Document Detail

Combining two strategies to improve perfusion and drug delivery in solid tumors.
MedLine Citation:
PMID:  24167277     Owner:  NLM     Status:  MEDLINE    
Blood perfusion in tumors can be significantly lower than that in the surrounding normal tissue owing to the leakiness and/or compression of tumor blood vessels. Impaired perfusion reduces oxygen supply and results in a hypoxic microenvironment. Hypoxia promotes tumor progression and immunosuppression, and enhances the invasive and metastatic potential of cancer cells. Furthermore, poor perfusion lowers the delivery of systemically administered drugs. Therapeutic strategies to improve perfusion include reduction in vascular permeability by vascular normalization and vascular decompression by alleviating physical forces (solid stress) inside tumors. Both strategies have shown promise, but guidelines on how to use these strategies optimally are lacking. To this end, we developed a mathematical model to guide the optimal use of these strategies. The model accounts for vascular, transvascular, and interstitial fluid and drug transport as well as the diameter and permeability of tumor vessels. Model simulations reveal an optimal perfusion region when vessels are uncompressed, but not very leaky. Within this region, intratumoral distribution of drugs is optimized, particularly for drugs 10 nm in diameter or smaller and of low binding affinity. Therefore, treatments should modify vessel diameter and/or permeability such that perfusion is optimal. Vascular normalization is more effective for hyperpermeable but largely uncompressed vessels (e.g., glioblastomas), whereas solid stress alleviation is more beneficial for compressed but less-permeable vessels (e.g., pancreatic ductal adenocarcinomas). In the case of tumors with hyperpermeable and compressed vessels (e.g., subset of mammary carcinomas), the two strategies need to be combined for improved treatment outcomes.
Triantafyllos Stylianopoulos; Rakesh K Jain
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-10-28
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  110     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2013 Nov 
Date Detail:
Created Date:  2013-11-13     Completed Date:  2014-01-08     Revised Date:  2014-02-05    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  18632-7     Citation Subset:  IM    
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MeSH Terms
Biomechanical Phenomena
Capillary Permeability / physiology*
Computer Simulation
Drug Delivery Systems / methods*
Models, Biological*
Neoplasms / blood supply*,  drug therapy*
Regional Blood Flow / physiology*
Grant Support
P01-CA080124/CA/NCI NIH HHS; R01-CA085140/CA/NCI NIH HHS; R01-CA096915/CA/NCI NIH HHS; R01-CA098706/CA/NCI NIH HHS; R01-CA115767/CA/NCI NIH HHS; R01-CA126642/CA/NCI NIH HHS; T32-CA073479/CA/NCI NIH HHS
Comment In:
Nat Rev Clin Oncol. 2014 Jan;11(1):4   [PMID:  24281060 ]

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