Home About us Contact
|
Home About us Contact | ||
|
|
||
I Expression (i + expression)
Kinds of I Expression Selected AbstractsDifferent effects of pioglitazone and rosiglitazone on lipid metabolism in mouse cultured liver explantsDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2010Louiza Djaouti Abstract Background Pioglitazone (PIO) and rosiglitazone (ROSI) are widely used as oral antidiabetic agents for treatment of type 2 diabetes. Although these medications exert similar effects on blood glucose, recent clinical studies indicated that PIO has a more pronounced beneficial effect on lipid parameters than ROSI. In order to get further insight into the lipid effects of both drugs, we tested whether PIO, compared to ROSI, could exert direct effects on lipid liver metabolism in relation with plasma lipids. Methods We performed in vitro studies using mice liver slices incubated 21 h either with ROSI (1 µmol/L) or PIO (7.5 µmol/L). Results We showed that both glitazones slightly reduced HMG-CoA reductase mRNA levels at the same degree but only PIO reduced intracellular cholesterol content, suggesting an alteration of cholesterol uptake rather than an inhibition of cholesterol biosynthesis. This concept was supported by the reduction of scavenger receptor class B type I expression, hepatic lipase activity and high-density lipoprotein cholesterol uptake in PIO-treated liver explants. Conversely, hepatic lipase mRNA levels were increased 3.5-fold. ROSI, but not PIO, induced acetyl-CoA carboxylase and fatty acid synthase gene expression and increased apoB secretion suggesting a stimulation of lipogenesis. Concurrently, peroxisome proliferator-activated receptor-, mRNA levels were induced by ROSI and not significantly changed by PIO. Besides, PIO appeared to be a more potent activator of AMP-Activated Protein Kinase than ROSI. Conclusions PIO and ROSI exert specific direct effects on liver and extrapolating these data to humans could explain the significant improvements in plasma lipids observed in diabetic patients treated with PIO. Copyright © 2010 John Wiley & Sons, Ltd. [source] Chronic erythropoietin treatment affects different molecular pathways of diabetic cardiomyopathy in mouseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 9 2009N. Shushakova Abstract Background, Recent studies in mice experimental models with acute ischaemic injury revealed that erythropoietin (EPO) has numerous tissue-protective effects in the heart, brain and kidneys. We therefore explored the tissue-protective properties of chronic EPO treatment in an experimental model of the db/db mouse with diabetic heart injury. Material and methods, We randomly treated 11 db/db mice with placebo (saline), 0·4 ,g of the continuous erythropoietin receptor activator (CERA) per week (n = 11) or 1·2 ,g CERA per week (n = 11) for 14 weeks, and analysed cardiac tissue. The lower CERA dose was a non-haematologically effective dose, whereas the second increased the haematocrit. Results, Compared with mice in the placebo group, CERA-treated mice had a reduction in TGF-,1 and collagen I expression in cardiac tissue (P < 0·01 vs. higher dose CERA). In addition, an increased expression of the pro-survival intracellular pathway p-AKT was observed (P < 0·05 vs. higher dose CERA). The values for the lower C.E.R.A had an intermediate nonsignificant effect. Furthermore, we were able to show that atrial natriuretic peptide (ANP) expression was increased in both CERA groups. Conclusions, Chronic treatment with CERA protects cardiac tissue in diabetic animals, i.e. it inhibits molecular pathways of cardiac fibrosis, and the effects are dose-dependent. [source] HIV-1: a molecular toolkit for analysis of major histomcompatibility complex class I expressionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 8 2000Howcroft No abstract is available for this article. [source] DNA supercoiling in Escherichia coli is under tight and subtle homeostatic control, involving gene-expression and metabolic regulation of both topoisomerase I and DNA gyraseFEBS JOURNAL, Issue 6 2002Jacky L. Snoep DNA of prokaryotes is in a nonequilibrium structural state, characterized as ,active' DNA supercoiling. Alterations in this state affect many life processes and a homeostatic control of DNA supercoiling has been suggested [Menzel, R. & Gellert, M. (1983) Cell34, 105,113]. We here report on a new method for quantifying homeostatic control of the high-energy state of in vivo DNA. The method involves making small perturbation in the expression of topoisomerase I, and measuring the effect on DNA supercoiling of a reporter plasmid and on the expression of DNA gyrase. In a separate set of experiments the expression of DNA gyrase was manipulated and the control on DNA supercoiling and topoisomerase I expression was measured [part of these latter experiments has been published in Jensen, P.R., van der Weijden, C.C., Jensen, L.B., Westerhoff, H.V. & Snoep, J.L. (1999) Eur. J. Biochem.266, 865,877]. Of the two regulatory mechanisms via which homeostasis is,conferred, regulation of enzyme activity or regulation of enzyme expression, we quantified the first to be responsible for 72% and the latter for 28%. The gene expression regulation could be dissected to DNA gyrase (21%) and to topoisomerase I (7%). On a scale from 0 (no homeostatic control) to 1 (full homeostatic control) we quantified the homeostatic control of DNA supercoiling at 0.87. A 10% manipulation of either topoisomerase I or DNA gyrase activity results in a 1.3% change of DNA supercoiling only. We conclude that the homeostatic regulation of the nonequilibrium DNA structure in wild-type Escherichia coli is almost complete and subtle (i.e. involving at least three regulatory mechanisms). [source] Characterization of a Novel Fiber Composite Material for Mechanotransduction Research of Fibrous Connective TissuesADVANCED FUNCTIONAL MATERIALS, Issue 5 2010Hazel R. C. Screen Abstract Mechanotransduction is the fundamental process by which cells detect and respond to their mechanical environment, and is critical for tissue homeostasis. Understanding mechanotransduction mechanisms will provide insights into disease processes and injuries, and may support novel tissue engineering research. Although there has been extensive research in mechanotransduction, many pathways remain unclear, due to the complexity of the signaling mechanisms and loading environments involved. This study describes the development of a novel hydrogel-based fiber composite material for investigating mechanotransduction in fibrous tissues. By encapsulating poly(2-hydroxyethyl methacrylate) rods in a bulk poly(ethylene glycol) matrix, it aims to create a micromechanical environment more representative of that seen in vivo. Results demonstrated that collagen-coated rods enable localized cell attachment, and cells are successfully cultured for one week within the composite. Mechanical analysis of the composite indicates that gross mechanical properties and local strain environments could be manipulated by altering the fabrication process. Allowing diffusion between the rods and surrounding matrix creates an interpenetrating network whereby the relationships between shear and tension are altered. Increasing diffusion enhances the shear bond strength between rods and matrix and the levels of local tension along the rods. Preliminary investigation into fibroblast mechanotransduction illustrates that the fiber composite upregulates collagen I expression, the main protein in fibrous tissues, in response to cyclic tensile strains when compared to less complex 2D and 3D environments. In summary, the ability to create and manipulate a strain environment surrounding the fibers, where combined tensile and shear forces uniquely impact cell functions, is demonstrated. [source] The KIR and CD94/NKG2 families of molecules in the rhesus monkeyIMMUNOLOGICAL REVIEWS, Issue 1 2001Michelle L. LaBonte Summary: Natural killer (NK) cells and a subset of T cells express families of receptors that are capable of detecting major histocompatibility complex (MHC) class I expression on the surface of cells. Molecules of the killer cell immunoglobulin-like receptor (KIR) family bind directly to MHC class I, while those of the CD94/NKG2 family recognize MHC class I signal sequences bound to HLA-E. Both the KIR and CD94/NKG2 families are composed of activating and inhibitory molecules that serve to regulate the function of NK cells as a result of their MHC class I recognition. Here we review the recently described KIR and CD94/NKG2 family members in the rhesus monkey. [source] Human cytomegalovirus and natural killer-mediated surveillance of HLA class I expression: a paradigm of host,pathogen adaptationIMMUNOLOGICAL REVIEWS, Issue 1 2001Miguel López-Botet Summary: Among various strategies to evade the host immune response, some viruses like human cytomegalovirus (HCMV) interfere with surface MHC class I expression and antigen presentation to T lymphocytes. The ability of natural killer (NK) cells to detect MHC class I molecules through inhibitory receptors can be envisaged as an adaptation of the immune system for responding to such pathological alterations. To fulfil that role, rodents use members of the Ly49 C-type lectin superfamily, whereas primates employ killer immunoglobulin-like receptors and the immunoglobulin-like transcript 2/leucocyte immunoglobulin-like receptor-1 receptor. CD94/NKG2 lectin-like heterodimers represent the most conserved receptor system for MHC class I molecules; by interacting with human HLA-E or murine Qa-1b, CD94/NKG2A inhibitory receptors broadly probe the biosynthesis pathway of other class I molecules. Reciprocally, HCMV has developed mechanisms to evade the NK response while modulating HLA class Ia expression. The ability of HCMV to maintain surface levels of HLA-E and to express an HLA class I surrogate (UL18) are herein discussed in the context of the interplay with human NKR systems. This work was supported by grants FIS 00/0181 and SAF98-0006. We thank Dr A. Angulo for helpful discussion. [source] Cytotoxic T lymphocytes recognize and lyse chondrocytes under inflammatory, but not non-inflammatory conditionsIMMUNOLOGY, Issue 1 2003E. Suzanne Cohen Summary The human major histocompatibility complex (MHC) class I allele HLA-B27 is strongly associated with seronegative spondyloarthropathies including ankylosing spondylitis and reactive arthritis. Although of unknown aetiology, one hypothesis suggests that a cytotoxic T cell (CTL) response against a self-antigen at sites of inflammation, such as entheses or joints may be involved. The chondrocyte is one of the major specialized cell types found both in articular cartilage and cartilaginous entheses and therefore is a possible source of such an antigen. CTL recognition of these cells is a potential mechanism for inflammation and cartilage damage, both through direct lysis of chondrocytes and the secretion of pro-inflammatory cytokines such as tumour necrosis factor and interferon-, (IFN-,). We test the feasibility of this hypothesis by examining the ability of chondrocytes to present antigen to CTL in vitro. Chondrocytes isolated from the ribcages of mice did not constitutively express detectable levels of MHC class I by fluorescence-activated cell sorting analysis. In addition, they were resistant to lysis by alloreactive and influenza A virus nucleoprotein (NP)-specific CTL. However, treatment of chondrocytes with IFN-, up-regulated MHC class I expression and rendered the cells susceptible to lysis by CTL. Similarly, IFN-,-treated chondrocytes infected with influenza A virus were recognized by NP-specific CTL, though with variable efficiency. Thus, we suggest that under certain circumstances CTL-mediated lysis of chondrocytes is potentially a potent mechanism for cartilage damage in vivo, but that low levels of MHC class I on healthy chondrocytes protects from immune recognition in health. [source] ABCG2 overexpression in colon cancer cells resistant to SN38 and in irinotecan-treated metastasesINTERNATIONAL JOURNAL OF CANCER, Issue 6 2004Laurent Candeil Abstract Overcoming drug resistance has become an important issue in cancer chemotherapy. Among all known mechanisms that confer resistance, active efflux of chemotherapeutic agents by proteins from the ATP-binding cassette family has been extensively reported. The aim of the present study was to determine the involvement of ABCG2 in resistance to SN38 (the active metabolite of irinotecan) in colorectal cancer. By progressive exposure to increasing concentrations of SN38, we isolated 2 resistant clones from the human colon carcinoma cell line HCT116. These clones were 6- and 53-fold more resistant to SN38 than the HCT116-derived sensitive clone. Topoisomerase I expression was unchanged in our resistant variants. The highest resistance level correlated with an ABCG2 amplification. This overexpression was associated with a marked decrease in the intracellular accumulation of SN38. The inhibition of ABCG2 function by Ko143 demonstrated that enhanced drug efflux from resistant cells was mediated by the activity of ABCG2 protein and confirmed that ABCG2 is directly involved in acquired resistance to SN38. Furthermore, we show, for the first time in clinical samples, that the ABCG2 mRNA content in hepatic metastases is higher after an irinotecan-based chemotherapy than in irinotecan-naive metastases. In conclusion, this study supports the potential involvement of ABCG2 in the development of irinotecan resistance in vivo. © 2004 Wiley-Liss, Inc. [source] Reduction of major histocompatibility complex class I expression on bladder carcinoma following tumor antigen-pulsed dendritic cell vaccine: Implications for immunoresistance in therapyINTERNATIONAL JOURNAL OF UROLOGY, Issue 7 2010Mengqiang Li Objectives: To clarify the relationship between a decreased major histocompatibility complex class I (MHC-I) expression on bladder tumors and decreased immunological efficacy of tumor antigen-pulsed dendritic cell vaccine in a rat bladder carcinoma model induced by N-methyl-N-nitrosourea irrigation. Methods: Enzyme-linked immunosorbent assay was used to evaluate interferon-gamma concentration in the serum and colorimetric lactate dehydrogenase release assay in vitro was used to test the cytotoxicity capability of T lymphocytes. MHC-I expression on tumor cells was detected by flow cytometry and analyzed with CellQuest software. Results: The tumor antigen sensitized dendritic cell vaccine group showed decreased hyperplastic formations, lower pathological stages in rat bladders and more potent cytotoxicity activity (P < 0.001) than the dendritic cell vaccine group. Additionally, immunization with pulsed dendritic cell vaccine induced higher specific cytokine production of interferon-gamma. Nevertheless, a decreased MHC-I expression on bladder tumors was tested after immunotherapy by pulsed dendritic cell vaccine on week 15. As expected, the cytotoxic activity of T lymphocytes from rats on tumor cells with low MHC-I expression was also decreased to 19.70 ± 4.82% as compared with tumor cells with high MHC-I (52.10 ± 8.66%, P = 0.005). Conclusions: Tumor antigen sensitized dendritic cell vaccine has beneficial activity on N-methyl-N-nitrosourea-induced bladder cancer in situ in rats, but therapeutic responses are accompanied by decreased MHC-I expression on tumors, possibly suggesting poor long-term therapeutic outcomes. [source] Enhanced type I interferon signaling and recruitment of chemokine receptor CXCR3-expressing lymphocytes into the skin following treatment with the TLR7-agonist imiquimodJOURNAL OF CUTANEOUS PATHOLOGY, Issue 4 2005Joerg Wenzel Introduction:, Imiquimod (AldaraÔ) is an immune response modifier approved for the topical treatment of external genital and perianal warts which can mediate regression of several cutaneous malignancies [basal cell carcinoma (BCC), Bowen's disease, actinic keratosis, and metastasis of malignant melanoma]. Recently, it was discovered that imiquimod acts through the toll-like receptor (TLR) 7. We hypothesize that TLR7-signaling strongly induces the production of interferon (IFN) ,, which is able to enhance Th1-mediated cellular antiviral and antitumor immunity. Patients and methods:, In the present study we analyzed the expression of MxA, a protein specifically induced by type I IFNs during topical imiquimod treatment in several patients suffering from different cutaneous malignancies (BCC, cutaneous metastasis of melanoma, and breast cancer), and characterized the inflammatory infiltrate, along with the expression of chemokine receptor CXCR3, by immunohistochemistry. Results:, Treatment with the TLR7-agonist imiquimod induced a significant lesional lymphocytic inflammation, associated with strong expression of MxA, indicating the induction of type I IFN signaling. The extent of lesional MxA staining closely correlated with the number of infiltrating T lymphocytes and the expression of the chemokine receptor CXCR3, characteristic for Th1-biased immune responses. Discussion:, Our in vivo results suggest an important role for TLR7-induced production of type I IFN, which links innate and adaptive immunity and promotes specific Th1-biased cellular immune response capable of eliminating cutaneous malignancies. MxA appears to be a valuable parameter to demonstrate IFN-type I expression in imiquimod therapy. [source] Peroxiredoxin I protects gastric mucosa from oxidative injury induced by H. pylori infectionJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 4 2008Daisuke Sato Abstract Background and Aim:, Helicobacter pylori (H. pylori) infection enhances the production of reactive oxygen species and peroxynitrite, thereby resulting in oxidative tissue damage. In this study, we examined the role of peroxiredoxin I (Prx I), a stress-induced antioxidant enzyme, in protecting gastric mucosa from H. pylori -induced gastric mucosal injury. Methods:, Wild type (Prx I+/+) and Prx I-deficient type (Prx I,/,) mice were maintained for 2 to 12 months with or without infection of H. pylori, Sydney strain-1. Gastric mucosal expression of Prx I was assessed by immunoblot analysis and immunohistochemistry. The degree of gastritis was evaluated by the updated Sydney system and by mucosal levels of inflammatory cytokines (MIP-2, IL-1,, and TNF-,). Oxidative DNA injury and apoptosis were analyzed by mucosal level of 8-hydroxy-2,-deoxyguanosine, and the number of apoptotic cells stained with a single-stranded DNA antibody, respectively. Results:,H. pylori infection upregulated gastric mucosal Prx I expression in the Prx I+/+ but not the Prx I,/, mice. H. pylori infection also induced more severe gastritis and a more prominent increase in MIP level, more marked oxidative DNA injury, and apoptosis in the Prx I,/, than the Prx I+/+ mice. In the absence of H. pylori infection, no changes were demonstrated in gastric mucosa in either the Prx I+/+ or the Prx I,/, mice. Conclusion:, These data suggest that H. pylori infection upregulates gastric mucosal Prx I expression, and further, that Prx I plays an important role in gastric mucosal protection against oxidative injury induced by H. pylori infection. [source] Developmental pattern of synapsin I expression in mouse somatosensory cortexJOURNAL OF NEUROCHEMISTRY, Issue 2003M. Liguz-Lecznar Synapsin I is a member of a synapsin family which are phosphoproteins associated with synaptic vesicles. It is thought to be involved in neuronal development and plasticity. We have shown the existence of two distinct patterns of synapsin I immunostaining in adult mice primary somatosensory cortex (SI). The first consisted of small, dispersed immunoreactive puncta in neuropil. The second is confined to the perikarya and proximal dendrites of the specific class of neurons present in layers IV and VI of SI, probably reflecting the expression of a novel isoform of synapsin I. The aim of this study was to examine the developmental pattern of synapsin I expression in mouse SI cortex. Using immunocytochemistry and Western blot analysis we found that this unique pattern of synapsin I expression in SI appeared between the 2nd and 3rd postnatal week and probably coincides with the increase in the number of synaptic contacts and the development of inhibitory circuits in SI. Acknowledgement: Supported by KBN grant no. 3P04C 008 22. [source] Changes in N -linked sugar chain patterns induced by moderate-to-high expression of the galactosyltransferase I gene in a brain-derived cell line, CG4JOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2005Krishnakumar N. Menon Abstract Oligosaccharides with biantennae and bisecting N -acetyl glucosamine (GlcNAc) residues attached to the mannose in the ,1-4 trimannosyl core (BA2) are enriched in the brain and considered brain-type sugar chains. We investigated the significance of the interplay between galactosyltransferase I (GalTase I) and BA2 formation in a brain-derived cell line, CG4. Increased GalTase expression in different glial- and neuronal-derived cell lines was accompanied by decreased or undetectable levels of BA2, depending on the level of GalTase expression. Forceful expression of GalTase I in CG4 cells expressing high levels of BA2 and low GalTase activity significantly reduced BA2 levels. In addition, a sixfold increase in an abnormal sugar chain A1(6)G1Fo and a moderate increase in A2G2Fo(6)F were evident. The increased levels of A1(6)G1Fo indicate a diversion or abrogation of the N -linked sugar chain biosynthetic pathway from normal. The accumulation of A1(6)G1Fo and increased A2G2Fo(6)F levels were accompanied by decreased levels of the high mannose-type sugar chains, M5A, M6B, M8A, and M9A. Increased GalTase I expression also led to stunted growth and abnormal morphology of CG4 cells, with increased mortality. Even moderate overexpression of GalTase I thus disrupts the normal biosynthetic pathway of N -linked sugar chains, and high overexpression is fatal to CG4 cells. © 2005 Wiley-Liss, Inc. [source] Multilayer tendon slices seeded with bone marrow stromal cells: A novel composite for tendon engineeringJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 7 2009Hiromichi Omae Abstract The ideal scaffold for tendon engineering would possess the basic structure of the tendon, native extracellular matrix, and capability of cell seeding. The purpose of this study was to assess the tissue engineering potential of a novel composite consisting of a decellularized multilayer sliced tendon (MST) scaffold seeded with bone marrow stromal cells (BMSC). BMSC and infraspinatus tendons were harvested from 20 dogs. The tendons were sectioned in longitudinal slices with a thickness of 50 µm. The slices were decellularized, seeded with BMSC, and then bundled into one composite. The composite was incubated in culture media for 14 days. The resulting BMSC-seeded MST was evaluated by qRT-PCR and histology. The BMSC viability was assessed by a fluorescent tracking marker. Histology showed that the seeded cells aligned between the collagen fibers of the tendon slices. Analysis by qRT-PCR showed higher tenomodulin and MMP13 expression and lower collagen type I expression in the composite than in the BMSC before seeding. BMSC labeled with fluorescent tracking marker were observed in the composite after culture. Mechanical testing showed no differences between scaffolds with or without BMSC. BMSC can survive in a MST scaffold. The increased tenomodulin expression suggests that BMSC might express a tendon phenotype in this environment. This new composite might be useful as a model of tendon tissue engineering. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 937,942, 2009 [source] IL-4,/, mice with lethal Mesocestoides corti infections , reduced Th2 cytokines and alternatively activated macrophagesPARASITE IMMUNOLOGY, Issue 12 2009A. E. O'CONNELL Summary Protection against Mesocestoides corti, a cestode that invades vital organs, is dependent on the production of IL-4, as IL-4,/, mice were found to have higher parasite burdens when compared with wild-type mice. The goal of this study was to investigate the role of IL-4 in immunity to M. corti, focusing on the immunological profile and on potential mediators of pathology. IL-4,/, mice infected with M. corti showed 100% mortality by 32 days, whereas wild-type mice survived for approximately 1 year. Parasite burdens were significantly increased in the liver, peritoneal, and thoracic cavities of IL-4,/, mice, associated with impaired recruitment of inflammatory cells and a reduction in monocytes and macrophages. IL-5 production by splenocytes and expression in liver tissue was decreased in infected IL-4,/, mice compared with wild-type mice. In contrast, IL-4,/, mice produced increased amounts of IFN, and TNF,. Alternatively activated macrophages were a major feature of liver granulomas in wild-type mice evidenced by Arginase I expression, while livers from infected IL-4,/, mice showed impaired alternative macrophage activation without increased classical macrophage activation. Thus, lethality during M. corti infection of IL-4,/, mice is associated with decreased Th2 cytokines, increased Th1 cytokines and impairment of alternatively activated macrophages. [source] The role of synaptotagmin I C2A calcium-binding domain in synaptic vesicle clustering during synapse formationTHE JOURNAL OF PHYSIOLOGY, Issue 1 2007Peter Gardzinski Synaptic vesicles aggregate at the presynaptic terminal during synapse formation via mechanisms that are poorly understood. Here we have investigated the role of the putative calcium sensor synaptotagmin I in vesicle aggregation during the formation of soma,soma synapses between identified partner cells using a simple in vitro synapse model in the mollusc Lymnaea stagnalis. Immunocytochemistry, optical imaging and electrophysiological recording techniques were used to monitor synapse formation and vesicle localization. Within 6 h, contact between appropriate synaptic partner cells up-regulated global synaptotagmin I expression, and induced a localized aggregation of synaptotagmin I at the contact site. Cell contacts between non-synaptic partner cells did not affect synaptotagmin I expression. Application of an human immunodeficiency virus type-1 transactivator (HIV-1 TAT)-tagged peptide corresponding to loop 3 of the synaptotagmin I C2A domain prevented synaptic vesicle aggregation and synapse formation. By contrast, a TAT-tagged peptide containing the calcium-binding motif of the C2B domain did not affect synaptic vesicle aggregation or synapse formation. Calcium imaging with Fura-2 demonstrated that TAT,C2 peptides did not alter either basal or evoked intracellular calcium levels. These results demonstrate that contact with an appropriate target cell is necessary to initiate synaptic vesicle aggregation during nascent synapse formation and that the initial aggregation of synaptic vesicles is dependent on loop 3 of the C2A domain of synaptotagmin I. [source] CPT-11 May Provide Therapeutic Efficacy for Esophageal Squamous Cell Cancer and the Effects Correlate with the Level of DNA Topoisomerase I ProteinCANCER SCIENCE, Issue 12 2001Yasuaki Nakajima CPT-11 is a potent anti-cancer drug and a specific inhibitor of DNA topoisomerase I (Topo I). In this study, we aim to evaluate the effects of CPT-11 on esophageal squamous cell cancers (ESCC) and to determine the correlation between the effects and the levels of Topo I expression. We examined the growth-inhibitory effect caused by SN-38, an active metabolite of CPT-11, in 14 human ESCC cell lines established from 10 primary and 4 metastatic lesions. CPT-11 was considered effective against 5 cell lines from primary lesions and one from metastatic lesions, and thus may show therapeutic efficacy against both primary and metastatic ESCC tumors. Although Topo I mRNA levels in these 14 ESCC cell lines, as quantitated by northern blot analysis, showed no correlation with the IC50 values, Topo I protein levels, as quantitated by western blot analysis, showed an inverse correlation with the IC50 values. Topo I protein levels could be an indicator of sensitivity to CPT-11. We also determined Topo I protein levels in 40 ESCC tumors and matched normal mucosae. Thirty-four tumors showed 1.2-22.3-fold increases in Topo I levels. Two patients receiving pre-operative chemotherapy and one receiving radiotherapy exhibited increased Topo I protein levels in their tumor lesions. It appeared that CPT-11 could provide selective therapeutic efficacy against ESCC tumors. CPT-11 may be effective for the treatment of metastatic ESCC tumors and as a second-line anti-cancer drug for ESCC. [source] | ||||||||||||||||||||||||||||