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Keywords:

  • angiogenesis inhibition;
  • apparent permeability surface area product;
  • chemotherapy;
  • macromolecular contrast media;
  • MRI;
  • VEGF

ABSTRACT

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 (KPS) in tumors to a macromolecular contrast medium (MMCM), to follow changes in KPS 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 KPS. These estimates of KPS were correlated with cytotoxic drug accumulations in the tumors.

Results: Anti-VEGF treatment reduced KPS 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 KPS values correlated significantly (r2 = .78; p < .0001) with the tumor cisplatin accumulation. No correlation (r2 = .001; p = .89) was found between KPS and tumor accumulation of the substantially smaller 5-FU molecule.

Conclusions: MMCM-enhanced MRI can be used to detect and estimate changes in KPS to this contrast agent following a single dose of anti-VEGF antibody. The decline in KPS 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.