The inflammatory bowel diseases (IBDs) are chronic incurable conditions that primarily present in young patients. Being incurable, the IBDs may be part of the patient’s life for many years and these condit...The inflammatory bowel diseases (IBDs) are chronic incurable conditions that primarily present in young patients. Being incurable, the IBDs may be part of the patient’s life for many years and these conditions require therapies that will be effective over the long-term. Surgery in Crohn’s disease does not cure the disease with endoscopic recurrent in up to 70% of patients 1 year post resection. This means that, the patient will require many years of medications and the goal of the treating physician is to induce and maintain long-term remission without side effects. The development of the anti-tumour necrosis factor alpha (TNFα) agents has been a magnificent clinical advance in IBD, but they are not always effective, with loss of response overtime and, at times, discontinuation is required secondary to side effects. So what options are available if of the anti-TNFα agents can no longer be used? This review aims to provide other options for the physician, to remind them of the older established medications like azathioprine/6-mercaptopurine and methotrexate, the less established medications like mycophenolate mofetil and tacrolimus as well as newer therapeutic options like the anti-integins, which block the trafficking of leukocytes into the intestinal mucosa. The location of the intestinal inflammation must also be considered, as topical therapeutic agents may also be worthwhile to consider in the long-term management of the more challenging IBD patient. The more options that are available the more likely the patient will be able to have tailored therapy to treat their disease and a better long-term outcome.展开更多
AIM To investigate the therapeutic effect of combined integrinα6β4-targeted radioimmunotherapy(RIT)and PI3 K/m TOR inhibitor BEZ235 in a pancreatic cancer model.METHODS Phosphorylation of Akt,m TOR,the downstream ef...AIM To investigate the therapeutic effect of combined integrinα6β4-targeted radioimmunotherapy(RIT)and PI3 K/m TOR inhibitor BEZ235 in a pancreatic cancer model.METHODS Phosphorylation of Akt,m TOR,the downstream effectors eukaryotic initiation factor 4 E binding protein 1(4 EBP1)and S6 ribosomal protein(S6)were evaluated in Bx PC-3 human pancreatic cancer cells treated with Yttrium-^(90)(^(90)Y)labeled anti-integrinα6β4 antibody(ITGA6 B4)and BEZ235 by western blotting.The cytotoxic effect of BEZ235 was investigated using a colony formation assay.Therapeutic efficacy enhancement by oral BEZ235 administration was assessed using mice bearing Bx PC-3 xenograft tumors.Tumor volume measurements and immunohistochemical analyses(cell proliferation marker Ki-67,DNA damage marker p-H2 AX and p-4 EBP1 staining)of tumors were performed for evaluation of combined treatment with^(90)Y-ITGA6 B4 plus BEZ235,or each arm alone.RESULTS We found that phosphorylation of Akt(p-Akt),4 EBP1(p-4 EBP1)and S6(p-S6)was inhibited by BEZ235.Colony formation in Bx PC-3 cells was additively suppressed by the combination of^(90)Y-ITGA6 B4 and BEZ235.Pretreatment with BEZ235 before^(90)Y-ITGA6 B4 exposure resulted in significant reduction of cells plating efficiency(PE)(0.54±0.11 vs 2.81±0.14 with 185 k Bq/m L^(90)Y-ITGA6 B4 exposure,P<0.01;0.39±0.08 vs 1.88±0.09 with 370 k Bq/m L^(90)Y-ITGA6 B4 exposure,P<0.01)when 5×10~3 cells per dish were plated.In vivo,the combined treatment with^(90)Y-ITGA6 B4 plus BEZ235 enhanced the inhibition of tumor growth and statistically significant differences of relative tumor volume were observed for 27 d after the treatment start date when compared with the^(90)Y-ITGA6 B4 single injection treatment(1.03±0.38 vs 1.5±0.15 at Day 27,P<0.05),and for 41 d when compared with the BEZ235 treatment alone(1.8±0.7 vs 3.14±1.19 at Day 41,P<0.05).Tumors from treatment groups showed reduction in volumes,decreased Ki-67-positive cells,increased p-H2 AX-positive cells and decreased p-4 EBP1 expression.CONCLUSION The therapeutic efficacy of^(90)Y-ITGA6 B4-RIT can be improved by combining with dual PI3 K and m TOR inhibitor,BEZ235,in a pancreatic cancer model suggesting potential clinical application.展开更多
Crohn’s disease is a chronic gastrointestinal inflammatory disorder,characterized by episodes of relapsing and remitting flares.As the disease mechanism becomes better elucidated,there is a significant increase in th...Crohn’s disease is a chronic gastrointestinal inflammatory disorder,characterized by episodes of relapsing and remitting flares.As the disease mechanism becomes better elucidated,there is a significant increase in the number of available biologic therapies.This article summarizes and synthesizes current Food and Drug Administration-approved biological therapy for Crohn’s disease and examines the positioning of medical therapy as emerging biologics break onto the market.展开更多
Ulcerative colitis(UC)is a major form of inflammatory bowel disease(IBD)worldwide.Better understanding of the pathogenesis of UC has led to the development of novel therapeutic agents that target specific mediators of...Ulcerative colitis(UC)is a major form of inflammatory bowel disease(IBD)worldwide.Better understanding of the pathogenesis of UC has led to the development of novel therapeutic agents that target specific mediators of the inflammatory cascade.A number of biological agents have been approved by the U.S.Food and Drug Administration(FDA)for the treatment of UC and several more are currently in various phases of drug development.The commonly used agents include TNFa antagonists(e.g.infliximab,adalimumab,and golimumab)and anti-integrin agents(vedolizumab).These biological agents have profoundly influenced the management of UC patients,especially those with refractory disease.This paper reviews the currently available knowledge and evidence for the use of various biological agents in the treatment of UC.展开更多
文摘The inflammatory bowel diseases (IBDs) are chronic incurable conditions that primarily present in young patients. Being incurable, the IBDs may be part of the patient’s life for many years and these conditions require therapies that will be effective over the long-term. Surgery in Crohn’s disease does not cure the disease with endoscopic recurrent in up to 70% of patients 1 year post resection. This means that, the patient will require many years of medications and the goal of the treating physician is to induce and maintain long-term remission without side effects. The development of the anti-tumour necrosis factor alpha (TNFα) agents has been a magnificent clinical advance in IBD, but they are not always effective, with loss of response overtime and, at times, discontinuation is required secondary to side effects. So what options are available if of the anti-TNFα agents can no longer be used? This review aims to provide other options for the physician, to remind them of the older established medications like azathioprine/6-mercaptopurine and methotrexate, the less established medications like mycophenolate mofetil and tacrolimus as well as newer therapeutic options like the anti-integins, which block the trafficking of leukocytes into the intestinal mucosa. The location of the intestinal inflammation must also be considered, as topical therapeutic agents may also be worthwhile to consider in the long-term management of the more challenging IBD patient. The more options that are available the more likely the patient will be able to have tailored therapy to treat their disease and a better long-term outcome.
基金Supported by(partially)a Grant-in-Aid for Scientific Research(C)from the Ministry of Education,Culture,Sports,Science and Technology,Japan,No.17K10460 to Aung W
文摘AIM To investigate the therapeutic effect of combined integrinα6β4-targeted radioimmunotherapy(RIT)and PI3 K/m TOR inhibitor BEZ235 in a pancreatic cancer model.METHODS Phosphorylation of Akt,m TOR,the downstream effectors eukaryotic initiation factor 4 E binding protein 1(4 EBP1)and S6 ribosomal protein(S6)were evaluated in Bx PC-3 human pancreatic cancer cells treated with Yttrium-^(90)(^(90)Y)labeled anti-integrinα6β4 antibody(ITGA6 B4)and BEZ235 by western blotting.The cytotoxic effect of BEZ235 was investigated using a colony formation assay.Therapeutic efficacy enhancement by oral BEZ235 administration was assessed using mice bearing Bx PC-3 xenograft tumors.Tumor volume measurements and immunohistochemical analyses(cell proliferation marker Ki-67,DNA damage marker p-H2 AX and p-4 EBP1 staining)of tumors were performed for evaluation of combined treatment with^(90)Y-ITGA6 B4 plus BEZ235,or each arm alone.RESULTS We found that phosphorylation of Akt(p-Akt),4 EBP1(p-4 EBP1)and S6(p-S6)was inhibited by BEZ235.Colony formation in Bx PC-3 cells was additively suppressed by the combination of^(90)Y-ITGA6 B4 and BEZ235.Pretreatment with BEZ235 before^(90)Y-ITGA6 B4 exposure resulted in significant reduction of cells plating efficiency(PE)(0.54±0.11 vs 2.81±0.14 with 185 k Bq/m L^(90)Y-ITGA6 B4 exposure,P<0.01;0.39±0.08 vs 1.88±0.09 with 370 k Bq/m L^(90)Y-ITGA6 B4 exposure,P<0.01)when 5×10~3 cells per dish were plated.In vivo,the combined treatment with^(90)Y-ITGA6 B4 plus BEZ235 enhanced the inhibition of tumor growth and statistically significant differences of relative tumor volume were observed for 27 d after the treatment start date when compared with the^(90)Y-ITGA6 B4 single injection treatment(1.03±0.38 vs 1.5±0.15 at Day 27,P<0.05),and for 41 d when compared with the BEZ235 treatment alone(1.8±0.7 vs 3.14±1.19 at Day 41,P<0.05).Tumors from treatment groups showed reduction in volumes,decreased Ki-67-positive cells,increased p-H2 AX-positive cells and decreased p-4 EBP1 expression.CONCLUSION The therapeutic efficacy of^(90)Y-ITGA6 B4-RIT can be improved by combining with dual PI3 K and m TOR inhibitor,BEZ235,in a pancreatic cancer model suggesting potential clinical application.
文摘Crohn’s disease is a chronic gastrointestinal inflammatory disorder,characterized by episodes of relapsing and remitting flares.As the disease mechanism becomes better elucidated,there is a significant increase in the number of available biologic therapies.This article summarizes and synthesizes current Food and Drug Administration-approved biological therapy for Crohn’s disease and examines the positioning of medical therapy as emerging biologics break onto the market.
文摘Ulcerative colitis(UC)is a major form of inflammatory bowel disease(IBD)worldwide.Better understanding of the pathogenesis of UC has led to the development of novel therapeutic agents that target specific mediators of the inflammatory cascade.A number of biological agents have been approved by the U.S.Food and Drug Administration(FDA)for the treatment of UC and several more are currently in various phases of drug development.The commonly used agents include TNFa antagonists(e.g.infliximab,adalimumab,and golimumab)and anti-integrin agents(vedolizumab).These biological agents have profoundly influenced the management of UC patients,especially those with refractory disease.This paper reviews the currently available knowledge and evidence for the use of various biological agents in the treatment of UC.
