Antitumor Effects of Combining Docetaxel (Taxotere) with the Antivascular Action of Ultrasound Stimulated Microbubbles.docVIP

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2017-05-07 发布于上海
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Antitumor Effects of Combining Docetaxel (Taxotere) with the Antivascular Action of Ultrasound Stimulated Microbubbles.doc

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Antitumor Effects of Combining Docetaxel (Taxotere) with the Antivascular Action of Ultrasound Stimulated Microbubbles

AntitumorEffectsofCombiningDocetaxel(Taxotere) withtheAntivascularActionofUltrasoundStimulated Microbubbles DavidE.Goertz1,2*,MargaritaTodorova1,2,OmidMortazavi2,VladAgache2,BransonChen2, RaffiKarshafian3,KullervoHynynen1,2 1Department of Medical Biophysics, University of Toronto, Toronto, Canada, 2Sunnybrook Research Institute, Toronto, Canada, 3Department of Physics, Ryerson University,Toronto,Canada Abstract Ultrasoundstimulatedmicrobubbles(USMB)arebeinginvestigatedfortheirpotentialtopromotetheuptakeofanticancer agentsintotumortissuebyexploitingtheirabilitytoenhancemicrovascularpermeability.Atsufficientlyhighultrasound transmit amplitudes it has also recently been shown that USMB treatments can, on their own, induce vascular damage, shutdown blood flow, and inhibit tumor growth. The objective of this study is to examine the antitumor effects of ‘antivascular’USMBtreatmentsinconjunctionwithchemotherapy,whichdiffersfrompreviousworkwhichhassoughtto enhancedruguptakewithUSMBsbyincreasingvascularpermeability.Conceptuallythisisastrategysimilartocombining vasculardisruptingagentswithachemotherapy,andwehaveselectedthetaxanedocetaxel(Taxotere)forevaluatingthis approachasithaspreviouslybeenshowntohavepotentantitumoreffectswhencombinedwithsmallmoleculevascular disrupting agents. Experiments were conducted on PC3 tumors implanted in athymic mice. USMB treatments were performed at a frequency of 1MHz employing sequences of 50ms bursts (0.00024 duty cycle) at 1.65MPa. USMB treatmentswereadministeredonaweeklybasisfor4weekswithdocetaxel(DTX)beinggivenintravenouslyatadoselevel of5mg/kg.TheUSMBtreatments,eitheraloneorincombinationwithDTX,inducedanacutereductionintumorperfusion whichwasaccompaniedatthe24hourpointbysignificantlyenhancednecrosisandapoptosis.Longitudinalexperiments showed a modest prolongation in survival but no significant growth inhibition occurred in DTX–only and USMB-only treatment groups relative to control tumors. The combined USMB-DTX treatment group produced t