Dynamic magnetic resonance imaging assessment of vascular targeting agent effects in rat intracerebral tumor models.
We used dynamic MRI to evaluate the effects of monoclonal antibodies targeting brain tumor vasculature. Female athymic rats with intracerebral human tumor xenografts were untreated or treated with intetumumab, targeting α(V)-integrins, or bevacizumab, targeting vascular endothelial growth factor (n = 4-6 per group). Prior to treatment and at 1, 3, and 7 days after treatment, we performed standard MRI to assess tumor volume, dynamic susceptibility-contrast MRI with the blood-pool iron oxide nanoparticle ferumoxytol to evaluate relative cerebral blood volume (rCBV), and dynamic contrast-enhanced MRI to assess tumor vascular permeability. Tumor rCBV increased by 27 ± 13% over 7 days in untreated rats; intetumumab increased tumor rCBV by 65 ± 10%, whereas bevacizumab reduced tumor rCBV by 31 ± 10% at 7 days (P < .001 for group and day). Similarly, intetumumab increased brain tumor vascular permeability compared with controls at 3 and 7 days after treatment, whereas bevacizumab decreased tumor permeability within 24 hours (P = .0004 for group, P = .0081 for day). All tumors grew over the 7-day assessment period, but bevacizumab slowed the increase in tumor volume on MRI. We conclude that the vascular targeting agents intetumumab and bevacizumab had diametrically opposite effects on dynamic MRI of tumor vasculature in rat brain tumor models. Targeting α(V)-integrins increased tumor vascular permeability and blood volume, whereas bevacizumab decreased both measures. These findings have implications for chemotherapy delivery and antitumor efficacy.
Department of Neurology, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, L603, Portland, OR 97239-3098, USA.
Leslie L
LL
Muldoon
Seymur
S
Gahramanov
Xin
X
Li
Deborah J
DJ
Marshall
Dale F
DF
Kraemer
Edward A
EA
Neuwelt
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology*; D002199:Capillary Permeability; D004195:Disease Models, Animal; D005260:Female; D019786:Gadolinium DTPA; D006801:Humans; D039564:Integrin alphaV / Q000737:chemistry / Q000276:immunology; D008279:Magnetic Resonance Imaging; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D051381:Rats; D011923:Rats, Nude; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000276:immunology
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D039564:Integrin alphaV; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000068258:Bevacizumab; C486839:intetumumab; D019786:Gadolinium DTPA