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    Tumor-Targeted Prodrug ICT2588 Demonstrates Therapeutic Activity Against Solid Tumors and Reduced Potential For Cardiovascular Toxicity

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    Publication date
    2014-03-18
    Author
    Gill, Jason H.
    Loadman, Paul M.
    Shnyder, Steven D.
    Cooper, Patricia A.
    Atkinson, Jennifer M.
    Ribeiro Morais, Goreti
    Patterson, Laurence H.
    Falconer, Robert A.
    Keyword
    Cancer therapy; Drug delivery; Nanotherapeutic; Peptide conjugate; Matrix metalloproteinase; Vascular disrupting agent
    Peer-Reviewed
    Yes
    
    Metadata
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    Abstract
    Development of therapeutic strategies for tumor-selective delivery of therapeutics through exploitation of the proteolytic tumor phenotype has significant scope for improvement of cancer treatment. ICT2588 is a peptide-conjugated prodrug of the vascular disrupting agent (VDA) azademethylcolchicine developed to be selectively hydrolyzed by matrix metalloproteinase-14 (MMP-14) within the tumor. In this report, we extend our previous proof-of-concept studies and demonstrate the therapeutic potential of this agent against models of human colorectal, lung, breast, and prostate cancer. In all tumor types, ICT2588 was superior to azademethylcolchicine and was greater or comparable to standard clinically used agents for the respective tumor type. Prodrug activation in clinical human lung tumor homogenates relative to stability in human plasma and liver was observed, supporting clinical translation potential. A major limiting factor to the clinical value of VDAs is their inherent cardiovascular toxicity. No increase in plasma von Willebrand factor (vWF) levels, an indicator of systemic vascular dysfunction and acute cardiovascular toxicity, was detected with ICT2588, thereby supporting the tumor-selective activation and reduced potential of ICT2588 to cause cardiovascular toxicity. Our findings reinforce the improved therapeutic index and tumorselective approach offered by ICT2588 and this nanotherapeutic approach.
    URI
    http://hdl.handle.net/10454/8823
    Version
    No full-text available in the repository
    Citation
    Gill JH, Loadman Paul M, Shnyder SD et al (2014) Tumor-Targeted Prodrug ICT2588 Demonstrates Therapeutic Activity against Solid Tumors and Reduced Potential for Cardiovascular Toxicity. Molecular Pharmaceutics. 11(4): 1294-1300.
    Link to publisher’s version
    http://pubs.acs.org/doi/abs/10.1021/mp400760b
    Type
    Article
    Collections
    Life Sciences Publications

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