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Effect of p53 Status on Tumor Response to Antiangiogenic Therapy
Joanne L. Yu,12Janusz W. Rak,3Brenda L. Coomber,4Daniel J. Hicklin,5Robert S. Kerbel12*
The p53 tumor suppressor gene is inactivated in the
majority of human cancers. Tumor cells deficient in p53 display a
diminishedrate of apoptosis under hypoxic conditions, a circumstance
thatmight reduce their reliance on vascular supply, and hence theirresponsiveness to antiangiogenic therapy. Here, we report thatmice
bearing tumors derived from p53/ HCT116
human colorectal cancer cells were less responsive toantiangiogenic
combination therapy than mice bearing isogenicp53+/+ tumors. Thus, although antiangiogenic
therapy targets geneticallystable endothelial cells in the tumor
vasculature, genetic alterationsthat decrease the vascular dependence
of tumor cells can influencethe therapeutic response of tumors to this
therapy.
1 Sunnybrook and Women's College Health
Sciences Centre, Molecular and Cellular Biology Research, Room S-218,
2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
2 Department of Medical Biophysics, University of
Toronto, Toronto, Ontario, Canada M5S 1A1.
3 Hamilton Civic Hospitals Research Centre, McMaster
University, Hamilton, Ontario, Canada L8V 1C3.
4 Department of Biomedical Sciences, Ontario
Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G
2W1.
5 ImClone Systems, Inc., 180 Varick Street, 7th
Floor, New York, NY 10014, USA.
*
To whom correspondence should be addressed. E-mail:
robert.kerbel{at}swchsc.on.ca
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[DOI: 10.1126/science.297.5581.471a] |Abstract »|Full Text »|PDF »
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