title: Dual targeting of tumor angiogenesis and chemotherapy by endostatin-cytosine deaminase-uracil phosphoribosyltransferase.
abstract: Several antiangiogenic drugs targeting VEGF/VEGF receptor (VEGFR) that were approved by the Food and Drug Administration for many cancer types, including colorectal and lung cancer, can effectively reduce tumor growth. However, targeting the VEGF signaling pathway will probably influence the normal function of endothelial cells in maintaining homeostasis and can cause unwanted adverse effects. Indeed, emerging experimental evidence suggests that VEGF-targeting therapy induced less tumor cell-specific cytotoxicity, allowing residual cells to become more resistant and eventually develop a more malignant phenotype. We report an antitumor therapeutic EndoCD fusion protein developed by linking endostatin (Endo) to cytosine deaminase and uracil phosphoribosyltransferase (CD). Specifically, Endo possesses tumor antiangiogenesis activity that targets tumor endothelial cells, followed by CD, which converts the nontoxic prodrug 5-fluorocytosine (5-FC) to the cytotoxic antitumor drug 5-fluorouracil (5-FU) in the local tumor area. Moreover, selective targeting of tumor sites allows an increasing local intratumoral concentration of 5-FU, thus providing high levels of cytotoxic activity. We showed that treatment with EndoCD plus 5-FC, compared with bevacizumab plus 5-FU treatment, significantly increased the 5-FU concentration around tumor sites and suppressed tumor growth and metastasis in human breast and colorectal orthotropic animal models. In addition, in contrast to treatment with bevacizumab/5-FU, EndoCD/5-FC did not induce cardiotoxicity leading to heart failure in mice after long-term treatment. Our results showed that, compared with currently used antiangiogenic drugs, EndoCD possesses potent anticancer activity with virtually no toxic effects and does not increase tumor invasion or metastasis. Together, these findings suggest that EndoCD/5-FC could become an alternative option for future antiangiogenesis therapy.
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Chun-Te
authors: CT
authors: Chen
authors: Hirohito
authors: H
authors: Yamaguchi
authors: Hong-Jen
authors: HJ
authors: Lee
authors: Yi
authors: Y
authors: Du
authors: Heng-Huan
authors: HH
authors: Lee
authors: Weiya
authors: W
authors: Xia
authors: Wen-Hsuan
authors: WH
authors: Yu
authors: Jennifer L
authors: JL
authors: Hsu
authors: Chia-Jui
authors: CJ
authors: Yen
authors: Hui-Lung
authors: HL
authors: Sun
authors: Yan
authors: Y
authors: Wang
authors: Edward T H
authors: ET
authors: Yeh
authors: Gabriel N
authors: GN
authors: Hortobagyi
authors: Mien-Chie
authors: MC
authors: Hung
references: Cancer Cell. 2009 Mar 3;15(3):232-9
references: 19249681
references: Zhonghua Zhong Liu Za Zhi. 2006 Feb;28(2):138-41
references: 16750022
references: Bioessays. 1991 Jan;13(1):31-6
references: 1722975
references: Nat Rev Clin Oncol. 2009 Oct;6(10):569-79
references: 19736552
references: Cancer Res. 2003 Oct 15;63(20):6847-54
references: 14583482
references: Gene Ther. 2001 Oct;8(20):1547-54
references: 11704815
references: Nature. 2010 Dec 9;468(7325):770-1
references: 21150987
references: Cancer Cell. 2009 Mar 3;15(3):167-70
references: 19249675
references: Cell. 1997 Jan 24;88(2):277-85
references: 9008168
references: J Clin Oncol. 2002 Sep 15;20(18):3772-84
references: 12228197
references: J Clin Oncol. 2006 Aug 1;24(22):3555-61
references: 16877721
references: J Gene Med. 2006 Sep;8(9):1086-96
references: 16832832
references: J Clin Oncol. 2008 Apr 10;26(11):1810-6
references: 18347007
references: Nat Rev Cancer. 2008 Aug;8(8):592-603
references: 18650835
references: IUBMB Life. 2009 Jun;61(6):613-26
references: 19472178
references: Breast. 2009 Oct;18 Suppl 3:S41-7
references: 19914541
references: Cancer Cell. 2009 Mar 3;15(3):220-31
references: 19249680
references: Nat Rev Cancer. 2007 May;7(5):332-44
references: 17457301
references: Nature. 2010 Dec 9;468(7325):829-33
references: 21102433
references: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4766-71
references: 12682293
references: Cancer Chemother Rep. 1966 May;50(4):219-44
references: 4957125
references: Nat Rev Cancer. 2002 Oct;2(10):727-39
references: 12360276
references: Nature. 2010 Dec 9;468(7325):824-8
references: 21102434
references: Nat Rev Cancer. 2007 Jun;7(6):475-85
references: 17522716
references: Nat Rev Cancer. 2008 Aug;8(8):604-17
references: 18497750
references: Cancer Res. 2001 Jan 15;61(2):478-81
references: 11212235
references: J Clin Oncol. 1999 Jul;17(7):2180-9
references: 10561274
references: Circ Res. 2010 Jun 25;106(12):1904-11
references: 20448213
references: J Clin Oncol. 2002 Sep 15;20(18):3792-803
references: 12228199
references: J Clin Pharm Ther. 2007 Feb;32(1):1-14
references: 17286784
references: Int J Biochem Cell Biol. 2001 Apr;33(4):357-69
references: 11312106
references: Cancer Res. 2006 Jan 1;66(1):378-84
references: 16397252
references: Heart Fail Rev. 2010 Jul;15(4):319-29
references: 19404737
references: Nat Med. 1999 May;5(5):495-502
references: 10229225
references: Nat Rev Drug Discov. 2007 Apr;6(4):273-86
references: 17396134
references: Cancer Res. 2000 Jul 15;60(14):3813-22
references: 10919655
references: J Clin Oncol. 2003 Jan 1;21(1):60-5
references: 12506171
references: Cancer Res. 1997 Mar 1;57(5):963-9
references: 9041202
references: J Am Coll Cardiol. 2009 Jun 16;53(24):2231-47
references: 19520246
references: Cell. 2007 Nov 2;131(3):463-75
references: 17981115
references: N Engl J Med. 2009 Feb 5;360(6):563-72
references: 19196673