Promising Agent (promising + agent)

Distribution by Scientific Domains


Selected Abstracts


BSc2118 is a novel proteasome inhibitor with activity against multiple myeloma

EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2010
Jan Sterz
Abstract Objectives:, The ubiquitin,proteasome system emerged as a new therapeutic target in cancer treatment. The purpose of this study was to elucidate the effects of the novel proteasome inhibitor BSc2118 on t(4;14) positive and negative multiple myeloma (MM) cells and normal peripheral blood mononuclear cells (PBMNC). Methods:, Human MM cell lines OPM-2, RPMI-8226, and U266 and primary MM cells from bone marrow aspirates were exposed to BSc2118. Cytotoxicity levels were evaluated using the MTT-test. BSc2118-induced apoptosis was analyzed by annexin-V assay. Further methods used included proteasomal activity determination, cell cycle analysis, western blot, and transcription factor assays. Results:, In OPM-2, RPMI-8226, U266 cell lines and primary MM cells, BSc2118 caused dose-dependent growth inhibitory effects. After 48 h, dose-dependent apoptosis occurred both in cell lines and primary myeloma cells irrespective of t(4;14). A significant G2-M cell cycle arrest occurred after 24 h. Furthermore, we observed a marked inhibition of intracellular proteasome activity, an increase in intracellular p21 levels, and an inhibition of NF-,B activation. The toxicity against PBMNC remained low, suggesting a broad therapeutic range of this agent. Conclusion:, Taken together, BSc2118 shows significant antimyeloma activity and may be considered as a promising agent in cancer drug development. [source]


Noggin blocks invasive growth of murine B16-F1 melanoma cells in the optic cup of the chick embryo,,

INTERNATIONAL JOURNAL OF CANCER, Issue 3 2008
Christian Busch
Abstract Melanoma cells originate from the neural crest and are characterized by high migratory potential and invasive growth. After transplantation into the neural tube of the chick embryo, melanoma cells spontaneously emigrate along the neural crest pathways without tumor formation or malignant growth. This emigration depends on the constitutive over-expression of bone morphogenetic protein-2 (BMP-2) and can be ablated by the BMP-antagonist noggin. When transplanted into the embryonic optic cup, melanoma cells invade the host tissue and form malignant tumors. Here, we asked if the invasive growth of melanoma cells in the optic cup could be influenced by BMP-2 or noggin. Mouse B16-F1 cells were grown as aggregates, treated with BMP-2 or noggin during aggregation and transplanted into the optic cup of 3-day chick embryos. After 3 days of subsequent incubation, embryos were evaluated for melanoma cell invasiveness. Immunohistochemical examination revealed that untreated and BMP-2-treated melanoma cells had grown malignantly into the host tissue. However, noggin pretreatment of the aggregates had blocked melanoma cell invasiveness and tumor formation. We conclude that invasive growth of melanoma cells in vivo is BMP-dependent and can be ablated by noggin, thus rendering noggin a promising agent for the treatment of BMP-over-expressing melanoma. 2007 Wiley-Liss, Inc. [source]


Diosmetin Induces Human Osteoblastic Differentiation Through the Protein Kinase C/p38 and Extracellular Signal-Regulated Kinase 1/2 Pathway,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2008
Ya-Ling Hsu
Abstract Introduction: The survival of osteoblasts is one of the determinants of the development of osteoporosis. This study is the first to investigate the osteoblastic differentiation induced by diosmetin, a flavonoid derivative, in osteoblastic cell lines MG-63, hFOB, and MC3T3-E1 and bone marrow stroma cell line M2-10B4. Materials and Methods: Osteoblastic differentiation was determined by assaying alkaline phosphatase (ALP) activity and mineralization degree and measuring various osteoblast-related markers using ELISA. Expression and phosphorylation of Runt-related transcription factor 2 (Runx2), protein kinase C, (PKC,), extracellular signal-regulated kinase (ERK), p38, and c- jun -N-terminal kinase (JNK) was assessed by immunoblot. Rac1 activity was determined by immunoprecipitation, and Runx2 activity was assessed by EMSA. Genetic inhibition was performed by small hairpin RNA plasmids or small interfering RNA (siRNA) transfection. Results: Diosmetin exhibited an effect on osteoblastic maturation and differentiation by means of ALP activity, osteocalcin, osteopontin, and type I collagen production, as well as Runx2 upregulation. Induction of differentiation by diosmetin was associated with increased PKC, phosphorylation and the activations of Rac1 and p38 and ERK1/2 kinases. Blocking PKC, by siRNA inhibition significantly decreased osteoblastic differentiation by inhibiting Rac1 activation and subsequently attenuating the phosphorylation of p38 and ERK1/2. In addition, blocking p38 and ERK1/2 by siRNA transfection also suppressed diosmetin-induced cell differentiation. Conclusions: In this study, we show that diosmetin induced osteoblastic differentiation through the PKC,-Rac1-MEK3/6-p38 and PKC,-Rac1-MEK1/2- ERK1/2-Runx2 pathways and that it is a promising agent for treating osteoporosis. [source]


Preparation of a technetium-99m SPECT agent for imaging the sigma-2 receptor status of solid tumors

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 13 2001
Robert H. Mach
Abstract The synthesis and in vitro binding of a novel 99mTc-labeled radiotracer for imaging the sigma-2 (,2) receptor status of breast tumors is described. Structural characterization and in vitro binding studies were conducted using the corresponding rhenium surrogate, Re-2. X-ray crystallographic studies revealed that the complexation reaction gave exclusively the syn isomer. In vitro binding studies indicated that this complex has a high affinity for ,2 (Ki=13.7 nM) versus ,1 receptors (Ki=1125 nM). These data indicate that [99mTc]2 may be a promising agent for imaging the ,2 receptor status of tumors in vivo with the functional imaging technique, single photon emission computed tomography (SPECT). Copyright 2001 John Wiley & Sons, Ltd. [source]


Anticancer effects of zoledronic acid against human osteosarcoma cells

JOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2006
B. Kubista
Abstract Based on neoadjuvant chemotherapy, the prognosis of osteosarcoma patients has improved dramatically. However, due to therapy resistance in patient subgroups, the development of new treatment strategies is still of utmost importance. The aim of our study was to test the effects of the nitrogen-containing bisphosphonate zoledronic acid (ZOL) on osteosarcoma cell lines (N,=,9). Exposure to ZOL at low micromolar concentrations induced a dose- and time-dependent block of DNA synthesis and cell cycle progression followed by microfilament breakdown and apoptosis induction. The ZOL-induced cell cycle accumulation in S phase was accompanied by significant changes in the expression of cyclins and cyclin-dependent kinase inhibitors with a prominent loss of cyclin E and D1. ZOL not only inhibited growth but also migration of osteosarcoma cells. The mevalonate pathway intermediary geranyl-geraniol (GGOH) but not farnesol (FOH) significantly inhibited the anticancer effects of ZOL against osteosarcoma cells. Correspondingly, ZOL sensitivity correlated with the blockade of protein geranylgeranylation indicated by unprenylated Rap1. Overexpression of even high levels of P-glycoprotein, as frequently present in therapy-resistant osteosarcomas, did not impair the anticancer activity of ZOL. Summarizing, our data suggest that ZOL, which selectively accumulates in the bone, represents a promising agent to improve osteosarcoma therapy. 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source]


Recombinant Human Lactoferrin is Effective in the Treatment of Helicobacter felis -infected Mice

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2000
E. J. DIAL
Recombinant human lactoferrin possesses in-vitro antibiotic and anti-inflammatory activity similar to the native form. It was tested for in-vivo activity in mice infected with the gastritis-inducing bacterium Helicobacter felis. A two-week course of treatment with lactoferrin was sufficient to partially reverse both infection-induced gastritis and the infection rate, and fully reverse gastric surface hydro-phobicity changes. A comparison of lactoferrin with amoxicillin and standard triple therapy revealed no differences in infection rate. These results show that recombinant human lactoferrin is effective in a mouse model of Helicobacter infection, and support further testing of this promising agent for this application. [source]


USE OF HIGH-DOSE GADOLINIUM AS CONTRAST MEDIA TO AVOID RADIOCONTRAST MEDIA-INDUCED NEPHROPATHY

JOURNAL OF RENAL CARE, Issue 1 2009
Prajej Ruangkanchanasetr
SUMMARY Patients at risk for radiocontrast media-induced nephropathy (RCIN) with suspected peripheral vascular disease were evaluated with high-dose (0.4 mmol/kg) gadolinium-based (Gd) contrast angiography (AG). The patients who were considered susceptible to RCIN were defined by having one or more of the following: (1) pre-existing serum creatinine (SCr) >124 ,mol/l, (2) diabetes mellitus and (3) age >60 years. An increase in SCr , 44 ,mol/l or , 25% of baseline was considered significant. Ten patients underwent peripheral AG using a high dose of Gd without any adverse reaction. The mean age was 67.8 years. Nine (90%) patients were diabetic. The quality of these images was satisfactory for diagnosis in eight out of 10 patients. None of these patients had significant change in SCr. The mean SCr (SD) before, at 48 hours and at 72 hours after AG were 182 97, 177 99 and 177 98 ,mol/l, respectively. Based on this limited study, Gd is a promising agent for peripheral angiographic study. In patients at risk for RCIN, the high dose of Gd appears to be safe without obvious nephrotoxicity. [source]


Delineating the impact of neuroantigen vs genetic diversity on MP4-induced EAE of C57BL/6 and B6.129 mice

APMIS, Issue 12 2009
STEFANIE KUERTEN
MBP-PLP fusion protein (MP4)-induced experimental autoimmune encephalomyelitis (EAE) is a model for multiple sclerosis (MS) that encompasses both a time-dependent attack on central nervous system (CNS) regions and a B cell component, mirroring important features of human multiple sclerosis. Comparing C57BL/6 with B6.129 mice immunized with MP4, we point out similarities regarding these hallmarks and thus propose that they are largely dependent on the nature of the MP4 antigen itself, while differences between the two strains suggest that additional fine-tuning is brought about by the genetic repertoire of the animal. Overall, our data imply that (i) the interplay between both the antigenic trigger and genetic variables can define the outcome of MP4-induced autoimmune encephalomyelitis in C57BL/6 and B6.129 mice and (ii) that MP4 is not only a strong neuroantigen when it comes to reproducing the dynamics in effector mechanisms as is typical of the disease but also a promising agent for studying interindividual heterogeneity derived from genetic diversity in EAE/MS. [source]


Triptolide abrogates oncogene FIP1L1-PDGFR, addiction and induces apoptosis in hypereosinophilic syndrome

CANCER SCIENCE, Issue 11 2009
Yanli Jin
The pathogenesis of hypereosinophilic syndrome (HES) in some patients is highly dependent on FIP1-Like-1 (FIP1L1),platelet-derived growth factor receptor alpha (PDGFR,), which can generate sustained activation signaling to maintain a cell malignant phenotype. HES usually shows good response to the tyrosine kinase inhibitor imatinib, but mutations in FIP1L1-PDGFR, (e.g. T674I) can confer acquired resistance to imatinib. An alternative therapeutic strategy other than with tyrosine kinase inhibitors is needed to overcome acquired drug resistance. We hypothesized that switching off the crucial chimeric oncoprotein FIP1L1-PDGFR, on which HES cells depend, should have deleterious effects on the cancer cells. We used low concentrations of triptolide, a transcription inhibitor, to shut down the expression of FIP1L1-PDGFR,. EOL-1 cells and BaF3 cells expressing wild-type or T674I FIP1L1-PDGFR, were treated with triptolide, and signaling pathways, cell cycling, and apoptosis were analyzed by RT-PCR, immunoblotting, and flow cytometry, respectively. The results revealed that at nanomolar concentrations triptolide decreased the levels of mRNA and protein of FIP1L1-PDGFR, and the growth of the neoplastic cells, regardless of the mutational status of PDGFR,. Triptolide also downregulated the signaling molecules Stat3, Akt, and Erk1/2, which are downstream from PDGFR,, and induced G1 cell-cycle arrest. Triptolide time- and dose-dependently induced apoptosis by decreasing the anti-apoptotic proteins Mcl-1 and Bcl-XL,triggering the intrinsic apoptotic pathway. In conclusion, triptolide has potent activity against malignant cells in HES bearing FIP1L1-PDGFR,, regardless of its mutational status that confer acquired resistance to imatinib. Our results suggest that triptolide may be a promising agent in the treatment of HES. (Cancer Sci 2009; 00: 000,000) [source]


Potent inhibition of in vivo angiogenesis and tumor growth by a novel cyclooxygenase-2 inhibitor, enoic acanthoic acid

CANCER SCIENCE, Issue 12 2007
Hye Jin Jung
Recent studies have shown that cyclooxygenase-2 is crucially involved in angiogenesis. In fact, several specific cyclooxygenase-2 inhibitors suppress angiogenesis in vivo, suggesting that cyclooxygenase-2 is a promising target for the treatment of angiogenesis-related diseases. In the present study we investigate the activity of a new cyclooxygenase-2 inhibitor, enoic acanthoic acid (EAA), which was synthesized from the known natural cyclooxygenase-2 inhibitor, acanthoic acid (AA). The demonstration of a high correlation between EAA- and celecoxib-induced gene expression signatures in microarray experiments validated the specificity of EAA on cyclooxygenase-2. In angiogenesis assays, EAA potently inhibited basic fibroblast growth factor-induced invasion and tube formation of bovine aortic endothelial cells in vitro. Moreover, this inhibitor prevented both neovascularization of the chorioallantoic membrane of growing chick embryo and basic fibroblast growth factor-induced mouse corneal angiogenesis in vivo. EAA also significantly suppressed the growth of bladder tumors in a mouse model, showing better antitumor activity than celecoxib. Furthermore, gelatin zymogram analysis revealed that EAA potently inhibited the activities of matrix metalloproteinase 2 and 9. These results clearly demonstrate that EAA is a promising agent for the prevention and treatment of angiogenesis-related diseases including cancer. (Cancer Sci 2007; 98: 1943,1948) [source]


DE-310, a novel macromolecular carrier system for the camptothecin analog DX-8951f: Potent antitumor activities in various murine tumor models

CANCER SCIENCE, Issue 2 2004
Eiji Kumazawa
DE-310 is a novel macromolecular conjugate composed of DX-8951f, a camptothecin analog, and a carboxymethyldextran polyalcohol carrier, which are covalently linked via a peptidyl spacer. In a murine Meth A (fibrosarcoma) solid tumor model, once daily5 treatments (qd5) with DX-8951f at the maximum tolerated dose (MTD) were required to shrink the tumor, and DX-8951f (qd5) at 1/4 MTD was required to inhibit tumor growth. A single treatment (qd1) with DE-310 at the MTD or 1/4 MTD shrank the tumor, with no body weight loss occurring at 1/4 MTD. Even at 1/16 MTD, DE-310 inhibited tumor growth. In a long-term assay, Meth A solid tumors disappeared in mice treated with DE-310 (qd1) at the MTD and 1/2 MTD, and all 6 mice remained tumor-free on the 60th day after administration. Repeated injection (4 times) on schedules of every 3 days, 7 days or 14 days demonstrated that multiple treatment with DE-310 produced greater tumor growth delay than a single treatment with DE-310. Against 5 human tumor (colon and lung cancer) xenografts in mice, DE-310 (qd1) was as effective as DX-8951f administered once every 4 days, 4 times. The life-prolonging activity of DE-310 was assessed in lung (3LL, Lewis lung carcinoma) and liver (M5076, histiocytoma) metastasis models. Against 3LL, DE-310 (qdx1) at the MTD to 1/3 MTD significantly prolonged survival, with an increase in life span (ILS) of 4.8- to 1.6-fold, respectively, over that in untreated control mice. Also, DE-310 (qd1) significantly prolonged survival in the liver metastasis model of M5076. These results demonstrate that DE-310 is a promising agent for the treatment of cancer. [source]


The effects of the caffeic acid phenethyl ester (CAPE) on erythrocyte membrane damage after hind limb ischaemia,reperfusion

CELL BIOCHEMISTRY AND FUNCTION, Issue 5 2004
Llfer Tamer
Abstract Reactive oxygen species have been implicated in pathogenesis injury after ischaemia,reperfusion (I/R). Caffeic Acid Phenethyl Ester (CAPE), an active component of honeybee propolis extract, exhibits antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects of CAPE on erythrocyte membrane damage after hind limb I/R. Rats were divided into two groups: I/R and I/R with CAPE pre-treatment. They were anaesthetized with intramuscular ketamine 100,mg,kg,1. A 4-h I/R period was performed on the right hind limb of all animals. In the CAPE-treated group, animals received CAPE 10,,m by intraperitoneal injection 1,h before the reperfusion. At the end of the reperfusion period, a midsternotomy was performed. A 5-ml blood sample was withdrawn from the ascending aorta for biochemical assays. Serum and erythrocyte membrane MDA levels were significantly lower in the CAPE-treated group when compared to the I/R group (,p,=,0.001 and p<0.001, respectively). Erythrocyte membrane Na+ -K+ ATPases activity in the CAPE-treated group was significantly higher than the I/R group (,p<0.001). In conclusion, CAPE seems to be effective in protecting against oxidative stress. Therefore, we suggest that in order to decrease I/R injury, pre-administration of CAPE may be a promising agent for a variety of conditions associated with I/R. Copyright 2004 John Wiley & Sons, Ltd. [source]


The current status of targeted therapy for non-small cell lung cancer

INTERNAL MEDICINE JOURNAL, Issue 9 2010
H. Francis
Abstract Lung cancer accounts for more cancer-related deaths than any other malignancy in Australia and worldwide. Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancers and is associated with a 5-year survival of only 15%. Treatment with platinum-based doublets in the first-line setting and single agent chemotherapy in the second-line setting has improved survival and quality of life in patients with NSCLC. However, the benefits associated with chemotherapy are modest and serve to stress the need for novel therapeutic approaches. In the last decade a range of targeted therapies has been evaluated in NSCLC. Dramatic and often durable responses were seen in patients treated with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) gefitinib and erlotinib particularly in females, non-smokers, patients of East Asian ethnicity and those with adenocarcinomas , a group subsequently found to be enriched for tumours with activating EGFR mutations. Large randomized phase III trials have since established a role for EGFR TKI in the second- and third-line setting as well as a potential role for the monoclonal antibodies bevacizumab and cetuximab, directed at vascular endothelial growth factor and EGFR, respectively, in the combination with chemotherapy in the first-line setting. Recently it has been shown that patients with EGFR mutations may benefit from gefitinib in the first-line setting. Other promising agents under evaluation are inhibitors of the insulin-like growth factor-1 receptor and inhibitors of recently described ALK gene rearrangements. [source]


Moxifloxacin-based strategies for first-line treatment of Helicobacter pylori infection

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2005
E. C. Nista
Summary Background :,Standard anti- Helicobacter pylori therapy may not achieve a satisfactory eradication rate. Fluoroquinolones, such as moxifloxacin, are safe and promising agents for H. pylori eradication. Aim :,To compare the efficacy of two 1-week moxifloxacin-based H. pylori eradication regimens with two standard treatments. Methods :,Three hundred and twenty H. pylori -positive subjects were randomized into four groups to receive: moxifloxacin, amoxicillin, esomeprazole (Group MAE); moxifloxacin, tinidazole and esomeprazole (Group MTE); standard triple therapies with clarithromycin, amoxicillin and esomeprazole (Group CAE) or tinidazole (Group CTE) for 7 days. H. pylori status was re-assessed 6 weeks after the end of therapy by 13C urea breath test. Results :,Three hundred and twenty patients completed the efficacy analysis per protocol; H. pylori eradication rate in group MTE was 90% (72 of 80) and 92% (72 of 78), in group MAE was 88% (70 of 80) and 89%, (70 of 79) in Group CAE was 73% (58 of 80) and 78% (58 of 74), and in Group CTE was 75% (60 of 80) and 79% (60 of 76), respectively, in intention-to-treat and in per protocol analyses. Eradication rates of moxifloxacin-based triple therapies were significantly higher than that observed using standard triple schemes. The incidence of side effects was significantly lower in moxifloxacin groups than in control groups. Conclusions :,Seven-day moxifloxacin-based triple therapies provide optimal eradication rates with a good compliance when compared with the standard triple therapy schemes. [source]


Tunable Bacterial Agglutination and Motility Inhibition by Self-Assembled Glyco-Nanoribbons

CHEMISTRY - AN ASIAN JOURNAL, Issue 11 2007
Yong-beom Lim Dr.
Abstract We explored a method of controlling bacterial motility and agglutination by using self-assembled carbohydrate-coated ,-sheet nanoribbons. To this aim, we synthesized triblock peptides that consist of a carbohydrate, a polyethylene glycol (PEG) spacer, and a ,-sheet-forming peptide. An investigation into the effect of PEG-spacer length on the self-assembly of the triblock peptides showed that the PEG should be of sufficiently length to stabilize the ,-sheet nanoribbon structure. It was found that the stabilization of the nanoribbon led to stronger activity in bacterial motility inhibition and agglutination, thus suggesting that antibacterial activity can be controlled by the stabilization strategy. Furthermore, another level of control over bacterial motility and agglutination was attained by co-assembly of bacteria-specific and -nonspecific supramolecular building blocks. The nanoribbon specifically detected bacteria after the encapsulation of a fluorescent probe. Moreover, the detection sensitivity was enhanced by the formation of bacterial clusters. All these results suggest that the carbohydrate-coated ,-sheet nanoribbons can be developed as promising agents for pathogen capture, inactivation, and detection, and that the activity can be controlled at will. [source]