Magnetic resonance macromolecular agents for monitoring tumor microvessels and angiogenesis inhibition.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using macromolecular contrast media enables assessments of the tumor vasculature based on the differential distribution of the contrast agent within normal and pathologic tissues. Quantitative assays of both morphologic and functional properties can provide useful diagnostic insight into tissue angiogenesis. The use of MRI enhanced with macromolecular agents for the characterization of tumor microvessels has been experimentally demonstrated in a range of malignant tumor types. Kinetic analysis of DCE-MRI data can be used to estimate microvascular permeability and tumor blood volume. By measuring these functional tumor properties, an accurate, noninvasive, and quantitative description of the microcirculation of individual tumors can be acquired, improving the specificity of imaging examinations for cancer diagnosis and for treatment and follow up. The noninvasive MRI assessment of tumor angiogenesis can be applied in the diagnostic differentiation between benign and malignant tumors and can also provide means for in vivo monitoring of antitumor therapy. In this review, the potential clinical applications and limitations of various macromolecular contrast agents applied for evaluations of tumor angiogenesis, with and without drug interventions, are discussed.

MR angiography of tumor-related vasculature: from the clinic to the micro-environment.

Angiogenesis is a very important process for tumor growth and proliferation. Given its high temporal and spatial resolution, magnetic resonance (MR) imaging is well suited for use in the assessment of angiogenesis. MR angiography can be used clinically and experimentally for identification of tumor feeding and draining vessels, for tumor characterization, and for treatment planning. The morphologic structure of tumor vessels can be investigated in relation to tumor vessel permeability with use of specific contrast agents. To gain insight into tumor angiogenesis in vivo, the authors compared images obtained with digital photography, high-resolution MR angiography, and intravital microscopy through a dorsal skin-fold window in a rodent model. The close correlation between images obtained with these various modalities, with regard to the depiction of the developing tumor vasculature, indicates that noninvasive quantification of angiogenesis may be possible with MR imaging. Future directions in tumor imaging may include so-called four-dimensional MR angiography, in which high-resolution three-dimensional MR angiography is combined with dynamic contrast-enhanced MR imaging.

Contribution of KATP+ channels to coronary vasomotor tone regulation is enhanced in exercising swine with a recent myocardial infarction.

Previous studies demonstrated a decreased flow reserve in the hypertrophied myocardium early after myocardial infarction (MI). Previously, we reported that exacerbation of hemodynamic abnormalities and neurohumoral activation during exercise caused slight impairment of myocardial O(2) supply in swine with a recent MI. We hypothesized that increased metabolic coronary vasodilation [via ATP-sensitive K(+) (K(ATP)(+)) channels and adenosine] may have partially compensated for the increased extravascular compressive forces and increased vasoconstrictor neurohormones, thereby preventing a more severe impairment of myocardial O(2) balance. Chronically instrumented swine were exercised on a treadmill up to 85% of maximum heart rate. Under resting conditions, adenosine receptor blockade [8-phenyltheophylline (8-PT), 5 mg/kg i.v.] and K(ATP)(+) channel blockade (glibenclamide, 3 mg/kg i.v.) produced similar decreases in myocardial O(2) supply in normal and MI swine. However, while glibenclamide's effect waned in normal swine during exercise (P < 0.05), it was maintained in MI swine. 8-PT's effect was maintained during exercise and was not different between normal and MI swine. Finally, in normal swine combined treatment with 8-PT and glibenclamide produced a vasoconstrictor response that equaled the sum of the responses to blockade of the individual pathways. In contrast, in MI swine the vasoconstrictor response to 8-PT and glibenclamide was similar to that produced by glibenclamide alone. In conclusion, despite significant hemodynamic abnormalities in swine with a recent MI, myocardial O(2) supply and O(2) consumption in remodeled myocardium are still closely matched during exercise. This close matching is supported by increased K(ATP)(+) channel-mediated coronary vasodilation. Although the net vasodilator influence of adenosine was unchanged in remodeled myocardium, it became exclusively dependent on K(ATP)(+) channel opening.