恶性肿瘤骨转移治疗的研究新进展-课件.ppt

1、占占80%Figure from L Mosekilde病病 理理 性性 骨骨 折折-EtidronatTiludronatClodronatOOP-COP-(CH)2OHN2)43OOP-COP-(CH)2)3OHNH2PamidronatAlendronatOP-COP-SClHOOOOOOOP-COOP-ClClOCH(CH)CH3OOONH2OOOOOOP-COOP-CH3OHO-OOP-COOP2)2OHIbandronat-O-O(CH)-Basic chemical structureORRCPOHOHPOHOOHHOOP-CONaOPOHZoledronat-O-OCH2-NH

2、OOP-CONaOPOHRisedronat-O-OCH2-NN唑来膦酸独有的双氮原子环状结构使其具备极强的生物活性唑来膦酸独有的双氮原子环状结构使其具备极强的生物活性抑制破骨细胞形成、移动和破骨活抑制破骨细胞形成、移动和破骨活性，促进凋亡性，促进凋亡骨骨质表面释放质表面释放成成骨骨细胞和破骨细胞活细胞和破骨细胞活动时浓度增加动时浓度增加调节成骨细胞和破骨细调节成骨细胞和破骨细胞之间的信号胞之间的信号体外相对抑制强度，骨培养体内相对抑制强度，高钙血症小鼠103102101100100 101 102 103 104 105 106唑来膦酸唑来膦酸利塞膦酸盐伊班膦酸盐阿仑膦酸盐奥帕膦酸盐Neri

3、dronate帕米膦酸盐氯屈膦酸盐羟乙二膦酸盐Green JR,et al.J Bone Miner Res.1994;9:745-751.FDAEMEAFDAEMEAFDAEMEAFDAEMEAFDAEMEAFDAEMEAEMEAEMEAEMEA唑来膦酸唑来膦酸是被美国和欧盟同时批是被美国和欧盟同时批准适应症最多的双膦酸盐准适应症最多的双膦酸盐 手术手术 化疗化疗 内分泌治疗内分泌治疗化疗、放疗化疗、放疗 放疗放疗死亡死亡确诊为恶性肿瘤确诊为恶性肿瘤 出现骨转移出现骨转移 出现骨痛出现骨痛化疗化疗 骨痛缓解骨痛缓解内分泌治疗内分泌治疗 内分泌内分泌治疗治疗 骨痛再次出现骨痛再次出现双膦酸盐双

4、膦酸盐-长期持续使用长期持续使用骨痛缓解骨痛缓解早期治疗早期治疗止痛治疗止痛治疗 放疗放疗维持治疗维持治疗唑来膦酸治疗恶性肿瘤骨转移唑来膦酸治疗恶性肿瘤骨转移SREs的的临床研究结果回顾临床研究结果回顾*恶性肿瘤所致的高钙血症也被作为骨骼相关事件之一恶性肿瘤所致的高钙血症也被作为骨骼相关事件之一.中位时间：唑来膦酸4mg488天安慰剂321天其他潜在的标记物包括：C-端1型胶原末端肽，I型胶原螺旋肽，抗酒石酸酸性磷酸酶，骨膜素,组织蛋白L等。Coleman et al.J Clin Oncol.2005;23:4925-4935.NTX levels(nmol/mmol creatinine)

5、:Low 50,Moderate 50-99,High 100.NSCLC=Non-small cell lung cancer.Coleman et al.J Clin Oncol.2005;23:4925-4935.Horizontal lines represent 95%confidence interval.NTX levels(nmol/mmol creatinine):Low 50,Moderate 50-99,High 100.SRE=Skeletal-related event;ZOL=Zoledronic acid.Coleman et al.J Clin Oncol.20

6、05;23:4925-4935.P .001 for all analyses shown1.01.52.02.53.03.54.04.55.02.032.35All SREs2.072.32Time to 1st SRE1.572.21Progression in bone3.114.80Death5.91Relative risk ratio中中高水平高水平NTX（50-100）vs 低水平低水平NTX（100）vs 低水平低水平NTX（50）N=1,462Lipton A,et al.(ASCO 2007;Abstract#9013)Lipton A,et al.(ASCO 2007;A

7、bstract#9013)3-monthNTXEEEN正常正常组组基线基线 NTX分层分层ZOL 4 mg/3-4 weeksE Group(64 nmol/mmol creatinine)N Group(64 nmol/mmol creatinine)正常正常Lipton A,et al.(ASCO 2007;Abstract#9013)BCNSCLC and OSTsHRPC8090706050403020100Normalized 3-month NTX(EN Group)Elevated 3-month NTX(EE Group)Patients,%HRPC=Hormone-refra

8、ctory prostate cancer;NSCLC=Non-small cell lung cancer;OST=Other solid tumors.Lipton A,et al.(ASCO 2007;Abstract#9013)0.517First SREBreast cancerHRPCDeathDeathFirst SRENSCLC/OSTDeathFirst SRE00.5050.4100.6150.51.01.52.00.430.614938.002048.0017.041159.000139.28057.012Risk reduction,%P valueIn favor o

9、f EE GroupIn favor of EN GroupLipton A,et al.(ASCO 2007;Abstract#9013)E-NE-E1008060402003691215182124Proportion deceased,%patientsTime on study,months(starting at month 3)Breast Cancer(n=379)Lipton A,et al.(ASCO 2007;Abstract#9013)P=.001710个月以上个月以上Time on study,months(starting at month 3)E-NE-E10080

10、604020031215182169Proportion deceased,%patientsNSCLC and OSTs(n=204)Lipton A,et al.(ASCO 2007;Abstract#9013)5个月以上个月以上E-NE-E10080604020039121518212427Proportion deceased,%patients6Time on study,months(starting at month 3)Prostate Cancer(n=314)Lipton A,et al.(ASCO 2007;Abstract#9013)10个月以上个月以上zoledron

11、ic acidZoledronic acidvehicle Zoledronic acid inhibits tumour-induced osteolysis in nude mice bearing B02 breast cancer cellsD0D18 D30Peyruchaud et al,JBMR,2001PC-3(lytic)LuCaP 23.1(blastic)Zoledronic acid dose:200 g/kg twice a weekvehicletreatmentvehicletreatmentCorey et al,Clin Cancer Res,2003Seru

12、m PSA(ng/ml)Zol.:250 g/kg,2x/w Serum PSA(ng/ml)Zol.:250 g/kg,2x/w Days after tumor cell inoculationDays after tumor cell inoculationCorey et al,Clin Cancer Res,2003MDA-MB-231Denoyelle et al.,Br.J.Cancer,2003DU145DU145+Zoled.(10-6 M)Coxon et al.,BJU Int.,2004010080604020Docetaxel concentration(ng/ml)00.010.11.010100Ulln et al,EWOC,2003DOC+ZOL,12.5 MDOC aloneDOC+ZOL,25 M Viable cellsat 72 hours(%control)510150Apoptosis(%)Cont.DOX alone50 nM,24hZOL alone25 M,1hDOX+ZOL1.5%DOX thenZOL*13.6%ZOL then DOX1.7%Neville-Webbe et al,Int.J.Cancer,2005