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Science 30 April 1999:
Vol. 284. no. 5415, pp. 808 - 812
DOI: 10.1126/science.284.5415.808
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Reports

Effects of Angiogenesis Inhibitors on Multistage Carcinogenesis in Mice

Gabriele Bergers, 1 Kashi Javaherian, 2 Kin-Ming Lo, 3 Judah Folkman, 2 Douglas Hanahan 1*

Solid tumors depend on angiogenesis for their growth. In a transgenic mouse model of pancreatic islet cell carcinogenesis (RIP1-Tag2), an angiogenic switch occurs in premalignant lesions, and angiogenesis persists during progression to expansive solid tumors and invasive carcinomas. RIP1-Tag2 mice were treated so as to compare the effects of four angiogenesis inhibitors at three distinct stages of disease progression. AGM-1470, angiostatin, BB-94, and endostatin each produced distinct efficacy profiles in trials aimed at preventing the angiogenic switch in premalignant lesions, intervening in the rapid expansion of small tumors, or inducing the regression of large end-stage cancers. Thus, anti-angiogenic drugs may prove most efficacious when they are targeted to specific stages of cancer.

1 Department of Biochemistry and Biophysics and Hormone Research Institute, University of California, San Francisco, 513 Parnassus Ave, San Francisco, CA 94143-0534, USA.
2 Department of Surgery, Children's Hospital Medical Center and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
3 Lexigen Pharmaceuticals, 125 Hartwell Avenue, Lexington, MA 02173, USA.
*   To whom correspondence should be addressed. E-mail: dh{at}biochem.ucsf.edu

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The transcription factor Net regulates the angiogenic switch.
H. Zheng, C. Wasylyk, A. Ayadi, J. Abecassis, J. A Schalken, H. Rogatsch, N. Wernert, S.-M. Maira, M.-C. Multon, and B. Wasylyk (2003)
Genes & Dev. 17, 2283-2297
   Abstract »    Full Text »    PDF »
Stage-Dependent Expression of an Angiogenic Agent and Vascular Organization in Experimental Skin Tumor Development.
V. Nayha, J. Laitakari, and F. Stenback (2003)
Toxicol Pathol 31, 539-548
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Inhibition of Angiogenesis and Angiogenesis-dependent Tumor Growth by the Cryptic Kringle Fragments of Human Apolipoprotein(a).
J.-S. Kim, J.-H. Chang, H.-K. Yu, J.-H. Ahn, J.-S. Yum, S.-K. Lee, K.-H. Jung, D.-H. Park, Y. Yoon, S.-M. Byun, et al. (2003)
J. Biol. Chem. 278, 29000-29008
   Abstract »    Full Text »    PDF »
Building a better Trap.
J. D. Hood and D. A. Cheresh (2003)
PNAS 100, 8624-8625
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Corneal Transduction to Inhibit Angiogenesis and Graft Failure.
R. C. Murthy, T. J. McFarland, J. Yoken, S. Chen, C. Barone, D. Burke, Y. Zhang, B. Appukuttan, and J. T. Stout (2003)
Invest. Ophthalmol. Vis. Sci. 44, 1837-1842
   Abstract »    Full Text »    PDF »
Inhibition of rat corneal angiogenesis by a nuclease-resistant RNA aptamer specific for angiopoietin-2.
R. R. White, S. Shan, C. P. Rusconi, G. Shetty, M. W. Dewhirst, C. D. Kontos, and B. A. Sullenger (2003)
PNAS 100, 5028-5033
   Abstract »    Full Text »    PDF »
Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis.
K. S. Moulton, K. Vakili, D. Zurakowski, M. Soliman, C. Butterfield, E. Sylvin, K.-M. Lo, S. Gillies, K. Javaherian, and J. Folkman (2003)
PNAS 100, 4736-4741
   Abstract »    Full Text »    PDF »
Molecular Therapeutics: Is One Promiscuous Drug against Multiple Targets Better than Combinations of Molecule-specific Drugs?.
C. L. Arteaga (2003)
Clin. Cancer Res. 9, 1231-1232
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Anti-angiogenic Activity of the Recombinant Kringle Domain of Urokinase and Its Specific Entry into Endothelial Cells.
K. S. Kim, Y.-K. Hong, Y. A. Joe, Y. Lee, J.-Y. Shin, H.-E. Park, I.-H. Lee, S.-Y. Lee, D.-K. Kang, S.-I. Chang, et al. (2003)
J. Biol. Chem. 278, 11449-11456
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Focal Adhesion Kinase Is Required for Blood Vessel Morphogenesis.
D. Ilic, B. Kovacic, S. McDonagh, F. Jin, C. Baumbusch, D. G. Gardner, and C. H. Damsky (2003)
Circ. Res. 92, 300-307
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Increased collagenase activity in macrophages from bronchial lavage as a diagnostic marker of non-small cell lung cancer.
Y Hakoda, Y Ito, A Nagate, K Minemura, K Utsumi, M Aoshima, and K Ohyashiki (2003)
Thorax 58, 122-126
   Abstract »    Full Text »    PDF »
Antitumor Activity of the 16-kDa Prolactin Fragment in Prostate Cancer.
J. Kim, W. Luo, D.-T. Chen, K. Earley, J. Tunstead, L.-Y. Yu-Lee, and S.-H. Lin (2003)
Cancer Res. 63, 386-393
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Prevention of leptin binding to its receptor suppresses rat leukemic cell growth by inhibiting angiogenesis.
P. O. Iversen, C. A. Drevon, and J. E. Reseland (2002)
Blood 100, 4123-4128
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New functional roles for non-collagenous domains of basement membrane collagens.
N. Ortega and Z. Werb (2002)
J. Cell Sci. 115, 4201-4214
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Safety and Pharmacokinetic Effects of TNP-470, an Angiogenesis Inhibitor, Combined With Paclitaxel in Patients With Solid Tumors: Evidence for Activity in Non-Small-Cell Lung Cancer.
R. S. Herbst, T. L. Madden, H. T. Tran, G. R. Blumenschein Jr, C. A. Meyers, L. F. Seabrooke, F. R. Khuri, V. K. Puduvalli, V. Allgood, H. A. Fritsche Jr, et al. (2002)
J. Clin. Oncol. 20, 4440-4447
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Laminin Modulates Morphogenic Properties of the Collagen XVIII Endostatin Domain.
K. Javaherian, S. Y. Park, W. F. Pickl, K. R. LaMontagne, R. T. T. Sjin, S. Gillies, and K.-M. Lo (2002)
J. Biol. Chem. 277, 45211-45218
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Vascular Permeability Factor/Vascular Endothelial Growth Factor: A Critical Cytokine in Tumor Angiogenesis and a Potential Target for Diagnosis and Therapy.
H. F. Dvorak (2002)
J. Clin. Oncol. 20, 4368-4380
   Abstract »    Full Text »    PDF »


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