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Marin JJG, Monte MJ, Macias RIR, Romero MR, Herraez E, Asensio M, Ortiz-Rivero S, Cives-Losada C, Di Giacomo S, Gonzalez-Gallego J, Mauriz JL, Efferth T, Briz O. Expression of Chemoresistance-Associated ABC Proteins in Hepatobiliary, Pancreatic and Gastrointestinal Cancers. Cancers (Basel) 2022; 14:cancers14143524. [PMID: 35884584 PMCID: PMC9320734 DOI: 10.3390/cancers14143524] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/14/2022] [Accepted: 07/14/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary One-third of the approximately 10 million deaths yearly caused by cancer worldwide are due to hepatobiliary, pancreatic, and gastrointestinal tumors. One primary reason for this high mortality is the lack of response of these cancers to pharmacological treatment. More than 100 genes have been identified as responsible for seven mechanisms of chemoresistance, but only a few of them play a critical role. These include ABC proteins (mainly MDR1, MRP1-6, and BCRP), whose expression pattern greatly determines the individual sensitivity of each tumor to pharmacotherapy. Abstract Hepatobiliary, pancreatic, and gastrointestinal cancers account for 36% of the ten million deaths caused by cancer worldwide every year. The two main reasons for this high mortality are their late diagnosis and their high refractoriness to pharmacological treatments, regardless of whether these are based on classical chemotherapeutic agents, targeted drugs, or newer immunomodulators. Mechanisms of chemoresistance (MOC) defining the multidrug resistance (MDR) phenotype of each tumor depend on the synergic function of proteins encoded by more than one hundred genes classified into seven groups (MOC1-7). Among them, the efflux of active agents from cancer cells across the plasma membrane caused by members of the superfamily of ATP-binding cassette (ABC) proteins (MOC-1b) plays a crucial role in determining tumor MDR. Although seven families of human ABC proteins are known, only a few pumps (mainly MDR1, MRP1-6, and BCRP) have been associated with reducing drug content and hence inducing chemoresistance in hepatobiliary, pancreatic, and gastrointestinal cancer cells. The present descriptive review, which compiles the updated information on the expression of these ABC proteins, will be helpful because there is still some confusion on the actual relevance of these pumps in response to pharmacological regimens currently used in treating these cancers. Moreover, we aim to define the MOC pattern on a tumor-by-tumor basis, even in a dynamic way, because it can vary during tumor progression and in response to chemotherapy. This information is indispensable for developing novel strategies for sensitization.
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Affiliation(s)
- Jose J. G. Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Correspondence: (J.J.G.M.); (O.B.); Tel.: +34-663182872 (J.J.G.M.); +34-663056225 (O.B.)
| | - Maria J. Monte
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Rocio I. R. Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Marta R. Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Elisa Herraez
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Sara Ortiz-Rivero
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
| | - Candela Cives-Losada
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
| | - Silvia Di Giacomo
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, 00185 Rome, Italy;
| | - Javier Gonzalez-Gallego
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Institute of Biomedicine (IBIOMED), University of León, Campus of Vegazana s/n, 24071 Leon, Spain
| | - Jose L. Mauriz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Institute of Biomedicine (IBIOMED), University of León, Campus of Vegazana s/n, 24071 Leon, Spain
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany;
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (M.J.M.); (R.I.R.M.); (M.R.R.); (E.H.); (M.A.); (S.O.-R.); (C.C.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain; (J.G.-G.); (J.L.M.)
- Correspondence: (J.J.G.M.); (O.B.); Tel.: +34-663182872 (J.J.G.M.); +34-663056225 (O.B.)
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Nobili S, Lapucci A, Landini I, Coronnello M, Roviello G, Mini E. Role of ATP-binding cassette transporters in cancer initiation and progression. Semin Cancer Biol 2020; 60:72-95. [PMID: 31412294 DOI: 10.1016/j.semcancer.2019.08.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 08/07/2019] [Accepted: 08/07/2019] [Indexed: 12/18/2022]
Abstract
ATP Binding Cassette (ABC) transporters, widely studied in cancer for their role in drug resistance, have been more recently also considered for their contribution to cancer cell biology. To date, many data provide evidences for their potential role in all the phases of cancer development from cancer susceptibility, tumor initiation, tumor progression and metastasis. Although many evidences are based on correlative analyses, data describing a direct or indirect role of ABC transporters in cancer biology are increasing. Overall, current available information suggests a relevant molecular effector role of some ABC transporters in cancer invasion and metastasis as reported in experimental tumor models. From a therapeutic point of view, due to the physiological relevant roles that ABC transporters play in the organism, the capability to selectively inhibit the function or the expression of ABC transporters in cancer stem cells or other tumor cells, represents the main challenge for researcher scientists. A detailed and updated description of the current knowledge on the role of ABC transporters in cancer biology is provided.
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Affiliation(s)
- Stefania Nobili
- Department of Health Sciences, University of Florence, Florence, Italy.
| | - Andrea Lapucci
- Department of Health Sciences, University of Florence, Florence, Italy
| | - Ida Landini
- Department of Health Sciences, University of Florence, Florence, Italy
| | | | | | - Enrico Mini
- Department of Health Sciences, University of Florence, Florence, Italy
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Abstract
Multidrug resistance presents one of the most important causes of cancer treatment failure. Numerous in vitro and in vivo data have made it clear that multidrug resistance is frequently caused by enhanced expression of ATP-binding cassette (ABC) transporters. ABC transporters are membrane-bound proteins involved in cellular defense mechanisms, namely, in outward transport of xenobiotics and physiological substrates. Their function thus prevents toxicity as carcinogenesis on one hand but may contribute to the resistance of tumor cells to a number of drugs including chemotherapeutics on the other. Within 48 members of the human ABC superfamily there are several multidrug resistance-associated transporters. Due to the well documented susceptibility of numerous drugs to efflux via ABC transporters it is highly desirable to assess the status of ABC transporters for individualization of treatment by their substrates. The multidrug resistance associated protein 1 (MRP1) encoded by ABCC1 gene is one of the most studied ABC transporters. Despite the fact that its structure and functions have already been explored in detail, there are significant gaps in knowledge which preclude clinical applications. Tissue-specific patterns of expression and broad genetic variability make ABCC1/MRP1 an optimal candidate for use as a marker or member of multi-marker panel for prediction of chemotherapy resistance. The purpose of this review was to summarize investigations about associations of gene and protein expression and genetic variability with prognosis and therapy outcome of major cancers. Major advances in the knowledge have been identified and future research directions are highlighted.
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Affiliation(s)
- Tereza Kunická
- Department of Toxicogenomics, National Institute of Public Health , Prague , Czech Republic
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Hu WQ, Peng CW, Li Y. The expression and significance of P-glycoprotein, lung resistance protein and multidrug resistance-associated protein in gastric cancer. J Exp Clin Cancer Res 2009; 28:144. [PMID: 19930704 PMCID: PMC2788536 DOI: 10.1186/1756-9966-28-144] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2009] [Accepted: 11/24/2009] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND To detect the expression of multidrug resistance molecules P-glycoprotein (P-gp), Lung resistnce protein (LRP) and Multidrug resistance-associated protein (MRP) and analyze the relationship between them and the clinico-pathological features. METHODS The expressions of P-gp, LRP and MRP in formalin-fixed paraffin-embedded tissue sections from 59 gastric cancer patients were determined by a labbelled Streptavidin-Peroxidase (SP) immunohistochemical technique, and the results were analyzed in correlation with clinicopathological data. None of these patients received chemotherapy prior to surgery. RESULTS The positive rates of P-gp, LRP, MRP were 86.4%, 84.7% and 27.1%, respectively. The difference between the positive rate of P-gp and MRP was significant statistically, as well as the difference between the expression of MRP and LRP. No significant difference was observed between P-gp and LRP, but the positively correlation between the expression of P-gp and LRP had been found. No significant correlation between the expression of P-gp, LRP, MRP and the grade of differentiation were observed. The expression of P-gp was correlated with clinical stages positively (r = 0.742), but the difference with the expression of P-gp in different stages was not significant. CONCLUSION The expressions of P-gp, LRP and MRP in patients with gastric cancer without prior chemotherapy are high, indicating that innate drug resistance may exist in gastric cancer.
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Affiliation(s)
- Wen-Qing Hu
- Department of Surgery, Heji Hospital Affiliated to Changzhi Medical College, Changzhi 046011, PR China
| | - Chun-Wei Peng
- Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan 430071, PR China
| | - Yan Li
- Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan 430071, PR China
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Basal cytokeratin expression in relation to biological factors in breast cancer. Hum Pathol 2008; 39:1744-50. [PMID: 18755493 DOI: 10.1016/j.humpath.2008.06.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2008] [Revised: 06/10/2008] [Accepted: 06/11/2008] [Indexed: 11/22/2022]
Abstract
The objective of this study was to determine the predictive impact of several established tumor biological markers and clinicopathological findings for basal-like carcinoma. Expression was determined by immunohistochemistry using antibodies to cytokeratins 5/6, 14, and 17, and the cases were divided into basal-like carcinoma and non basal-like carcinoma. These subgroups were compared in terms of biological markers (HER2, estrogen receptor, progesterone receptor, Ki-67, P-53, and P-glycoprotein) and clinicopathological behavior. Of the 49 basal-like carcinoma cases, 25(51.0%) were P-53-positive, whereas 100 (35.9%) of the 278 non basal-like carcinoma cases were P-53-positive. A high ratio of nuclear Ki-67 expression was detected in 39 (79.6%) of 49 basal-like carcinoma cases and was significantly more common than in non basal-like carcinoma cases (81/278, 29.1%). P-glycoprotein expression was identified in 29 (59.2%) of 49 basal-like carcinomas but only 85 (30.6%) of 278 non basal-like carcinomas. We observed high levels of P-53, Ki-67, and P-glycoprotein, with the reduction or loss of estrogen receptor, progesterone receptor, and HER2 being more obvious, in basal-like carcinomas than in non basal-like carcinomas. Our findings provide further evidence that basal-like carcinoma has different mechanisms of histogenesis.
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Bakos E, Homolya L. Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1). Pflugers Arch 2006; 453:621-41. [PMID: 17187268 DOI: 10.1007/s00424-006-0160-8] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2006] [Revised: 05/10/2006] [Accepted: 05/24/2006] [Indexed: 10/23/2022]
Abstract
MRP1 (ABCC1) is a peculiar member of the ABC transporter superfamily for several aspects. This protein has an unusually broad substrate specificity and is capable of transporting not only a wide variety of neutral hydrophobic compounds, like the MDR1/P-glycoprotein, but also facilitating the extrusion of numerous glutathione, glucuronate, and sulfate conjugates. The transport mechanism of MRP1 is also complex; a composite substrate-binding site permits both cooperativity and competition between various substrates. This versatility and the ubiquitous tissue distribution make this transporter suitable for contributing to various physiological functions, including defense against xenobiotics and endogenous toxic metabolites, leukotriene-mediated inflammatory responses, as well as protection from the toxic effect of oxidative stress. In this paper, we give an overview of the considerable amount of knowledge which has accumulated since the discovery of MRP1 in 1992. We place special emphasis on the structural features essential for function, our recent understanding of the transport mechanism, and the numerous assignments of this transporter.
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Affiliation(s)
- Eva Bakos
- Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary
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Li DQ, Wang ZB, Bai J, Zhao J, Wang Y, Hu K, Du YH. Reversal of multidrug resistance in drug-resistant human gastric cancer cell line SGC7901/VCR by antiprogestin drug mifepristone. World J Gastroenterol 2004; 10:1722-5. [PMID: 15188493 PMCID: PMC4572256 DOI: 10.3748/wjg.v10.i12.1722] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To explore the reversal effect of mifepristone on multidrug resistance (MDR) in drug-resistant human gastric cancer cell line SGC7901/VCR and its mechanisms.
METHODS: Expression of multidrug resistance-associated protein (MRP) was detected using reverse transcription-polymerase chain reaction (RT-PCR). Flow cytometry was used to assay the expression of P-glycoprotein (P-gp), Bcl-2, Bax, and the mean fluorescent intensity of intracellular rhodamine 123 in the cells. Meanwhile, the protein levels of Bcl-2 and Bax were also detected by Western blotting analysis. The sensitivity of cells to the anticancer agent, vincrimycin (VCR), and the intracellular [3H]VCR accumulation were determined by tetrazolium blue (MTT) assay and a liquid scintillation counter, respectively.
RESULTS: Expression of MRP and P-gp in SGC7901/VCR cells was 6.04-and 8.37-fold higher as compared with its parental SGC7901 cells, respectively. After treatment with 1, 5, 10, and 20 μmol/L mifepristone, SGC7901/VCR cells showed a 1.34-, 2.29-, 3.11-, and 3.71-fold increase in the accumulation of intracellular VCR, a known substrate of MRP, and a 1.03-, 2.04-, 3.08-, and 3.68-fold increase in the retention of rhodamine 123, an indicator of P-gp function, respectively. MTT assay revealed that the resistance of SGC7901/VCR cells to VCR was 11.96-fold higher than that of its parental cells. The chemosensitivity of SGC7901/VCR cells to VCR was enhanced by 1.02-, 7.19-, 12.84-, and 21.17-fold after treatment with mifepristone at above-mentioned dose. After 96 h of incubation with mifepristone 10 μmol/L, a concentration close to plasma concentrations achievable in human, the expression of Bcl-2 protein was decreased to (9.21 ± 0.65)% from (25.32 ± 1.44)%, whereas the expression of Bax protein was increased to (19.69 ± 1.13)% from (1.24 ± 0.78)% (P < 0.01). Additionally, the effects of mifepristone on the expression of Bcl-2 and Bax proteins in SGC7901/VCR cells were further demonstrated by Western blotting analysis.
CONCLUSION: Mifepristone has potent reversal effect on MDR in SGC7901/VCR via inhibiting the function of MRP and P-gp, modulating the expression of Bcl-2 and Bax proteins, and enhancing the sensitivity to anticancer agent VCR.
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Affiliation(s)
- Da-Qiang Li
- State Key Laboratory of Ultrasound Engineering in Medicine, Chongqing Medical University, PO Box 153, Chongqing 400016, China. lidaqiang1974@ sohu.com
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Sasaki T, Hankins GR, Helm GA. Major vault protein/lung resistance-related protein (MVP/LRP) expression in nervous system tumors. Brain Tumor Pathol 2003; 19:59-62. [PMID: 12622134 DOI: 10.1007/bf02478928] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Lung resistance-related protein (LRP) was identified as the major vault protein (MVP), the main component of multimeric vault particles. It functions as a transport-associated protein that can be associated with multidrug resistance. In previous studies, expression of MVP/LRP has been documented in tumors of various types. In general, good correlations have been reported for expression of MVP/LRP and decreased sensitivity to chemotherapy and poor prognosis. MVP/LRP expression has been documented in glioblastomas, but its expression in nervous system tumors in general has not been well characterized. Immunohistochemistry using anti-human MVP/LRP antibody (LRP-56) was performed on formalin-fixed, paraffin-embedded archival tissue from 69 primary central nervous system tumors. Expression of MVP/LRP was observed in 81.2% (56/69) of primary nervous system tumors, including astrocytomas (11/13), oligodendrogliomas (1/2), oligoastrocytomas (5/5), ependymoma (1/1), meningiomas (35/45), schwannomas (2/2), and neurofibroma (1/1). Various degrees and distributions of immunoreactivity to MVP/ LRP were observed. Neither the presence nor the degree of immunoreactivity to MVP/LRP showed any correlation with either tumor grade or the presence of brain invasion.
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Affiliation(s)
- Tsutomu Sasaki
- Molecular Neurosurgery Laboratory, Department of Neurosurgery, PO Box 800212, University of Virginia, Charlottesville, VA 22908, USA.
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Yin F, Shi YQ, Chen CP, Qiao TD, Chen BJ, Miao JY, Fan DM. Expression of cDNA fragment encoding MGr1-Ag1 detected by MDR related antibody MGr1 in gastric cancer. Shijie Huaren Xiaohua Zazhi 2003; 11:18-21. [DOI: 10.11569/wcjd.v11.i1.18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the distribution and significance of the possible cDNA fragments encoding MGr1-Ag1 in human gastric cancer.
METHODS: We investigated MGr1-Ag1 expression in gastric cancer using in situ hybridization(ISH) techniques in 42 cases of gastric carcinomas in cryostatic sections collected from Xijing Hospital.
RESULTS: MGr1-Ag1 mRNA was positive in cytoplasm of gastric glandulous epithelia with intensive staining in 50.00% (21/42) cases with gastric cancer, and 71.42% (30/42) cases in paracancerous gastric tissues. Eleven of 16 (68.75%) cases were well differentiated, 8/14 (57.14%) cases were moderately differentiated and 1/10 (10.00%) cases were poorly differentiated. The positive rate of MGr1-Ag1 mRNA in gastric cancer was significantly different from that in paracancerous gastric tissues (71.42%). There was no significant difference in positive rate of MGr1-Ag1 mRNA among normal, paracancerous gastric tissues, well and moderately differentiated tissues, but the positive rate in the poorly differentiated tissues was low, being significantly different from that in well or moderately differentiated tissues.
CONCLUSION: MGr1-Ag1 mRNA is mainly localized in epithelial cells, and the level of its expression is correlated with the tumor differentiation.
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Choi JH, Lim HY, Joo HJ, Kim HS, Yi JW, Kim HC, Cho YK, Kim MW, Lee KB. Expression of multidrug resistance-associated protein1,P-glycoprotein, and thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection. Br J Cancer 2002; 86:1578-85. [PMID: 12085207 PMCID: PMC2746581 DOI: 10.1038/sj.bjc.6600305] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 01/03/2002] [Accepted: 03/20/2002] [Indexed: 02/07/2023] Open
Abstract
Both 5-fluorouracil and doxorubicin are commonly used agents in chemotherapy of gastric cancer in adjuvant setting as well as metastatic disease. In a variety of malignancies, high expression of multidrug resistance-associated protein1 and P-glycoprotein has been associated with resistance to doxorubicin, whereas 5-fluorouracil resistance has correlated with the level of thymidylate synthase expression. We evaluated the expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase using immunohistochemistry in 103 locally advanced gastric cancer patients (stage IB-IV) who underwent 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection and investigated the association between their expression and clinicopathologic characteristics including prognosis of the patients. While high expression (> or =5% of tumour cells positive) of multidrug resistance-associated protein1 and P-glycoprotein was observed in 70 patients (68%) and 42 patients (41%), respectively, 65 patients (63%) had primary tumours with high expression (> or =25% of tumour cells positive) of thymidylate synthase. There was a significant association between multidrug resistance-associated protein1 and P-glycoprotein expression (P<0.0001) as well as P-glycoprotein and thymidylate synthase expression (P<0.0001). High multidrug resistance-associated protein1 and P-glycoprotein expressions were associated with well and moderately differentiated histology (P<0.0001 and P=0.03, respectively) and intestinal type (P<0.0001 and P=0.009, respectively). High multidrug resistance-associated protein1 expression correlated with lymph node metastasis (P=0.037), advanced stage (P=0.015), and older age (P=0.021). Five-year disease-free survival and overall survival of total patients were 55.2% and 56.2%, respectively, with a median follow-up of 68 months. There were no significant differences in disease-free survival and overall survival according to the expression of multidrug resistance-associated protein1 (P=0.902 and P=0.975, respectively), P-glycoprotein (P=0.987 and P=0.955, respectively), and thymidylate synthase (P=0.604 and P=0.802, respectively). Concurrent high expression of these proteins (high multidrug resistance-associated protein1/P-glycoprotein, high multidrug resistance-associated protein1/thymidylate synthase, high P-glycoprotein/thymidylate synthase) did not correlate with disease-free survival or overall survival. Even high expression of all three proteins was not associated with poor disease-free survival (P=0.919) and overall survival (P=0.852). In conclusion, high expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase did not predict poor prognosis of gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy. A larger study including patients treated with surgical resection alone would be necessary.
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Affiliation(s)
- J-H Choi
- Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, 442-721, Korea (Rep.)
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Soini Y, Järvinen K, Kaarteenaho-Wiik R, Kinnula V. The expression of P-glycoprotein and multidrug resistance proteins 1 and 2 (MRP1 and MRP2) in human malignant mesothelioma. Ann Oncol 2001; 12:1239-45. [PMID: 11697834 DOI: 10.1023/a:1012292230480] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Malignant mesothelioma is a malignancy with a primary resistance to chemo- and radiotherapies for reasons which are still unclear. Multidrug resistance proteins might explain the observed resistance, but no studies have assessed their expression in mesothelioma. PATIENTS AND METHODS Immunohistochemical expression of P-glycoprotein (P-gp), and the multidrug resistance proteins 1 and 2 (MRP1 and MRP2) were investigated in 36 cases of malignant mesothelioma and in samples from normal mesothelium. RESULTS P-gp immunopositivity was found in 61%, MRP1 immunopositivity in 58% and MRP2 positivity in 33% of the cases. Normal mesothelium did not express these multidrug-resistant proteins. There was a significant association between P-gp and MRP2 (P = 0.022) expression. No or weak P-gp, MRP1 or MRP2 immunostaining was significantly more frequent in sarcomatoid mesothelimas than in epithelial or biphasic mesotheliomas (P = 0.031, P = 0.034 and P = 0.024, respectively). There was no significant association between patient survival and expression of the multidrug-resistant proteins. CONCLUSIONS The results show that P-gp, MRP1 and MRP2 are induced and expressed in malignant mesothelial cells. Regardless of their expression no association with survival of the patients was seen, suggesting that the primary resistance of malignant mesotheliomas is not solely dependent on their expression or function.
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Affiliation(s)
- Y Soini
- Department of Pathology, University of Oulu, Finland.
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