Mechanisms and analysis of the CNS distribution of cediranib, a molecularly-targeted anti-angiogenic agent.
2011-08
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Mechanisms and analysis of the CNS distribution of cediranib, a molecularly-targeted anti-angiogenic agent.
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2011-08
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Abstract
The role of vascular endothelial growth factor (VEGF) in brain tumor angiogenesis via
stimulation of its receptor (VEGFR) is well established, indicating that the tumor
endothelium may be a potential target for brain tumor treatment. However, the current
angiogenesis inhibitors used in clinical trials so far have shown limited effects on tumor
growth and improvement in survival. Cediranib is an orally available small-molecule
kinase inhibitor of all three VEGFR isoforms, with additional activity against PDGFRß
and c-KIT. Its broad activities against critical targets, especially the anti-angiogenic
activity, make cediranib an attractive option for therapy in central nervous system (CNS)
tumors. Cediranib has shown promising anti-angiogenic efficacy in early clinical trials in glioblastoma (GBM), but its anti-tumor mechanisms and its effect on the efficacy of
concurrent chemotherapies remain unclear. ATP-binding cassette transporters p-glycoprotein (P-gp) and breast cancer resistance
protein (BCRP) have been shown to work in concert to restrict brain penetration of
several tyrosine kinase inhibitors. This study investigated the influence of P-gp and
BCRP at the blood-brain barrier (BBB) on the CNS penetration of cediranib. Although in
vitro studies suggest that both P-gp and BCRP significantly affect intracellular delivery
of cediranib, in vivo data indicated that P-gp is a dominant efflux transporter for cediranib
and BCRP plays a minor role in limiting transport of cediranib across the BBB. The
interaction of cediranib with these brain efflux transporters could limit the antiangiogenic
and anti-tumor action in cells in the brain parenchyma and might lead to poor iv
outcomes in clinical trials. A more thorough understanding of the mechanisms controlling
the delivery of cediranib to its targets will allow more efficacious use of this drug in
GBM.
To better understand the brain distributional kinetics, simulation strategies were employed to
explore the appropriate ways to compare the true brain partitioning among different
transporter deficient transgenic mouse groups, which, in general, helps in exploring the
contribution of each drug transporter to the brain drug delivery. There are two partial-areas analyses utilized to determine the exit rate constant from the brain, the performances of
which were evaluated and compared in the current study. The requirement for accurate
determination of the brain-to-plasma ratio of the area under the concentration-time curve
(AUC) also warrants the investigation of a Bayesian approach to estimate the variability
around the ∞
o AUC and the tissue-to-plasma ∞
o AUC ratio obtained by destructive sampling Since anti-angiogenic agents are commonly used in combination therapy for GBM, the
influence of anti-angiogenic therapy on tumor delivery of traditional chemotherapy and
molecularly-targeted agents was examined using a xenograft GBM model. It has been
shown that restoration of the BBB integrity by cediranib and bevacizumab could decrease
the tumor site delivery of both temozolomide and erlotinib, and even the delivery of
cediranib itself, which could also be one of the reasons for the limited efficacy of
cediranib in clinical trials.
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University of Minnesota Ph.D. dissertation. August 2011. Major: Pharmaceutics. Advisor: Dr. William F. Elmquist. 1 computer file (PDF); xi, 225 pages, appendices I-III.
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Wang, Tianli. (2011). Mechanisms and analysis of the CNS distribution of cediranib, a molecularly-targeted anti-angiogenic agent.. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/116534.
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