Objective: Osteosarcoma (OS) is highly metastatic and the most common primary malignant bone tumor. Hypoxia and CXCR4-overexpression in OS may play a role in resistance to radiotherapy. Using a metastatic OS mouse model, we investigated whether combining radiotherapy with a stroma-modifying drug (the angiotensin receptor 1 blocker losartan) and an anti-metastatic agent (the CXCR4 inhibitor AMD3100) is an effective OS treatment strategy.

Material and Methods: A highly metastatic, CXCR4-overexpressing Os-P0107 cell line was used to generate subcutaneous isografts in syngeneic C3Hf/Sed mice. When the tumors reached 6 mm in diameter, we treated the mice with either losartan (40 mg/kg body weight, gavage), AMD3100 (AMD, 5 mg/kg body weight, i.p.), or a combination of both drugs daily for 14 days, with 20 Gy local irradiation (IR) on day 7. We evaluated the tumorgrowth delay (TGD), distant metastases and host survival, as well as tumor vascular perfusion and tumor hypoxia.

Results: Treatment with IR, Losartan+IR, or AMD+IR resulted in a significant and comparable TGD (12 to 20 days) in Os-P0107 tumors versus the controls (all p<0.01). However, only the combination of Losartan+AMD+IR significantly enhanced tumor response to radiation by increasing TGD (additional 12 days, Losartan+AMD+IR vs. IR p=0.0215), decreasing distant metastasis (p=0.008), and increasing survival (p=0.025). Losartan treatment significantly increased CD31 positive tumor vascular density and decreased pimonidazole positive (hypoxic) areas (Percentage of CD31 and Pimo positive area; Losartan vs. Control, both p<0.01).

sushihouse kolstads americanpridefasteners trueforge hotelposeidon youngswoodfinishing arditomason thebestofreno eeclongisland doktervanhecke famsales adla bogatylaw prefplastics kirbycontractinginc unlsp boban dottoressaromolimonica thebestofsanfrancisco vernix digitaldocuments tristatepropertybrokers sotrafib cemcorpny agenziaimmobiliarebuti joesitalianfoodmarket corpoguardiedicitta icsatc antoniniassicurazioni besel strappedincarseatsafety drevobeton blessingconstructionny centre-endorphine qmbtunisia elearning 357 mpress rrappliance ciaautomazioni antikva stubbanvel tacticalpublicrelations mpulshnk paulyboybrand lordshoes ijd-procom thebestrestaurants atkpalvelut ceat leonfukspc pilotexamssa ashgrovecabins universalshielding thebestofcharlotte johnjmazurinc rollnroaster thecabinetwarehouse pocketchangeduo thebestofmilwaukee resan sooli vwe centralwindowcleaning reinforcedplasticslab bugbustersofli ciandrigiardini arfada centrumeigenwijs thebestofmemphis maisonpearly islipll dcgraphicsinc agetranquille relisandroth thebestofcharleston traiteur-wn safi-ingenierie justmyvoice harrishardware louisbarbatolandscaping brightstartoursworld rga-insurance calacatajumper ezantia mrcheapocds van4holiday cigap richtour fagyhatar sicc weshopmall ventovuori sobatrapcapbon unityrubberllc thebestofsaltlakecity ircinc sescoindustries connply storen-servicesenter psnry greatneckcollision ironfitendurance tuscanycountryhouse sansovinocalcio bbradydesign samsam vdtarification springersoil thebestofdayton milantechnology labradoodlesoflongisland daliamohamed theconsultantpowerhouse gunnbrush kruunuosk shulmanproduce balcosupply conso-med federalnetworks bellmoreglass alwaysaffordableconcrete jayteeinsurance carolina-cabins cmorfinance stretchritepackaging dishaairwaysenterprise biocontrol distribio peterivill lcc inspekta jvidesigns royalroseinc calabriapizza fadhila prato-pronto-effetto arbemachine olsonelectricnj tkbl tuttifotokft alpernmd ggsupplywholesale almaxcorporation sotuflex ecustomgutter studenipotok metal-lineconcept rettsodontologi nutecsystems aclotbeach gjonnes-bygg cavalierinternational mnemos southfloridashuttles ajchemicalsupply rachelsfireisland concepto nesponge ultimatestylesofamerica techniquesmadeeasydrivingschool stevesmeatsfreeport eastwest gritbrush plussplan biosens viltkam wikaya paintballconcept justmyvoice securecarkeysupply justmyvoice allcountylegal catt plugandcharge ttandlcontracting justmyvoice islandboatlettering gms-tunisie sportsiena bloeiop touchofclasscollision kotekservice ittoscana pallongislandlacrosse industrialfinishings painoutband rakvag-batforening konemies rrfamilychiropractic infienile shbcgroup footpharmacydirect scuolaguidaprato ans-nettoyage autoskola saafa autolaky1 fixcars longislandelitelandscaping rayscan palaconstruction studio44 crealhome viniferi gavinburke ciprianigiardini davidpokorny osteriailcapodaglio thebestoffairfax centroorafofaccioli ateliervb bbdps thebestoffresno prodigus stratpak umisushirestaurant sotim suldalrenovasjon amer-equip k-kleven jerryspridepotatoes neuroky psicologozampoli jjslandscaping thebestofoklahomacity responsivesales paratie-antiallagamento-shop hearproof cfat ruspinameubles planetbioplastics lynbrook-plumber fcdf-ye brechanparkett valley-stream-plumber diagnosismaker aquavaria jedit garageennour heimdalbygg thebestoflittlerock raybomarine bayshorepaper gmstowing potatura-abbattimento-piante thebestoflouisville michaelalbert thebestofannarbor unitypavers mtnfueloil durub-mudiya lesgensdere dormerking thusney italianvistatravel maiemad gtiuniformcleaning suddenimpactli levituuli sourisalavie mayoiltank mschwartzfeather rands arieslimousines orthoticworld longislandcocktailhours waterjet allislandpaving dukediagnostic klfgoteborg yanezviaggi apruk decogato springeroilltd semapsolar irisgioiellicomprooro msedpsoftware fourcmanagement holemans 7consulting medinet evertile robertwitcomblandscape ceramics adrobotengineering volt-energy huisjacobs chimneyserviceboston eastmainstdental gcbt rememberingbriank elligiardiniespurghi paulslandscaping luisrestorations mgstunisie fixcarsny crcdd hotelprincipessalucca turvahallinta ralphjr thales irrigazione-giardini spantecsystems biomedic fgt-trading sols-egypt spectrumlaboratoriesinc prosecurite spongewarehouse afsainc dellafrancadevelopmentgroup leragazzedifirenze ferrettiwatches dovreentreprenor digitalhvac mostlymica fleurs-velghe autoscuolalebadie interlockingrubbertiles meadowcreekhoa bcn corpjetsupport jrkitchensflooring arteletti