Functional CT for quantifying tumor perfusion in antiangiogenic therapy in a rat model.
OBJECTIVE
To determine the histologic basis of perfusion parameters measured at functional computed tomography (CT) and to examine the relationship between changes in perfusion and changes in histologic parameters after antiangiogenic therapy in a rat model.


METHODS
This study had institutional animal care and use committee approval. Among 20 Fischer rats with implanted FN13762 tumors in the liver, 10 were treated with SU5416, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, and 10 were treated with the diluent only as control rats. Six rats chosen at random from each group underwent functional CT for the measurement of tumor blood flow, blood volume, mean transit time, and permeability-surface area product. Tumor tissue slides corresponding to functional CT sections were examined to measure tumor microvascular density, number of luminal vessels, vascular perimeter, and vascular area. Two-tailed Student t testing was used to determine differences in growth, numbers of metastases to major organs, vascularity, and perfusion between SU5416-treated and control tumors. Pearson correlation coefficients were used to investigate relationships between vascular parameters.


RESULTS
Mean tumor volume and number of metastases, respectively, were lower in SU5416-treated rats than in control rats (1580 mm3 +/- 830 [standard deviation] vs 2330 mm3 +/- 960 and 22.4 +/- 11.0 vs 35.2 +/- 17.3); however, these differences were not significant (P = .084 and P = .079). Mean tumor microvascular density was significantly lower in SU5416-treated rats than in control rats (6.4 vessels per field +/- 4.6 vs 17.2 vessels per field +/- 7.5, P < .001); however, vessel perimeter and vessel area, respectively, were significantly larger in treated rats than in control rats (470 microm per field +/- 320 vs 360 microm per field +/- 270, P = .02; and 4010 microm2 per field +/- 2990 vs 2230 microm2 per field +/- 1750, P = .001). Significant correlations were observed between microvascular density and vessel perimeter and area (r = 0.59 and r = 0.25, respectively; P < .01 for both) in SU5416-treated tumors but not control tumors. Blood flow, blood volume, and permeability-surface area product at functional CT were significantly higher in SU5416-treated tumors than in control tumors (P < .001 for all).


CONCLUSIONS
These results validate the idea that functional CT can help quantify the perfusion function of mature vessels but not changes in microvessel density in antiangiogenic therapy.
Kan
Zuxing
Z
Department of Diagnostic Radiology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. zkan@di.mdacc.tmc.edu
Phongkitkarun
Sith
S
Kobayashi
Satoshi
S
Tang
Yi
Y
Ellis
Lee M
LM
Lee
Ting Y
TY
Charnsangavej
Chusilp
C
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D005260:Female; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008114:Liver Neoplasms, Experimental / Q000098:blood supply* / Q000000981:diagnostic imaging*; D008833:Microcirculation / Q000033:anatomy & histology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D014057:Tomography, X-Ray Computed
D020533:Angiogenesis Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C116890:Semaxinib