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Combination of rapamycin and Imatinib in Treating Refractory Chronic Myeloid Leukemia Myeloid Blast Crisis:a Case Report

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Chinese Medical Sciences Journal 2013年第2期28卷 127-128页

作者： Jing Xie Xiang Zhang Bao-zhi Fang Guang-sheng He Yun Zhao De-pei Wu Key Laboratory of Thrombosis and Hemostasis of Ministry of Health the First Affiliated Hospital of Soochow University Cyrus Tang Hematology Center Jiangsu Institute of Hematologythe First Affiliated Hospital of Soochow University

HRONIC myeloid leukemia （CML） is characterized by the presence of the BCR/ABL fusion gene, which is the result of a reciprocal translo cation between chromosomes 9 and 22, calledPhiladelphia （Ph） chromosome. Imatinib mesylate （imatinib）, a specific small molecular inhibitor of BCR/ABL, could improve the prognosis of CML and is now the standard drug applied in all phases of this disease} Despite the efficacy of imatinib, the development of resistance and the persistence of minimal residual disease have seriously impaired the efficiency of this medicine. Resistance may develop through several different mechanisms, such as mutations in the Abl kinase domain, BCR/ABL overexpression, or compensatory phosphatidylinositol 3 kinase （PI3K）/Akt/ mammalian target of rapamycin （mTOR） activation.2,3 rapamycin, with mTOR as a potential therapeutic target, has been studied in patients with hematologic malignancies. Here we report a case of refractory CML myeloid blast crisissuccessfully treated by the combination of rapamycin and imatinib.

关键词： chronic myeloid leukemia imatinib imatinib-resistent rapamycin mammaliantarget of rapamycin

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Trends of rapamycin in survival benefits of liver transplantation for hepatocellular carcinoma

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World Journal of Gastrointestinal Surgery 2021年第9期13卷 953-966页

作者： Yang Zhao Yu Liu Lin Zhou Guo-Sheng Du Qiang He Department of Hepatobiliary and Pancreaticosplenic Surgery Beijing Chaoyang HospitalCapital Medical UniversityBeijing 100020China Department of Hepato-Pancreato-Biliary Surgery Chinese PLA General HospitalBeijing 100853China

The proportion of liver transplantation(LT)for hepatocellular carcinoma(HCC)has kept on increasing over the past years and account for 20%-40%of all ***-transplant HCC recurrence is considered the most important factor affecting the long-term survival of *** use of different types of immunosuppressive agents after LT is closely associated with an increased risk for HCC *** most commonly used conventional immunosuppressive drugs include the calcineurin inhibitors tacrolimus(FK506)and mammalian target of rapamycin inhibitor rapamycin(RAPA).Compared with tacrolimus,RAPA may carry an advantage in survival benefit because of its anti-tumor ***,no sufficient evidence to date has proven that RAPA could increase long-term recurrence-free survival and its anti-tumor mechanism of combined therapy remains incompletely *** this review,we will focus on recent advances in clinical application experience and basic research results of RAPA in patients undergoing LT for HCC to further guide the clinical practice.

关键词： rapamycin Hepatocellular carcinoma Liver transplantation Lenvatinib Programmed death protein-1 Huaier granule

Six-month results of a biodegradable polymer and rapamycin-coating stent for coronary artery disease

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Journal of Geriatric Cardiology 2006年第2期3卷 67-70页

作者： Yuxiao ZHANG Caiyi LU Qiao XUE Peng LIU Wei YAN Rui CHEN Institute of Geriatric Cardiology General Hospital of Chinese PLA Beijing 100853 China Institute of Geriatric Cardiology General Hospital of Chinese PLA Beijing 100853 China Institute of Geriatric Cardiology General Hospital of Chinese PLA Beijing 100853 China Institute of Geriatric Cardiology General Hospital of Chinese PLA Beijing 100853 China Institute of Geriatric Cardiology General Hospital of Chinese PLA Beijing 100853 China Institute of Geriatric Cardiology General Hospital of Chinese PLA Beijing 100853 China

Objective To assess the safety and efficacy of a novel biodegradable polymer and rapamycin-coating stent, the EXCEL stent, in the treatment of coronary artery disease (CAD), as compared with the CypherTM stent. Methods In this prospective, non-randomized study, 60 consecutive patients with symptomatic CAD received either an EXCEL stent (n=32), or a CypherTM stent(n=28),according to their respective treatment intention. Follow-up angiography was performed at a mean of 180±40 days. The primary endpoint of the study was the occurrence of a major adverse cardiac event (MACE), including death, myocardial infarction, or target-vessel revascularization during the 6 months after stenting. The secondary end points included the in-stent late luminal loss (LLL), percentage of in-stent stenosis of the luminal diameter, and the rate of restenosis (luminal narrowing of 50 percent or more) at 6 months. Results There were no significant differences between the two groups in baseline characteristics, including the distribution of target vessel and lesion types. During the follow up period of 6 months, there were no occurrences of MACE in either group. Twenty-seven patients(84%) in the EXCEL group and 10 (36 %) in the CypherTM group underwent quantitative coronary angiography at 6 months. For these patients, no restenosis occurred, and there were no differences in the in-stent stenosis of the luminal diameter (5.98±5.52% vs 5.21 ±6.3%,P＞0.05) and the LLL (-0.02±0.09 mm vs -0.01±0.07 mm, P＞0.05). Conclusions Compared with the CypherTM stent, the EXCEL Stent with biodegradable polymer and rapamycin-coating showed similar efficacy in the prevention of neointimal proliferation, restenosis, and associated clinical events in CAD patients.

关键词： coronary artery disease stent, rapamycin biodegradable polymer

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EFFECTS OF rapamycin ON INTRACELLULAR CHOLESTEROL HOMEOSTASIS OF GLOMERULAR MESANGIAL CELL IN THE PRESENCE OF INTERLEUKIN-1β

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Chinese Medical Sciences Journal 2008年第4期23卷 205-211页

作者： Guo-iuan Zhang Hang Li Xue-wang Li Department of Nephrology Peking Union Medical College Hospital Chinese Academy of Medical Sciences ＆ Peking Union Medical College Beijing 100730

Objective To investigate the effects of rapamycin on cholesterol homeostasis of glomerular mesangial cells and the underlying mechanisms. Methods Intracellular cholesterol accumulation was measured by Oil Red O staining and high performance liquid chromatography. The effects of rapamycin on interleukin-1β（1L-1β）-induced mRNA and protein changes of low-density lipoprotein receptor （LDLR） and ATP-binding cassette transporter Al （ABCAl） were assayed by quantitative real-time PCR and Western blot. Transient expressions of 3 types of mammalian target of rapamycin （mTOR）, including mTOR-WT （wild type）, mTOR-RR （rapamycin resistant, with kinase activity）, and mTOR-RR-KD （rapamycin resistant, without kinase activity）, were obtained by plasmid transfection. Results rapamycin had no significant influence on intracellular cholesterol concentration trader normal condition, but it significantly decreased the intracellular cholesterol concentration in the presence of IL-1β. rapamycin dose-dependently suppressed the increased expression of LDLR induced by IL-1β and up-regulated the suppressed expression of ABCAl caused by IL-1β Transient expression of 3 types of mTOR all reduced ABCAl mRNA expression significantly, which all could be overroded by rapamycin. Conclusions rapamycin may contribute to the maintaining of glomerular mesangial cell intracellular cholesterol homeostasis under inflammatory state by both reducing cholesterol uptake and increasing cholesterol effiux. And the effect may be not completely mediiated by mTOR.

关键词： rapamycin glomerular mesangial cell cholesterol low-density lipoprotein receptor ATP-binding ca, sette transporter A1

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Indirect targeting of MYC sensitizes pancreatic cancer cells to mechanistic target of rapamycin (mTOR) inhibition

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Cancer Communications 2022年第4期42卷 360-364页

作者： Christian Schneeweis Zonera HassanKatja Ascherl Matthias Wirth Stella Koutsouli Felix Orben Lukas Krauß Carolin Schneider Rupert Ollinger Oliver HKrämer Roland Rad Maximilian Reichert Maria SRobles Dieter Saur Günter Schneider Medical Clinic and Polyclinic II Klinikum rechts der IsarTechnical University MunichMunich 81675Germany Department of Hematology Oncology and Tumor ImmunologyCharite-Universitatsmedizin BerlinCorporate Member of Freie Universitat BerlinHumboldt-Universitat zu Berlin and Berlin Institute of HealthBerlin 12203Germany Institute of Medical Psychology and Biomedical Center(BMC) Faculty of MedicineLMU MunichMunich 80336Germany Institute of Molecular Oncology and Functional Genomics TUM School of MedicineTechnical University MunichMunich 81675Germany Department of Toxicology University of Mainz Medical CenterMainz 55131Germany German Cancer Research Center(DKFZ)and German Cancer Consortium(DKTK) Heidelberg 69120Germany Center for Protein Assemblies(CPA) Technical University of MunichGarching 85747Germany Institute for Translational Cancer Research and Experimental Cancer Therapy Technical University MunichMunich 81675Germany Department of General Visceral and Pediatric SurgeryUniversity Medical Center GottingenGottingen 37075Germany

Dear Editor,Pancreatic ductal adenocarcinoma(PDAC)remains a significant health problem with an increase in the incidence and a five-year survival rate of only 10%[1].The Phosphoinositide 3-kinase-protein kinase-B-mechanistic target of rapamycin(PI3K-AKT-mTOR)pathway is a driver pathway in PDAC and an important therapeutic target[2].We[3]and others[4–6]have demonstrated that the mTOR kinase is a therapeutic target in PDAC,and rationally designed mTOR inhibitor(mTORi)-based combination therapies are emerging[2].

关键词： rapamycin therapeutic adenocarcinoma

Paradoxical effect of rapamycin on S6 phosphorylation in rats with or without seizures

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中国药理学与毒理学杂志 2012年第3期 435-436页

作者：曾玲晖 Zhejiang University City College

OBJECTIVE Accumulating data have demonstrated that seizures induced by kainate or pilocarpine activate the mammalian target of rapamycin（mTOR） pathway and mTOR inhibitor rapamycin can inhibit mTOR activation which subsequently has potential anti-epileptic ***,a preliminary study showed a paradoxical exacerbation of increased mTOR pathway activity reflected by S6 phosphorylation when rapamycin was administrated within a short period before kainate *** the present study,we examined this paradoxical effect of rapamycin in more detail,both in normal rats and kainate-injected *** The expression of mTOR signaling target both of phosphorylated and unphosphorylated forms were detected by Western Blotting *** onset and duration was monitored by *** cell death was detected by Fluoro-Jade B *** In normal rats,we found that rapamycin showed the expected dose-dependent inhibition of S6 phosphorylation 3;4 h after injection,while a paradoxical elevation of S6 phosphorylation was observed 1 h after ***,pretreatment with rapamycin over 10 h prior to kainate inhibits the kainate-induced mTOR *** contrast,rapamycin administered 1-6 h before kainate causes a paradoxical increase in the kainate-induced mTOR *** pretreated with rapamycin 1h prior to kainate showed an increase in severity and duration of seizures and more neuronal cell death as compared to vehicle treated *** contrast,rapamycin pretreated 10 h prior to KA had no effect on the seizures and decreased neuronal cell *** paradoxical effect of rapamycin on S6 phosphorylation was correlated with upstream mTOR signaling and reversed by pre-treatment of perifosine,an akt *** These data indicate the complexity of S6 regulation and its effect on *** effects of rapamycin need to be considered in clinical applications,such as potential treatments for epilepsy and other neurological

关键词： rapamycin mTOR signaling pathway S6 phosphorylation Kainate paradoxical effect

Mechanistic target of rapamycin inhibitors:successes and challenges as cancer therapeutics

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Cancer Drug Resistance 2019年第4期2卷 1069-1085页

作者： Muireann NíBhaoighill Elaine A.Dunlop Division of Cancer and Genetics Cardiff UniversityCardiffCF144XNUK

Delineating the contributions of specific cell signalling cascades to the development and maintenance of tumours has greatly informed our understanding of tumorigenesis and has advanced the modern era of targeted cancer *** has been revealed that one of the key pathways regulating cell growth,the phosphatidylinositol 3-kinase/mechanistic target of rapamycin(PI3K/mTOR)signalling axis,is commonly dysregulated in *** a specific,well-tolerated inhibitor of mTOR available,the impact of inhibiting this pathway at the level of mTOR has been tested *** review highlights some of the promising results seen with mTOR inhibitors in the clinic and assesses some of the challenges that remain in predicting patient outcome following mTOR-targeted therapy.

关键词： Mechanistic target of rapamycin cancer rapamycin rapalog clinical trial resistance

Protective autophagy by thymidine causes resistance to rapamycin in colorectal cancer cells in vitro

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Cancer Drug Resistance 2021年第3期4卷 719-727页

作者： I.V.Bijnsdorp Godefridus J.Peters Department of Medical Oncology Amsterdam UMClocation VUMC1007 MB AmsterdamNetherlands Department of Urology Amsterdam UMClocation VUMC1007 MB AmsterdamNetherlands Department of Biochemistry Medical University of Gdansk80-210 GdanskPoland

Aim:Thynidine phosphorylase(TP)acts as a proangiogenic growth factor which may regulate mammalian Target of rapamycin(mTOR).We investigated whether the TP substrate thymidine and overexpression of TP affected mTOR signaling by comparing Colo320(TP deficient)cells and its TP-transfected variant(Colo320TP1).Methods:Drug resistance was assessed with the sulforhodamine B assay,protein expression with Western blotting,cell cycle distribution and cell death with Fluorescence-activated cell sorting analysis,and autophagy with ***:Colo320 and Colo320TP1 cells had comparable levels of sensitivity to the mTOR inhibitor *** treatment led to 13-and 50-fold resistance to rapamycin in Colo320 and Colo320TP1 cells,*** Colo320TP1 cells,the thymidine phosphorylase inhibitor(TPI)reversed the thymidine induced resistance to rapamycin,but not in Colo320 cells,indicating a role for TP in the *** increased p70/S6k-phosphorylation(downstream of mTOR)in Colo320TP1,but it was not affected in *** a mechanism behind resistance,we studied the levels of autophagy and found that,in Colo320TP1 cells,autophagy was highly induced by thymidine-rapamycin,which was decreased by *** addition,the autophagy inhibitor 3-methyl-adenine completely inhibited autophagy and its ***:rapamycin resistance in TP-expressing cancer cells may therefore be related to thymidine-mediated autophagy activation.

关键词： Thymidine phosphorylase mTOR rapamycin thymidine thymidine phosphorylase inhibitor autophagy

Real-world five-year outcomes of FlexyRap®cobalt-chromium rapamycin-eluting stents with biodegradable polymer in patients with de-novo coronary artery disease

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World Journal of Cardiology 2023年第3期15卷 84-94页

作者： Nitish Garg Raman Chawla Vivek Tandon Deepak Garg Nilesh Parshottam Preeti Vani Malte Neuss Department of Interventional Cardiology Cardinova HospitalJalandhar 144001India Department of Interventional Cardiology CareMax HospitalJalandhar 144001India Department of Interventional Cardiology EMC HospitalAmritsar 143001India Department of Interventional Cardiology Moga Medicity HospitalMoga 142001India Department of Interventional Cardiology Sunshine Global HospitalSurat 394370India Medical Division Sahajanand Laser Technology Ltd.GandhinagarGujarat382028India

BACKGROUND The use of biodegradable polymer drug-eluting stents(BP-DES)has been proven to minimize restenosis and stent *** current post-marketing monitoring was observed at the 5-year clinical outcomes of individuals who had been treated with FlexyRap®DES in the real *** To assess the safety and effectiveness of FlexyRap®DES at the 5-year follow-up in real-world *** Findings from a retrospective,multi-center,observational,post-market clinical follow-up study of patients treated with FlexyRap®DES for de novo coronary artery disease(CAD)were *** the 12-mo follow-up,the primary endpoint was target lesion failure,which was defined as the composite of cardiovascular death, target vessel myocardial infarction(TV-MI), and clinically driven target lesion *** The data of 500 patients received with FlexyRap®DES was obtained at the completion of the surveillance timeline of *** the implantation of FlexyRap®DES,the device success rate was 100%.Adverse events that led to major bleeding,permanent disability,or death were not experienced in the *** major adverse cardiac event rate at 12-mo,3-year,and 5-year follow-up was 1(0.2%),0(0%),and 1(0.2%)respectively with 0(0%)cardiovascular death,2(0.4%)TV-MI,and 0(0%)TLR ***,late stent thrombosis was found in 2(0.4%)patients at the follow-up of 12-mo,very late stent thrombosis was observed in 2 patients(0.4%)at 3-year *** FlexyRap®DES was proved to be safe and efficacious in real-world patients with de novo CAD,indicating a lowered rate of cardiac events and stent thrombosis at 5-year follow-up.

关键词： Coronary artery disease Drug-eluting stents Percutaneous coronary intervention rapamycin Sirolimus