Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A cell line, GBM, was established from a human malignant glioblastoma and was characterized with particular reference to its response to conventional drugs. The GBM cell line exhibited a 73 +/- 7 h doubling time in monolayer cultures. Expression of glial fibrillary acidic and S-100 proteins was observed. Karyotype analysis of GBM cells at early passages revealed the presence of two near-triploid clones (A and B) with multiple chromosome rearrangements; a 100% frequency for clone B was observed in the established cell line. GBM cells had tumorigenic properties, since the s.c. injection of cultured cells into nude mice gave rise to slowly growing tumors. The morphology of GBM cells was retained during in vitro and in vivo passages, as judged by light microscopy. GBM cells were relatively resistant to most conventional drugs; among the tested drugs, only taxol exhibited a marked cytotoxic effect comparable to that found in cells of a different tumor type. GBM cells were found positive for the epidermal growth factor receptor, HER2-neu and P-glycoprotein by flow cytometry of cells labelled with monoclonal antibodies. In spite of the expression of relatively high gamma-glutamyltransferase activity, the intracellular glutathione level was comparable to that of other chemosensitive tumor cells. This glioblastoma cell line is a suitable model for the identification and preclinical studies of new agents and provides an additional system to explore the molecular basis of the intrinsic drug resistance of glioblastoma.
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PMID:Characterization of an established human, malignant, glioblastoma cell line (GBM) and its response to conventional drugs. 792 29

Fas and Fas ligand (FasL) mediate T-lymphocyte cytotoxicity and may also induce physiologic apoptosis in breast epithelium associated with menstruation and cessation of lactation. Altered expression may thus be associated with breast carcinoma progression, chemotherapy response, or outcome. We performed a clinicopathologic analysis of immunohistochemical staining for Fas and FasL, as well as bax, bcl-2, glutathione-s-transferase, HER-2 (c-erbB-2), Ki67, P-glycoprotein, p53, and hormone receptors in pretreatment breast biopsies from 34 patients with locally advanced or limited stage IV breast carcinoma who received preoperative (neoadjuvant, primary) chemotherapy followed by lumpectomy or mastectomy. Neoplastic cells expressed Fas in 44% and FasL in 85% of pretreatment biopsies. Fas immunostaining was more frequent in tumors with larger size (p = 0.02) and pretreatment metastases (p = 0.03). Combined Fas and p53 staining correlated with pathologic complete response (4 of 5 CR versus 6 of 29 other, p = 0.02), as did combined p53 and lack of FasL staining (2 of 5 CR versus 0 of 29 other, p = 0.02), but individually Fas, p53, and lack of FasL immunostaining demonstrated only trends to correlation with CR (p = 0.13-0.15). No other biomarkers correlated with chemotherapeutic response. Neither FasL nor Fas expression was associated with the degree of peritumoral lymphocytic infiltration, or with expression of the other biomarkers. Recurrence was more frequent in Fas-expressing tumors (recurrent cases 7 of 10 Fas positive versus nonrecurrent 8 of 24 Fas positive, p = 0.07). In this patient group, Fas expression is associated with aggressive tumor behavior. Biomarker immunostaining correlates weakly with pathologic response to preoperative chemotherapy, in keeping with complex or heterogeneous tumor-drug interactions.
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PMID:Clinicopathologic Analysis of Fas, Fas Ligand, and Other Biomarkers in Locally Advanced Breast Carcinoma. 1134 71

Intrinsic or acquired resistance to chemotherapy is responsible for failure of current treatment regimens in breast cancer patients. The Y-box protein YB-1 regulates expression of the P-glycoprotein gene mdr1, which plays a major role in the development of a multidrug-resistant tumor phenotype. In human breast cancer, overexpression and nuclear localization of YB-1 is associated with upregulation of P-glycoprotein. In our pilot study, we analyzed the clinical relevance of YB-1 expression in breast cancer (n = 83) after a median follow-up of 61 months and compared it with tumor-biologic factors already used for clinical risk-group discrimination, i.e., HER2, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1). High YB-1 expression in tumor tissue and surrounding benign breast epithelial cells was significantly associated with poor patient outcome. In patients who received postoperative chemotherapy, the 5-year relapse rate was 66% in patients with high YB-1 expression. In contrast, in patients with low YB-1 expressions, no relapse has been observed so far. YB-1 expression thus indicates clinical drug resistance in breast cancer. Moreover, YB-1 correlates with breast cancer aggressiveness: in patients not treated with postoperative chemotherapy, those with low YB-1 expression are still free of disease, whereas the 5-year relapse rate in those with high YB-1 was 30%. There was no significant correlation between YB-1 expression and either HER2 expression or uPA and PAI-1 levels. Risk-group assessment achieved by YB-1 differed significantly from that by HER2 or uPA/PAI-1. In conclusion, YB-1 demonstrated prognostic and predictive significance in breast cancer by identifying high-risk patients in both the presence and absence of postoperative chemotherapy, independent of tumor-biologic factors currently available for clinical decision making.
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PMID:Y-box factor YB-1 predicts drug resistance and patient outcome in breast cancer independent of clinically relevant tumor biologic factors HER2, uPA and PAI-1. 1177 77

In the wake of recent progress in understanding the genetic pathways involved in the development of brain tumors, a major goal is to correlate molecular data with clinical outcome, survival, and response to treatment modalities. This is of particular importance among the pediatric population. Reliable prognostic factors could potentially permit a tailoring of therapy in that only patients with the most aggressive tumors would receive the most intense treatments. A survey of publications about prognosis-related molecular features among pediatric brain tumors revealed 74 series, of which 46 presented statistically significant outcome-associated parameters as defined by a p value <0.05. Most investigations revealing significant prognosis-related features were performed on medulloblastomas (34 publications), followed by astrocytic tumors (6 publications) and ependymomas (5 publications). Promising approaches and molecular markers include gene expression profiles, DNA ploidy, loss of heterozygosity and chromosomal aberrations as detected by CGH and FISH (1q, 17p, 17q), as well as oncogenes/ tumor suppressor genes and their proteins (TP53, PTEN, c-erbB2, N-myc, c-myc), growth factor and hormonal receptors (PDGFRA, VEGF, EGFR, HER2, HER4, ErbB-2, hTERT, TrkC), cell cycle genes (p27) and cell adhesion molecules, as well as factors potentially related to therapeutic resistance (multi-drug resistance, DNA topoisomerase IIalpha, metallothionein, P-glycoprotein, tenascin). This review discusses the predictive potential of molecular markers for clinical outcome and their influence on therapeutic decision-making among children with brain tumors.
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PMID:Prognosis-related molecular markers in pediatric central nervous system tumors. 1562 58

Brain tumors account for approximately 20% of all childhood cancers, and are the leading cause of cancer morbidity and mortality among children. Although numerous demographic, clinical and therapeutic parameters have been identified over the past few years that have significant prognostic bearing for some pediatric brain tumors, predicting the clinical course and outcome among children with central nervous system tumors is still difficult. A survey of publications on prognosis-related histopathological and immunohistochemical features among pediatric brain tumors revealed 172 series, of which 91 presented statistically significant outcome-associated parameters as defined by a P value of less than 0.05. Most investigations revealing significant prognosis-related markers were performed on medulloblastomas (30 publications), ependymomas (25) and astrocytic tumors (18). In total, 16 cohorts consisted of more than 100 cases (5 on ependymomas, 3 each on medulloblastomas and astrocytic tumors). On the other hand, there were also 13 series with fewer than 20 cases (5 on medulloblastomas). Potentially prognostic histopathological markers vary among different entities and consist of assessment of necroses, mitoses, differentiation, vascular proliferation, and growth pattern, whereas immunohistochemical features include proliferation markers (Ki-67, MIB-1), expression of oncogenes/tumor suppressor genes and their proteins (TP53, c-erbB2), growth factor and hormonal receptors (VEGF, EGFR, HER2, HER4, ErbB-2), cell cycle genes (p27, p14ARF) and cell adhesion molecules, as well as factors potentially related to therapeutic resistance (DNA topoisomerase IIalpha, metallothionein, P-glycoprotein, tenascin). This review discusses the prognostic potential of histopathological and immunohistochemical markers that can be investigated by the practicing neuropathologist as part of the routine diagnostic workload, and scrutinizes their benefit for predicting therapy response and patient outcome among children with brain tumors.
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PMID:Prognosis-related histomorphological and immunohistochemical markers in central nervous system tumors of childhood and adolescence. 1564 46

Expression of HER2 was evaluated by immunohistochemical techniques in 84 osteosarcoma (OS) and 113 Ewing's sarcoma (ES) paraffin-embedded tumour biopsies. HER2 gene status was also assessed in a panel of cell lines as well as in vitro efficacy of trastuzumab (a humanised antibody directed against HER2) as single agent or in combination with the insulin-like growth factor I receptor (IGF-IR) IR3 antibody. Overexpression of HER2 was present in 32% of OS and 16% of ES and was significantly associated with the increased expression of P-glycoprotein, a surface molecule responsible for multidrug resistance. Event-free survival analyses revealed a prognostic value for HER2 and/or P-glycoprotein expression in OS, but not in ES. However, despite its prognostic relevance, no therapeutic effectiveness was observed pre-clinically for trastuzumab-driven therapy, in both OS or ES cell lines, unless the antibody was associated with anti-IGF-IR targeting strategies. Therefore, the therapeutic potential of trastuzumab in these neoplasms may be better exploited in combined treatments with anti-IGF-IR approaches.
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PMID:Prognostic and therapeutic relevance of HER2 expression in osteosarcoma and Ewing's sarcoma. 1591 90

Patients with metastatic breast cancer receive multiple lines of cytotoxic chemotherapy, with taxane and anthracycline-based regimens being the most active. Anthracyclines carry the risk of significant cardiotoxicity at high cumulative doses and when combined with trastuzumab, an anti-HER2 antibody. Carboplatin has shown promising single-agent activity in advanced breast cancer, is not a P-glycoprotein substrate, and is conveniently administered on an outpatient basis. Preclinical experiments demonstrated schedule-dependent synergistic cytotoxic effects of the paclitaxel first/carboplatin last (PC) combination. Pharmacokinetic parameters of paclitaxel and carboplatin were studied by Hellenic Cooperative Oncology Group (HECOG) and no significant interaction or correlation with clinical parameters were found. We assessed PC both as salvage as well as first-line treatment of advanced breast cancer patients in phase II studies which disclosed 40-60% response rates and median survival times of 12-20 mo with manageable toxicity. These results were confirmed by other groups and prompted us to the first randomized phase III trial comparing PC to the standard of epirubicin/paclitaxel (EP), a trial that showed equivalent efficacy and tolerable toxicity for PC. Registry retrospective analysis identified factors prognostic for improved outcome: good performance status, low tumor burden, lack of anthracycline exposure and of hormonal maintenance therapy. PC combinations with HER1 or HER2 modulators are being evaluated both by HECOG and by international groups. Paclitaxel coupled with carboplatin provides an alternative therapeutic option for anthracycline-exposed patients and warrants further clinical research in the direction of anthracycline-free management of metastatic breast cancer.
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PMID:Paclitaxel-carboplatin combination chemotherapy in advanced breast cancer: accumulating evidence for synergy, efficacy, and safety. 1672 Sep 15

Ovarian cancer represents the fifth most frequent cause of death as a result of malignant processes after cancers of the breast, large intestine, lung and stomach. Owing to the localisation of ovarian cancer, approximately 75% of cases are diagnosed at the III and IV stages of advancement according to FIGO. Because of the advanced stage of the disease surgery has to be followed by chemotherapy in most cases of ovarian cancer and therefore resistance to cytostatic drugs represents a major clinical problem. The potential to predict the response to therapy with the use of cytostatic drugs would enable the most effective drugs to be applied in individual cases, thus improving the efficiency of the treatment and restricting the development of resistance to cytostatic drugs. In the present paper the progress made so far in the prediction of the clinical course of ovarian cancer is reviewed. The significance of the expression of the ATP-binding cassette (ABC) transporters is described, including P-glycoprotein and MRP2, the principal representatives of the protein group. The importance of disturbed control of apoptosis and the overexpression of HER-2 and topoisomerase 1A are also discussed. Two sections are devoted to the most recent studies in the biology of ovarian cancer, pangenomic studies on gene expression using DNA microarrays and aberrations of DNA methylation.
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PMID:Prediction of the response to chemotherapy in ovarian cancers. 1717 7

Breast cancer is the most common cancer and the second leading cause of cancer death in American women. It was the second most common cancer in the world in 2002, with more than 1 million new cases. Despite advances in early detection and the understanding of the molecular bases of breast cancer biology, about 30% of patients with early-stage breast cancer have recurrent disease. To offer more effective and less toxic treatment, selecting therapies requires considering the patient and the clinical and molecular characteristics of the tumor. Systemic treatment of breast cancer includes cytotoxic, hormonal, and immunotherapeutic agents. These medications are used in the adjuvant, neoadjuvant, and metastatic settings. In general, systemic agents are active at the beginning of therapy in 90% of primary breast cancers and 50% of metastases. However, after a variable period of time, progression occurs. At that point, resistance to therapy is not only common but expected. Herein we review general mechanisms of drug resistance, including multidrug resistance by P-glycoprotein and the multidrug resistance protein family in association with specific agents and their metabolism, emergence of refractory tumors associated with multiple resistance mechanisms, and resistance factors unique to host-tumor-drug interactions. Important anticancer agents specific to breast cancer are described. Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. In 2002, 209,995 new cases of breast cancer were registered, and 42,913 patients died of it. In 5 years, the annual prevalence of breast cancer will reach 968,731 cases in the United States. World wide, the problem is just as significant, as breast cancer is the most frequent cancer after nonmelanoma skin cancer, with more than 1 million new cases in 2002 and an expected annual prevalence of more than 4.4 million in 5 years. Breast cancer treatment currently requires the joint efforts of a multidisciplinary team. The alternatives for treatment are constantly expanding. With the use of new effective chemotherapy, hormone therapy, and biological agents and with information regarding more effective ways to integrate systemic therapy, surgery, and radiation therapy, elaborating an appropriate treatment plan is becoming more complex. Developing such a plan should be based on knowledge of the benefits and potential acute and late toxic effects of each of the therapy regimens. Despite advances in early detection and understanding of the molecular bases of breast cancer biology, approximately 30% of all patients with early-stage breast cancer have recurrent disease, which is metastatic in most cases. The rates of local and systemic recurrence vary within different series, but in general, distant recurrences are dominant, strengthening the hypothesis that breast cancer is a systemic disease from presentation. On the other hand, local recurrence may signal a posterior systemic relapse in a considerable number of patients within 2 to 5 years after completion of treatment. To offer better treatment with increased efficacy and low toxicity, selecting therapies based on the patient and the clinical and molecular characteristics of the tumor is necessary. Consideration of these factors should be incorporated in clinical practice after appropriate validation studies are performed to avoid confounding results, making them true prognostic and predictive factors. A prognostic factor is a measurable clinical or biological characteristic associated with a disease-free or overall survival period in the absence of adjuvant therapy, whereas a predictive factor is any measurable characteristic associated with a response or lack of a response to a specific treatment. The main prognostic factors associated with breast cancer are the number of lymph nodes involved, tumor size, histological grade, and hormone receptor status, the first two of which are the basis for the AJCC staging system. The sixth edition of the American Joint Committee on Cancer staging system allows better prediction of prognosis by stage. However, after determining the stage, histological grade, and hormone receptor status, the tumor can behave in an unexpected manner, and the prognosis can vary. Other prognostic and predictive factors have been studied in an effort to explain this phenomenon, some of which are more relevant than others: HER-2/neu gene amplification and protein expression, expression of other members of the epithelial growth factor receptor family, S phase fraction, DNA ploidy, p53 gene mutations, cyclin E, p27 dysregulation, the presence of tumor cells in the circulation or bone marrow, and perineural and lymphovascular space invasion. Systemic treatment of breast cancer includes the use of cytotoxic, hormonal, and immunotherapeutic agents. All of these agents are used in the adjuvant, neoadjuvant, and metastatic setting. Adjuvant systemic therapy is used in patients after they undergo primary surgical resection of their breast tumor and axillary nodes and who have a significant risk of systemic recurrence. Multiple studies have demonstrated that adjuvant therapy for early-stage breast cancer produces a 23% or greater improvement in disease-free survival and a 15% or greater increase in overall survival rates. Recommendations for the use of adjuvant therapy are based on the individual patient's risk and the balance between absolute benefit and toxicity. Anthracycline-based regimens are preferred, and the addition of taxanes increases the survival rate in patients with lymph node-positive disease. Adjuvant hormone therapy accounts for almost two thirds of the benefit of adjuvant therapy overall in patients with hormone-receptor-positive breast cancer. Tamoxifen is considered the standard of care in premenopausal patients. In comparison, the aromatase inhibitor anastrozole has been proven to be superior to tamoxifen in postmenopausal patients with early-stage breast cancer. The adjuvant use of monoclonal antibodies and targeted therapies other than hormone therapy is being studied. Interestingly, some patients have an early recurrence even though they have a tumor with good prognostic features and at a favorable stage. These recurrences have been explained by the existence of certain cellular characteristics at the molecular level that make the tumor cells resistant to therapy. Selection of resistant cell clones of micrometastatic disease has also been proposed as an explanation for these events. Neoadjuvant systemic therapy, which is the standard of care for patients with locally advanced and inflammatory breast cancer, is becoming more popular. It reduces the tumor volume, thus increasing the possibility of breast conservation, and at the same time allows identification of in vivo tumor sensitivity to different agents. The pathological response to neoadj uvant systemic therapy in the breast and lymph nodes correlates with patient survival. Use of this treatment modality produces survival rates identical to those obtained with the standard adjuvant approach. The rates of pathological complete response (pCR) to neoadjuvant systemic therapy vary according to the regimen used, ranging from 6% to 15% with anthracycline-based regimens to almost 30% with the addition of a noncross-resistant agent such as a taxane. In one study, the addition of neoadjuvant trastuzumab in patients with HER-2-positive breast tumors increased the pCR rate to 65%. Primary hormone therapy has also been used in the neoadjuvant systemic setting. Although the pCR rates with this therapy are low, it significantly increases breast conservation. Currently, neoadjuvant systemic therapy is an important tool in not only assessing tumor response to an agent but also studying the mechanisms of action of the agent and its effects at the cellular level. However, no tumor response is observed in some cases despite the use of appropriate therapy. The tumor continues growing during treatment in such cases, a phenomenon called primary resistance to therapy. The use of palliative systemic therapy for metastatic breast cancer is challenging. Five percent of newly diagnosed cases of breast cancer are metastatic, and 30% of treated patients have a systemic recurrence. Once metastatic disease develops, the possibility of a cure is very limited or practically nonexistent. In this heterogeneous group of patients, the 5-year survival rate is 20%, and the median survival duration varies from 12 to 24 months. In this setting, breast cancer has multiple clinical presentations, and the therapy for it should be chosen according to the patient's tumor characteristics, previous treatment, and performance status with the goal of improving survival without compromising quality of life. Treatment resistance is most commonly seen in such patients. They initially may have a response to different agents, but the responses are not sustained, and, in general, the rates of response to subsequent agents are lower. Table 1 summarizes metastatic breast cancer response rates to single-agent systemic therapy.
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PMID:Overview of resistance to systemic therapy in patients with breast cancer. 1799 29

Chemotherapy plays a vital role in the treatment and management of breast cancer and is associated with significant improvements in survival. Regimens such as CMF (cyclophosphamide/methotrexate/5-fluorouracil) and, more recently, TAC (docetaxel/doxorubicin/cyclophosphamide) have been used with good response rates and complete remissions achieved in approximately 15% of cases. However, a significant proportion of women experience a recurrence of metastatic disease, with an average survival between 1-2 years. The monoclonal antibody trastuzumab is used in the treatment of HER2/neu-positive breast cancer. Although such targeted agents have heralded an exciting new era in cancer therapy, they are limited by the fact that only a subset of patients can benefit from treatment and by the emergence of resistance. Thus, the pursuit of a strategy that modulates resistance to standard chemotherapeutics remains valid. Accumulating evidence indicates that a number of mechanisms known to contribute to clinical drug resistance might be relevant to breast cancer. Tumor cell drug resistance might arise as a result of systemic pharmacologic factors, changes in the tumor microenvironment (eg, pH), cellular pharmacokinetics, drug metabolism and detoxification, drug target modifications, DNA repair, and apoptotic mechanisms. The adenotriphosphate-binding cassette membrane transporter family contributes to clinical drug resistance, especially in breast cancer. The most frequently described of this family is P-glycoprotein, followed by multidrug resistance protein-1. This review describes the factors thought to play a role in clinical breast cancer drug resistance and describes potential methods by which it might be circumvented.
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PMID:The role of efflux pumps in drug-resistant metastatic breast cancer: new insights and treatment strategies. 1802 75


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