CI: 0.2%-3.0%) women developed brain metastasis. Time to onset of brain metastasis was significantly longer than that for other recurrent sites (median time to recurrence after initial cytoreduction, brain vs. lung vs. liver, 21.4 vs. 12.6 vs. 11.0 months, P< 0.05). Significantly increased expression of MDR-1 was seen in tumors from women who developed brain metastasis (brain vs. nonbrain sites, 80% vs. 4.2%-24.3%, P= 0.004). In multivariate analysis, MDR-1 was the only significant variable associated with the risk of brain metastasis. MDR-1 expression predicted brain metastasis (receiver-operator-characteristic curve analysis, AUC 0.808, P= 0.018), and with a 10% positive expression of MDR-1 as the cutoff value, sensitivity, specificity, positive predictive value, negative predictive value, accuracy of prediction of brain metastasis were 80%, 86.1%, 15.4%, 99.3%, and 85.9%, respectively (odds ratio: 24.7, 95% CI: 2.64-232, P= 0.002). CONCLUSIONS: Increased expression of MDR-1 in the tumor tissue obtained at initial cytoreduction is associated with increased risk of developing brain metastases in women with epithelial ovarian, fallopian tube, or peritoneal cancer.

BACKGROUND: To evaluate risk factors that predict brain metastasis in epithelial ovarian, fallopian tube, and peritoneal cancer. METHODS: All patients with FIGO stage I to IV who underwent initial cytoreductive surgery between January 1995 and January 2009 were evaluated. The tumor samples were evaluated for 7 markers including multidrug resistance gene (MDR-1), DNA aneuploidity and S-phase fraction, human epidermal growth factor receptor 2, estrogen receptor, progesterone receptor, p53 mutation, epidermal growth factor receptor, and CD31. Biomarker expression was evaluated as a predictor of hematogenous metastasis to the following locations: (i) liver and spleen, (ii) lung, and (iii) brain. RESULTS: There were 309 cases identified during the period. Of those, 5 (1.6%, 95% CI: 0.2%-3.0%) women developed brain metastasis. Time to onset of brain metastasis was significantly longer than that for other recurrent sites (median time to recurrence after initial cytoreduction, brain vs. lung vs. liver, 21.4 vs. 12.6 vs. 11.0 months, P< 0.05). Significantly increased expression of MDR-1 was seen in tumors from women who developed brain metastasis (brain vs. nonbrain sites, 80% vs. 4.2%-24.3%, P= 0.004). In multivariate analysis, MDR-1 was the only significant variable associated with the risk of brain metastasis. MDR-1 expression predicted brain metastasis (receiver-operator-characteristic curve analysis, AUC 0.808, P= 0.018), and with a 10% positive expression of MDR-1 as the cutoff value, sensitivity, specificity, positive predictive value, negative predictive value, accuracy of prediction of brain metastasis were 80%, 86.1%, 15.4%, 99.3%, and 85.9%, respectively (odds ratio: 24.7, 95% CI: 2.64-232, P= 0.002). CONCLUSIONS: Increased expression of MDR-1 in the tumor tissue obtained at initial cytoreduction is associated with increased risk of developing brain metastases in women with epithelial ovarian, fallopian tube, or peritoneal cancer.