Fractionated Therapy of HER2-Expressing Breast and Ovarian Cancer Xenografts in Mice with Targeted Alpha Emitting 227Th-DOTA-p-benzyl-trastuzumab 英文参考文献.docVIP

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Fractionated Therapy of HER2-Expressing Breast and Ovarian Cancer Xenografts in Mice with Targeted Alpha Emitting 227Th-DOTA-p-benzyl-trastuzumab 英文参考文献.doc

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Fractionated Therapy of HER2-Expressing Breast and Ovarian Cancer Xenografts in Mice with Targeted Alpha Emitting 227Th-DOTA-p-benzyl-trastuzumab 英文参考文献

FractionatedTherapyofHER2-ExpressingBreastand OvarianCancerXenograftsinMicewithTargetedAlpha Emitting 227Th-DOTA-p-benzyl-trastuzumab HelenHeyerdahl1*,NasirAbbas1,EllenMengshoelBrevik2,CamillaMollatt1,JosteinDahle1,3 1DepartmentofRadiationBiology,InstituteforCancerResearch,OsloUniversity,Hospital-TheNorwegianRadiumHospital,Oslo,Norway,2DepartmentofResearchand Development,AlgetaASA,Oslo,Norway,3DepartmentofResearchandDevelopment,NordicNanovectorAS,Oslo,Norway Abstract Background:Theaimofthisstudywastoinvestigatetherapeuticefficacyandnormaltissuetoxicityofsingledosageand fractionatedtargetedalphatherapy(TAT)inmicewithHER2-expressingbreastandovariancancerxenograftsusingthelow doserateradioimmunoconjugate 227Th-DOTA-p-benzyl-trastuzumab. Methodology/Principal Findings: Nude mice carrying HER2-overexpressing subcutaneous SKOV-3 or SKBR-3 xenografts weretreatedwith1000kBq/kg 227Th-trastuzumabassingleinjectionorfourinjectionsof250kBq/kgwithintervalsof4– 5days, 2weeks, or 4weeks. Control animals were treated with normal saline or unlabeled trastuzumab. In SKOV-3 xenografts tumor growth to 10-fold size was delayed (p,0.01) and survival with tumor diameter less than 16mm was prolonged (p,0.05) in all TAT groups compared to the control groups. No statistically significant differences were seen amongthetreatedgroups.InSKBR-3xenograftstumorgrowthto10-foldsizewasdelayedinthesingleinjectionand4– 5daysintervalgroups(p,0.001)andallexceptthe4weeksintervalTATgroupshowedimprovedsurvivaltothecontrol groups(p,0.05).Toxicitywasassessedbybloodcellcounts,clinicalchemistrymeasurementsandbodyweight.Transient reduction in white blood cells was seen for the single injection and 4–5days interval groups (p,0.05). No significant changes were seen in red blood cells, platelets or clinical chemistry parameters. Survival without life threatening loss of bodyweightwassignificantlyprolongedin4weeksintervalgroupcomparedtosingleinjectiongroup(p,0.05)forSKOV-3 animalsandin2weeksintervalgroupcompare