姜秋红;程能能;高惠君;

• 1:复旦大学药学院药理学教研室
• 2:复旦大学附属妇产科医院药剂科
• 3:上海市食品药品安全研究中心

摘要(Abstract)：

蛋白酪氨酸激酶(PTK)是一类具有酪氨酸激酶活性的蛋白质,在细胞内的信号转导通路中占据了十分重要的地位。其中,P【-3K/AKT/mTOR信号通路和Ras/MARK信号通路与肿瘤的发生、发展、侵润及转移密切相关,已成为当前抗肿瘤药物研究的重要靶点。本文就近年来以这2条信号转导通路为靶点的抗肿瘤药物作一综述。

关键词(KeyWords)： 肿瘤;信号通路;mTOR抑制剂;法尼基转移酶抑制剂

Abstract:

Keywords:

基金项目(Foundation):

作者(Authors): 姜秋红;程能能;高惠君;

DOI: 10.19577/j.cnki.issn10074406.2011.06.019

参考文献(References)：

• [1]Halilovic E,Solit DB.Therapeutic strategies for inhibiting oncogenic BRAF signaling[J].Curr Opin Pharmacol,2008,8(4):419.
• [2]Shaw RJ,Cantley LC.Ras,PI(3)K and mTOR signaling controls tumour cell growth[J].Nature,2006,441(7092):424.
• [3]Kang S,Bader AG,Vogt PK.Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic[J].Proc Natl Acad Sci USA, 2005,102(3):802.
• [4]Martelli AM,Tazzari PL,Evangelisti C,et al.Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy:from bench to bedside[J].Curr Med Chem,2007,14(19):2009.
• [5]郑合勇,胡建达,郑志宏,等.大黄素可能通过抑制Akt信号通路诱导HL-60细胞凋亡[J].药学学报,2007,42(11):1142.
• [6]Sabatini DM.mTOR and cancer:insight into a complex relationship[J]. Nat Rev Cancer,2006,6(9):729.
• [7]Phung TL,Ziv K,Dabydeen D,et al.Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin[J].Cancer Cell,2006,10(2):159.
• [8]Young SK,Jae CK.Inhibiting of comeal neovascularization by rapamycin [J].Exp Mol Med,2006,38(2):173.
• [9]Mirshahi P,Toprak SK,Farssat AM,et al.Malignant hematopoietic cells induce an increased expression of VEGFR-1 and VEGFR-3 on bone marrow endothelial cells via AKT and mTOR signaling pathways[J]. Biochem Biophys Res Common,2006,349(3):1003.
• [10]Cloughesy TF,Yoshimoto K,Nghiemphu P,et al.Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-deficient glioblastoma[J].PLoS Med,2008,5(1):e8.
• [11]Ito D,Fujimoto K,Mori T,et al.In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer[J].Int J Cancer,2006,118(9):2337.
• [12]Skotnicki JS,Leone CL,Smith AL,et al.Design,synthesis and biological evaluation of C-42 hydroxyesters of rapamycin:the identification of CCI-779[J].din Cancer Res,2001,7(Suppl):S3749.
• [13]Raymond E,Alexandre J,Depenbiock H,et al.CCI-779,an ester analogue of repamycin that interacts with PTEN/PI3-kinase pathways:a phaseⅠstudy utilizing a weekly intravenous schedule[J].Clin Cancer Res,2006,6:S4549.
• [14]Hidalgo M,Rowinsky E,Erlichman C,et al.PhaseⅠand pharmacological study of CCI-779,a cell cycle inhibitor[J].Clin Cancer Res, 2006,6:S4548.
• [15]Hidalgo M.Buckner JC,Erliehman C,et al.A phaseⅠand pharmacokinctic study of temsirolimus(CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer[J]. Clin Cancer Res,2006,12(19):5755.
• [16]Hudes C,Carducci M,Tomczak P,et al.Temsirolimus,interferon alfa of both for advanced renal-cell carcinoma[J].N Engl J Med,2007, 356(22):2271.
• [17]Amato RJ,Jac J,Giessinger S,et al.A phaseⅡstudy with a daily regimen of the oral mTOR inhibitor RAD001(everolimus) in patients with metastatic clear cell renal cell cancer[J].Cancer,2009,115 (11):2438.
• [18]Sharma AM,Staels B.Review:peroxisome proliferator- activated receptor gamma and adipose tissueunderstanding obesity-related changes in regulation of lipid and glucose metabolism[J].J Clin Endocrinol Metab,2007,92(2):386.
• [19]Motzer RJ,Escudier B,Oudard S,et al.Efficacy of everolimus in advanced renal cell carcinoma:a double-blind,randomized,placebo-controlled phaseⅢtrial efficacy of everolimus in advanced renal cell carcinoma [J].Lancet,2008,372(9637):449.
• [20]Sternberg CN.Everolimus(RAD001) vs placebo after VEGFR-TKI failure in metastatic renal cell carcinoma[C].33rd European Society for Medical Oncology(ESMO) Congress Stockholm,Sweden,2008: 720.
• [21]Baumann P,Hagemeier H,Mandl-Weber S,et al.Myeloma cell growth inhibition is augmented by synchronous inhibition of the insulinlike growth factor-1 receptor by NVP-AEW541 and inhibition of mammalian target of rapamycin by RadOOl[J].Anticancer Drugs,2009, 20(4):259.
• [22]Mabuchi S,Altomare DA,Connolly DC,et al.RAD001(everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer[J].Cancer Res,2007,67(6):2408.
• [23]Lane HA,Wood JM,McSheehy PM.mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor[J].Clin Cancer Res,2009,15(5): 1612.
• [24]Gerry JM,Pascual G.Narrowing in on cardiovascular disease:the atheroprotective role of peroxisome proliferator activated receptor gamma [J].Trends Cardiovasc Med,2008,18(2):39.
• [25]Molavi B,Rassouli N,Bagwe S,et al.A review of thiazolidinediones and metformin in the treatment of type 2 diabetes with focus on cardiovaacular complications[J].Vasc Health Risk Manag,2007,3(6): 967.
• [26]Hall JM,McDonnell DP.The molecular mechanisms underlying the proinflammatory actions of thiazolidinediones in human macrophages [J].Mol Endocrinol,2007,21(8):1756.
• [27]Chawla SP,Tolcher AW,Staddon AP,et al.Survival results with AP23573, a novel mTOR inhibitor,in patients(pts) with advanced soft tissue or bone sarcomas:update of phaseⅡtrial[C].Symposium of ASCO,2007:al0076.
• [28]Schetbakova EA,Ryballdna Y,Stromskaya P,et al.Participation of mTOR in the regulation of multidrug resistance of tumor cells[J].Biochemistry (Supp 1 Series A:Membrane and Cell Biology),2009,3: 184.
• [29]Missiaglia E,Dalai I,Barbi S,et al.Pancreatic endocrine tumors:expression profiling evidences a role for AKT-mTOR pathway[J].J Clin Oncol,2010,28(2):245.
• [30]Mita MM,Britten CD,Poplin E,et al.Deforolimus trial 106:a phase I trial evaluating 7 regimens of oral deforolimus(AP23573,MK-8669) [J].J Clin Oncol,2008,26:3509.
• [31]Messersmith WA,Ahnen DJ.Targeting EGFR in colorectal cancer[J]. N Engl J Med,2008,359(17):1834.
• [32]Trader P,Bold G,Buchdunger E,et al.Tyrosine kinase inhibitors: from rational design to clinical trials[J].Med Res Rev,2001,21(6): 499.
• [33]Bell IM.Inhibitors of famesyltransferase:a rational approach to cancer chemotherapy[J].J Med Chem,2004,47(8):1869.
• [34]Taveras AG,Kirschmeier P,Baum CM.Sch-66336(sarasar) and other benzocycloheptapyridyl famesyl protein transferase inhibitors:discovery, biology and clinical observations[J].Curr Top Med Chem,2003, 3(10):1103.
• [35]Neadyn E,Lipton A,Zhu Y,et al.Phase I study of the famesyl-transferase inhibitor lonafamib with weekly paclitaxel in patients with solid tumors[J].Clin Cancer Res,2007,13(2Pt1):576.
• [36]Borthakur G,Kantarjian H,Daley G,et al.Pilot study of lonafamib, a famesyltransferase inhibitor,in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy[J].Cancer,2006,106(2):346.
• [37]Taylor SA,Marrinan CH,Liu G,et al.Combining the famesyltransferase inhibitor lonafamib with paclitaxel results in enhanced growth inhibitory effects on human ovarian cancer models in vitro and in vivo [J].Gynecol Oncol,2008,109(1):97.
• [38]Harousseau JL.Famesyltransferase inhibitors in hematologic malignancies [J].Blood Rev,2007,21(4):173.
• [39]Awada A,Zhang S,Gli T,et al.A phase I clinical and pharmacokinetic study of tipifamib in combination with docetaxel in patients with advanced solid malignancies[J].Curr Med Res Opin,2007,23(5): 991.
• [40]Korycka A,Smolewski P,Robak T.The influence of famesyl protein transferase inhibitor R115777(Zamestra) alone and in combination with purine nucleoside analogs on acute myeloid leukemia progenitors in vitro[J].Eur J Haematol,2004,73(6):418.
• [41]Wamberg F,White D,Anderson E,et al.Effect of a famesyltransferase inhibitor(R115777) on ductal carcinoma in situs of breast in a human xenograft model and on breast and ovarian cancer cell growth in vitro and in vivo[J].Breast Cancer Res,2006,8(2):R21.
• [42]Harousseau JL,Lancet JE,Reiffers J,et al.A phaseⅡstudy of the oral famesyltransferase inhibitor tipifamib in patient with refractory of relapsed acute myeloid leukemia[J].Blood,2007,109(12):5151.
• [43]Harousseau JL,Maitinelli G,Jedizejczak WW,et al.A randomized phaseⅢstudy of tipifamib compared to best supportive care(including hydroxyurea) in the treatment of newly diagnosed acute myeloid leukemia(AML) in patients 70 years or older[J].Blood,2009,114 (6):1166.
• [44]Sparano JA,Moulder S,Kazi A,et al.Targeted inhibition of famesyltransferase in locally advanced breast cancer:a phaseⅠandⅡtrial of tipifamib plus dose-dense doxorubicin and cyclophosphamide[J].J Clin Oncol,2006,24(19):3013.
• [45]Cortes J,Quintas-cardama A,Carcia-nunero G,etal.PhaseⅠstudy of tipifamib in combination with imatinib for patients with chronic myelogenous leukemia in chronic phase after imatinib failure[J].Cancer, 2007,110(9):2000.
• [46]Lancet JE,Cojo I,Gotlib J,et al.A phaseⅡstudy of the famesyl-transferase inhibitor tipifamib in poor- risk and elderly patients with previously untreated acute myelogenous leukemia[J].Blood,2007, 109(4):1387.
• [47]Copland M,Pellicano F,Richmond L,et al.BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synerqizes with tyrosine kinase inhibitors[J].Blood,2008,111 (5):2843.
• [48]Baileyh H,Albertid B,Thomas JP,et al.PhaseⅠtrial of weekly paclitaxel and BMS-214662 in patients with advanced solid tumors[J]. Clin Cancer Res,2007,13(12):3623.