Early antiangiogenic activity of SU11248 evaluated in vivo by dynamic contrast-enhanced magnetic resonance imaging in an experimental model of colon carcinoma.
OBJECTIVE
To compare two dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) techniques in terms of their ability in assessing the early antiangiogenic effect of SU11248, a novel selective multitargeted tyrosine kinase inhibitor, that exhibits direct antitumor and antiangiogenic activity via inhibition of the receptor tyrosine kinases platelet-derived growth factor receptor, vascular endothelial growth factor receptor, KIT, and FLT3.


METHODS
A s.c. tumor model of HT29 human colon carcinoma in athymic mice was used. Two DCE-MRI techniques were used based, respectively, on macromolecular [Gd-diethylenetriaminepentaacetic acid (DTPA)-albumin] and low molecular weight (Gd-DTPA) contrast agents. The first technique provided a quantitative measurement of transendothelial permeability and fractional plasma volume, accepted surrogate markers of tumor angiogenesis. With the second technique, we quantified the initial area under the concentration-time curve, which gives information related to tumor perfusion and vascular permeability. Experiments were done before and 24 hours after a single dose administration of SU11248.


RESULTS
The early antiangiogenic effect of SU11248 was detected by DCE-MRI with macromolecular contrast agent as a 42% decrease in vascular permeability measured in the tumor rim. The effect was also detected by DCE-MRI done with Gd-DTPA as a 31% decrease in the initial area under the concentration-time curve. Histologic slices showed a statistically significant difference in mean vessel density between the treated and control groups.


CONCLUSIONS
The early antiangiogenic activity of SU11248 was detected in vivo by DCE-MRI techniques using either macromolecular or low molecular weight contrast agents. Because DCE-MRI techniques with low molecular weight contrast agents can be used in clinical studies, these results could be relevant for the design of clinical trials based on new paradigms.
Marzola
Pasquina
P
Dipartimento di Scienze Morfologico-Biomediche, Sezione di Anatomia ed Istologia, Università di Verona, Verona, Italy. pasquina.marzola@univr.it
Degrassi
Anna
A
Calderan
Laura
L
Farace
Paolo
P
Nicolato
Elena
E
Crescimanno
Caterina
C
Sandri
Marco
M
Giusti
Anna
A
Pesenti
Enrico
E
Terron
Andrea
A
Sbarbati
Andrea
A
Osculati
Francesco
F
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D003110:Colonic Neoplasms / Q000098:blood supply / Q000175:diagnosis / Q000188:drug therapy*; D003287:Contrast Media; D019786:Gadolinium DTPA; D019073:HT29 Cells; D006801:Humans; D007089:Image Enhancement; D007211:Indoles / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control; D011758:Pyrroles / Q000627:therapeutic use*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D000077210:Sunitinib; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D007211:Indoles; D011758:Pyrroles; D019786:Gadolinium DTPA; D000077210:Sunitinib