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SU6668 inhibits Flk‐1/KDR and PDGFRβ in vivo, resulting in rapid apoptosis of tumor vasculature and tumor regression in mice
Author(s) -
Laird A. Douglas,
Christensen James G.,
Li Guangmin,
Carver Jeremy,
Smith Kimberly,
Xin Xiaohua,
Moss Katherine G.,
Louie Sharianne G.,
Mendel Dirk B.,
Cherrington Julie M.
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.01-0700com
Subject(s) - in vivo , microvessel , apoptosis , biology , cancer research , platelet derived growth factor receptor , angiogenesis , ex vivo , growth factor , endocrinology , receptor , medicine , biochemistry , microbiology and biotechnology
SU6668 is a small molecule inhibitor of the angiogenic receptor tyrosine kinases Flk‐1/KDR, PDGFRβ, and FGFR1. In mice, SU6668 treatment resulted in regression or growth arrest of all large established human tumor xenografts examined associated with loss of tumor cellularity. The events underlying loss of tumor cellularity were elucidated in detail in several tumor models. SU6668 treatment induced apoptosis in tumor microvessels within 6 h of the initiation of treatment. Dose‐dependent decreases in tumor microvessel density were observed within 3 days of the first treatment. These changes were accompanied by decreased tumor cell proliferation and increased tumor cell apoptosis. Rapid increases in VEGF transcript levels were seen, consistent with the induction of tumor hypoxia. Using Western blot analyses, we determined that these in vivo antiangiogenic and proapoptotic effects of SU6668 occur at doses comparable to those required to inhibit Flk‐1/KDR and PDGFRβ phosphorylation in tumors. Potent, dose‐dependent inhibition of Flk‐1/KDR activity in vivo was independently demonstrated using vascular permeability as a readout. These data demonstrate that SU6668‐induced inhibition of angiogenic receptor tyrosine kinase activity in vivo is associated with rapid vessel killing in tumors, leading to broad and potent antitumor effects.