Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Miltefosine is a phospholipid analog that exhibits antineoplastic activity against breast cancer metastases, but its mechanism of action remains uncertain. The aim of this study was to investigate the transport mechanism for the removal of miltefosine and [99mTc]-hexakis-2-methoxyisobutyl isonitrile (99mTc-MIBI) from multidrug-resistant cells. The P-glycoprotein pump function, cell viability, and 99mTc-MIBI and 2-[18F]fluoro-2-deoxy-D-glucose (18FDG) uptakes were measured in NIH 3T3 (3T3) and NIH 3T3MDR1 G185 (3T3MDR1) mouse fibroblasts and human lymphoid B JY cells. Miltefosine treatment increased the permeability and fluidity of these tumor cells in a concentration-dependent manner. The multidrug-sensitive cells were 3-4 times more sensitive to miltefosine than the multidrug-resistant ones. The extent of 99mTc-MIBI accumulation in the P-glycoprotein-expressing cells increased in the presence of miltefosine, whereas the rhodamine123 and daunorubicin uptakes of the cells did not change significantly. In the 3T3MDR1 cells verapamil reinstated the rhodamine123 and daunorubicin accumulation, but not the 99mTc-MIBI uptake. Cyclosporin A reinstated the uptakes of 99mTc-MIBI, daunorubicin and rhodamine123 by the 3T3MDR1 cells. In a concentration-dependent manner miltefosine decreased the extents of 99mTc-MIBI, rhodamine123, daunorubicin and 18FDG accumulation in the JY and 3T3 cells. Our findings indicate a common transport mechanism for 99mTc-MIBI and miltefosine, which is distinct from that for rhodamine123 and daunorubicin in MDR cells.
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PMID:Effects of miltefosine on membrane permeability and accumulation of [99mTc]-hexakis-2-methoxyisobutyl isonitrile, 2-[18F]fluoro-2-deoxy-D-glucose, daunorubucin and rhodamine123 in multidrug-resistant and sensitive cells. 1578 39

In the present review, a new theory that the mechanisms of general evolutionary persistent resistance to damaging factors are closely related to the development of tumour cells is introduced. Evolutionary resistance and its variability have an immense power to drive and control the process of carcinogenesis and the success of microbial and antitumour chemotherapy. First, this phenomenon of adaptation is characteristic of microbial cells whose resistance to antibiotics and other chemotherapeutic drugs is manifested through ATP-dependent transmembrane transporters. The structure and function of some multidrug transporters of resistance are conserved from microorganisms to mammals. When somatic cells are exposed to carcinogens and develop into tumour cells, they also acquire resistance to the toxic effects of carcinogens through these same transmembrane transporters (P-glycoprotein, glutathione S-transferases and other products of evolutionary resistance-related genes arisen for detoxification and exportation of cytotoxic xenobiotics and drugs). Cancerous cells acquire a persistent evolutionary resistance to chemotherapy drugs or irradiation through the same ATP-dependent transporters encountered in prokaryotic and eukaryotic cells. The mechanism of acquired resistance of cells to damaging factors, which becomes manifested during tumorigenic process formation, is a general biological law of primary significance in carcinogenesis. This resistance can be called malignant as, once formed, it does not disappear, as does also a clone of malignant cells. In tumorous cells, the mutagenic processes, morphological and functional modifications are a mechanism of secondary significance in carcinogenesis, contributing to formation of damage-resistant cells. This mechanism characterizes the processes of simplification arising in damage-resistant cells. Such cells acquire parasitic features. To survive under unfavourable conditions, they get adapted as if returning down the evolutionary stairs back to a more primitive stage of atavistic regression, which is characteristic of primitive forms of existence. Therefore they cease obeying the growth-regulating mechanisms in the organism and acquire the potential of unlimited division and accelerated growth (metastases) as do unicellular organisms or their forms resistant to damaging factors in the environment and in the host organism. Thus, cancer is a natural self-protective response of the damaged cells to the biological, physical and chemical damage and oxidative stress. This response has been developed in the process of evolution under the impact of the general biological Darwinian law of nature--to survive through variability and adaptation to the changed environmental conditions. Thus, malignization is the consequence of an evolutionary variety of the general biological resistance of cells to damage and stress in order to survive.
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PMID:Neoplastic growth: the consequence of evolutionary malignant resistance to chronic damage for survival of cells (review of a new theory of the origin of cancer). 1591 62

Invasion and metastases of cancer cells and the development of resistance to anticancer therapies are the main causes of morbidity and mortality from cancer. For more than two decades, these two important but not clearly related aspects in the biology of cancer have been extensively studied. Specifically, P-glycoprotein and CD44 have been characterized and are known to be determinants of multidrug resistance (MDR) and metastases. Despite this body of knowledge, few reports have linked the two phenotypes and only recently have there been reasons to suspect a direct connection. In this report, we show that a novel physical and genetic interaction between CD44s and P-glycoprotein is in part responsible for the correlation between MDR and invasive potential in cancer cells. P-glycoprotein-specific substrates that interfere with its function reduced in vitro invasion, migration, and the physical colocalization of CD44s and P-glycoprotein. CD44 expression in sensitive cells promoted the expression of P-glycoprotein and the MDR phenotype. RNA interference of MDR1 inhibited the rate of cell migration. These data indicate that there is a close interaction between CD44 and P-glycoprotein that results in the concurrent expression and modulation of two malignant phenotypes, invasion and MDR.
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PMID:The CD44 receptor interacts with P-glycoprotein to promote cell migration and invasion in cancer. 1606 46

In 140 mixed primary soft tissue sarcomas with a median follow-up of 6 years, the prognostic importance of tumor size, tumor depth, grade, necrosis, vascular invasion, and peripheral growth pattern (pushing versus infiltrating) was evaluated on whole-tumor sections. Immunohistochemical expression of Ki-67, p53, cyclin A, bcl-2, beta-catenin, CD44, and P-glycoprotein was determined using tissue microarray from the peripheral growth zone. Local recurrences developed in 17% of the patients and correlated with necrosis, vascular invasion, and cyclin A expression. No local recurrence developed in tumors with a pushing growth pattern, regardless of tumor grade and depth. Metastasis developed in 39% of the patients. Vascular invasion was identified in 36% of the tumors and was the strongest prognostic factor for metastasis with a hazard ratio of 3.5. Growth pattern and tumor necrosis were also strong prognostic factors for metastasis, whereas malignancy grade, tumor size, and tumor depth did not have any independent prognostic value. Immunostaining showed independent prognostic information for Ki-67, beta-catenin, CD44, and P-glycoprotein. The results indicate that whole-tumor sections could facilitate identification of vascular invasion, necrosis, and peripheral growth pattern and that immunohistochemical profiling from the growth zone also provides independent prognostic information for metastasis in soft tissue sarcoma.
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PMID:Improved prognostication in soft tissue sarcoma: independent information from vascular invasion, necrosis, growth pattern, and immunostaining using whole-tumor sections and tissue microarrays. 1615 63

Over a million new cases of cancers are diagnosed each year in the United States and over half of these patients die from these devastating diseases. Thus, cancers cause a major public health problem in the United States and worldwide. Chemotherapy remains the principal mode to treat many metastatic cancers. However, occurrence of cellular multidrug resistance (MDR) prevents efficient killing of cancer cells, leading to chemotherapeutic treatment failure. Numerous mechanisms of MDR exist in cancer cells, such as intrinsic or acquired MDR. Overexpression of ATP-binding cassette (ABC) drug transporters, such as P-glycoprotein (P-gp or ABCB1), breast cancer resistance protein (BCRP or ABCG2) and/or multidrug resistance-associated protein (MRP1 or ABCC1), confers an acquired MDR due to their capabilities of transporting a broad range of chemically diverse anticancer drugs. In addition to their roles in MDR, there is substantial evidence suggesting that these drug transporters have functions in tissue defense. Basically, these drug transporters are expressed in tissues important for absorption, such as in lung and gut, and for metabolism and elimination, such as in liver and kidney. In addition, these drug transporters play an important role in maintaining the barrier function of many tissues including blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier. Thus, these ATP-dependent drug transporters play an important role in the absorption, disposition and elimination of the structurally diverse array of the endobiotics and xenobiotics. In this review, the molecular mechanism of ATP-dependent solute transport by MRP1 will be addressed.
Cancer Metastasis Rev 2007 Mar
PMID:A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1. 1729 59

Inter-individual variability in drug response and the emergence of adverse drug reactions are main causes of treatment failure in cancer therapy. Recently, membrane transporters have been recognized as an important determinant of drug disposition, thereby affecting chemosensitivity and -resistance. Genetic factors contribute to inter-individual variability in drug transport and targeting. Therefore, pharmacogenetic studies of membrane transporters can lead to new approaches for optimizing cancer therapy. This review discusses genetic variations in efflux transporters of the ATP-binding cassette (ABC) family such as ABCB1 (MDR1, P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2 (BCRP), and uptake transporters of the solute carrier (SLC) family such as SLC19A1 (RFC1) and SLCO1B1 (SLC21A6), and their relevance to cancer chemotherapy. Furthermore, a pharmacogenomic approach is outlined, which using correlations between the growth inhibitory potency of anticancer drugs and transporter gene expression in multiple human cancer cell lines, has shown promise for determining the relevant transporters for any given drugs and predicting anticancer drug response.
Cancer Metastasis Rev 2007 Mar
PMID:Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy. 1732 26

Resistance to anticancer drugs and consequent failure of chemotherapy is a complex problem severely limiting therapeutic options in metastatic cancer. Many studies have shown a role for drug efflux pumps of the ATP-binding cassette transporters family in the development of drug resistance. ClC-3, a member of the CLC family of chloride channels and transporters, is expressed in intracellular compartments of neuronal cells and involved in vesicular acidification. It has previously been suggested that acidification of intracellular organelles can promote drug resistance by increasing drug sequestration. Therefore, we hypothesized a role for ClC-3 in drug resistance. Here, we show that ClC-3 is expressed in neuroendocrine tumor cell lines, such as BON, LCC-18, and QGP-1, and localized in intracellular vesicles co-labeled with the late endosomal/lysosomal marker LAMP-1. ClC-3 overexpression increased the acidity of intracellular vesicles, as assessed by acridine orange staining, and enhanced resistance to the chemotherapeutic drug etoposide by almost doubling the IC(50) in either BON or HEK293 cell lines. Prevention of organellar acidification, by inhibition of the vacuolar H(+)-ATPase, reduced etoposide resistance. No expression of common multidrug resistance transporters, such as P-glycoprotein or multidrug-related protein-1, was detected in either the BON parental cell line or the derivative clone overexpressing ClC-3. The probable mechanism of enhanced etoposide resistance can be attributed to the increase of vesicular acidification as consequence of ClC-3 overexpression. This study therefore provides first evidence for a role of intracellular CLC proteins in the modulation of cancer drug resistance.
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PMID:ClC-3 expression enhances etoposide resistance by increasing acidification of the late endocytic compartment. 1736 91

Traditional prognostic determinants in osteosarcoma have included demographics (age, sex), tumour size, site, stage, and the response to chemotherapy. Many of these are determined using varying techniques and units of measurement, which can make comparison between studies difficult. The absence of survival difference between limb sparing surgery and amputation has been repeatedly demonstrated in primary disease, and even in the setting of pathological fracture. On the other hand, there is still some controversy over the existence of increased local recurrence for limb-sparing surgery, and the implications of this. Commonly used prognostic determinants such as metastases, and response to chemotherapy enable a high degree of prognostic accuracy but usually at a late stage in the course of disease. Leading on from this, there is a need to uncover molecular pathways with specific influence over osteosarcoma progression to facilitate earlier treatment changes. Some important pathways are already being defined, for example the association of CXCR4 with metastases on presentation, the likelihood of doxorubicin resistance with positive P-glycoprotein, and the reduced survival prediction of over expressed survivin. It is anticipated that the future of osteosarcoma treatment will involve treatment tailored to the molecular profile of tumours at diagnosis, adjuvant therapy directed towards dysfunctional molecular pathways rather than the use of cytotoxics, and a more standardised approach to the measurement of clinical prognostic factors.
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PMID:A review of clinical and molecular prognostic factors in osteosarcoma. 1796 83

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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