Decrease in tumor apparent permeability-surface area product to a MRI macromolecular contrast medium following angiogenesis inhibition with correlations to cytotoxic drug accumulation.
BACKGROUND
New strategies for cancer therapy include the combination of angiogenesis inhibitors with cytotoxins. However, angiogenesis inhibitors may alter tumor microvessel structure and transendothelial permeability thereby reducing tumoral delivery of cytotoxic agents. The aim of this study was to estimate quantitatively the apparent permeability-surface area product (K(PS)) in tumors to a macromolecular contrast medium (MMCM), to follow changes in K(PS) induced by antibodies to vascular endothelial growth factor (anti-VEGF), and to correlate the findings with tumor accumulation of cisplatin, a highly protein-bound cytotoxin, and 5-fluorouracil (5-FU), a small unbound cytotoxin.


METHODS
Dynamic MRI enhanced with a MMCM (albumin-(Gd-DTPA)(30)) was analyzed using a two-compartment tumor tissue model (plasma and interstitial water) to quantitatively estimate K(PS). These estimates of K(PS) were correlated with cytotoxic drug accumulations in the tumors.


RESULTS
Anti-VEGF treatment reduced K(PS) to MMCM in tumor tissue from 0.013 mL h(-1) cm(-3) (n = 9) at baseline to 0.003 mL h(-1) cm(-3) (n = 9) 24 h later (p <.05). The K(PS) values correlated significantly (r(2) =.78; p <.0001) with the tumor cisplatin accumulation. No correlation (r(2) =.001; p =.89) was found between K(PS) and tumor accumulation of the substantially smaller 5-FU molecule.


CONCLUSIONS
MMCM-enhanced MRI can be used to detect and estimate changes in K(PS) to this contrast agent following a single dose of anti-VEGF antibody. The decline in K(PS) induced by this inhibitor of angiogenesis is associated with reduced tumor concentration of a protein-bound cytotoxin, similar in molecular weight to the contrast agent. MRI assays of microvascular status as performed here may be useful to clinically monitor responses to anti-angiogenesis drugs and to optimize the choice and timing of cytotoxic drug administration.
Daldrup-Link
Heike E
HE
Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California, San Francisco, California 94143-0628, USA.
Okuhata
Yoshitaka
Y
Wolfe
Allan
A
Srivastav
Sudesk
S
Øie
Sven
S
Ferrara
Napoleone
N
Cohen
Robert L
RL
Shames
David M
DM
Brasch
Robert C
RC
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics; D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002945:Cisplatin / Q000493:pharmacokinetics; D003287:Contrast Media / Q000493:pharmacokinetics; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D011923:Rats, Nude; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
D020533:Angiogenesis Inhibitors; D000906:Antibodies; D000970:Antineoplastic Agents; D003287:Contrast Media; D042461:Vascular Endothelial Growth Factor A; D002945:Cisplatin; D005472:Fluorouracil