Increase in tumour permeability following TGF-beta type I receptor-inhibitor treatment observed by dynamic contrast-enhanced MRI.
BACKGROUND
To enhance the success rate of nanocarrier-mediated chemotherapy combined with an anti-angiogenic agent, it is crucial to identify parameters for tumour vasculature that can predict a response to the treatment of the anti-angiogenic agent.


METHODS
To apply transforming growth factor (TGF)-beta type I receptor (TbetaR-I) inhibitor, A-83-01, to combined therapy, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was carried out in mice bearing colon 26 cells using gadolinium (Gd)-DTPA and for its liposomal formulation to evaluate changes in tumour microvasculature following A-83-01. Tumour vascular parameters from DCE-MRI were compared with histological assessment and apparent diffusion coefficient of water in tumour generated by diffusion-weighted MRI.


RESULTS
Contrary to evaluations reported for anti-angiogenic agents, A-83-01 treatment increased the initial area under the Gd concentration-time curve (IAUGC60), volume transfer constant (K(trans)) and fractional plasma volume (v(p)) significantly within 24 h, that was positively related to alpha-smooth muscle actin-positive pericyte coverage and tumour cell proliferation, and was correlated inversely with the apparent diffusion coefficient. The vascular function of the tumour improved by A-83-01 treatment was well assessed on post-liposomal Gd-DTPA-enhanced MR images, which predicted delivery of a liposomal drug to the tumour.


CONCLUSIONS
These findings suggest that DCE-MRI and, in particular, K(trans) and v(p) quantitation, provide important additional information about tumour vasculature by A-83-01 treatment.
Minowa
T
T
Institute of Medicinal Chemistry, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan.
Kawano
K
K
Kuribayashi
H
H
Shiraishi
K
K
Sugino
T
T
Hattori
Y
Y
Yokoyama
M
M
Maitani
Y
Y
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003287:Contrast Media; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D019786:Gadolinium DTPA / Q000493:pharmacokinetics*; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D013859:Thiocarbamates / Q000494:pharmacology*; D013882:Thiosemicarbazones
C507011:A-83-01; D003287:Contrast Media; D011720:Pyrazoles; D018125:Receptors, Transforming Growth Factor beta; D013859:Thiocarbamates; D013882:Thiosemicarbazones; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D019786:Gadolinium DTPA