Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Science 26 May 2006:
Vol. 312. no. 5777, pp. 1171 - 1175
DOI: 10.1126/science.1125950

Perspective

Antiangiogenic Therapy: A Universal Chemosensitization Strategy for Cancer?

Robert S. Kerbel

For more than 50 years, a major goal of research in cancer therapeutics has been to develop universally effective agents that render cancer cells more sensitive to cytotoxic chemotherapy without substantially increasing toxicity to normal cells. The results of recent clinical trials indicate that certain antiangiogenic drugs may produce this long-sought effect. Here, I describe three distinct mechanisms that may help to explain the chemosensitizing activity of these drugs: normalizing tumor vasculature, preventing rapid tumor cell repopulation, and augmenting the antivascular effects of chemotherapy. I then discuss how these potential mechanisms might be exploited to maximize therapeutic efficacy.

Sunnybrook Health Sciences Centre, Departments of Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M4N 3M5, Canada.

E-mail: robert.kerbel{at}sri.utoronto.ca

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model.
S. L. C. Lee, P. Rouhi, L. D. Jensen, D. Zhang, H. Ji, G. Hauptmann, P. Ingham, and Y. Cao (2009)
PNAS 106, 19485-19490
   Abstract »    Full Text »    PDF »
Randomized Double-Blind Placebo-Controlled Trial of Thalidomide in Combination With Gemcitabine and Carboplatin in Advanced Non-Small-Cell Lung Cancer.
S. M. Lee, R. Rudd, P. J. Woll, C. Ottensmeier, D. Gilligan, A. Price, S. Spiro, N. Gower, M. Jitlal, and A. Hackshaw (2009)
J. Clin. Oncol. 27, 5248-5254
   Abstract »    Full Text »    PDF »
Contribution of Granulocyte Colony-Stimulating Factor to the Acute Mobilization of Endothelial Precursor Cells by Vascular Disrupting Agents.
Y. Shaked, T. Tang, J. Woloszynek, L. G. Daenen, S. Man, P. Xu, S.-R. Cai, J. M. Arbeit, E. E. Voest, D. J. Chaplin, et al. (2009)
Cancer Res. 69, 7524-7528
   Abstract »    Full Text »    PDF »
Tumor and Host-Mediated Pathways of Resistance and Disease Progression in Response to Antiangiogenic Therapy.
J. M. L. Ebos, C. R. Lee, and R. S. Kerbel (2009)
Clin. Cancer Res. 15, 5020-5025
   Abstract »    Full Text »    PDF »
Epidermal Growth Factor Receptor Inhibitors and Antiangiogenic Agents for the Treatment of Non-Small Cell Lung Cancer.
L. Horn and A. Sandler (2009)
Clin. Cancer Res. 15, 5040-5048
   Abstract »    Full Text »    PDF »
Anti-angiogenic Therapy Using Thalidomide Combined With Chemotherapy in Small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial.
S. M. Lee, P. J. Woll, R. Rudd, D. Ferry, M. O'Brien, G. Middleton, S. Spiro, L. James, K. Ali, M. Jitlal, et al. (2009)
J Natl Cancer Inst 101, 1049-1057
   Abstract »    Full Text »    PDF »
Antiangiogenic Properties of Viscum Album Extracts Are Associated with Endothelial Cytotoxicity.
S. R. ELLURU, J.-P. D. VAN HUYEN, S. DELIGNAT, F. PROST, D. HEUDES, M. D. KAZATCHKINE, A. FRIBOULET, and S. V. KAVERI (2009)
Anticancer Res 29, 2945-2950
   Abstract »    Full Text »    PDF »
Impact of Tumor Cell VEGF Expression on the In Vivo Efficacy of Vandetanib (ZACTIMATM; ZD6474).
D. W. SIEMANN, C. M. NORRIS, A. RYAN, and W. SHI (2009)
Anticancer Res 29, 1987-1992
   Abstract »    Full Text »    PDF »
Angiogenesis as a Therapeutic Target in Malignant Gliomas.
A. S. Chi, A. G. Sorensen, R. K. Jain, and T. T. Batchelor (2009)
Oncologist 14, 621-636
   Abstract »    Full Text »    PDF »
Angiogenesis in the Treatment of Non-Small Cell Lung Cancer.
L. Horn and A. B. Sandler (2009)
Proceedings of the ATS 6, 206-217
   Abstract »    Full Text »    PDF »
Dominant Effect of Antiangiogenesis in Combination Therapy Involving Cyclophosphamide and Axitinib.
J. Ma and D. J. Waxman (2009)
Clin. Cancer Res. 15, 578-588
   Abstract »    Full Text »    PDF »
TSU68 Prevents Liver Metastasis of Colon Cancer Xenografts by Modulating the Premetastatic Niche.
M. Yamamoto, H. Kikuchi, M. Ohta, T. Kawabata, Y. Hiramatsu, K. Kondo, M. Baba, K. Kamiya, T. Tanaka, M. Kitagawa, et al. (2008)
Cancer Res. 68, 9754-9762
   Abstract »    Full Text »    PDF »
In Vivo Bioluminescence Imaging Monitoring of Hypoxia-Inducible Factor 1{alpha}, a Promoter That Protects Cells, in Response to Chemotherapy.
R. J. Viola, J. M. Provenzale, F. Li, C.-Y. Li, H. Yuan, J. Tashjian, and M. W. Dewhirst (2008)
Am. J. Roentgenol. 191, 1779-1784
   Abstract »    Full Text »    PDF »
Chemotherapy for Malignant Brain Tumors of Childhood.
N. G. Gottardo and A. Gajjar (2008)
J Child Neurol 23, 1149-1159
   Abstract »    PDF »
Tumor Recovery by Angiogenic Switch from Sprouting to Intussusceptive Angiogenesis after Treatment with PTK787/ZK222584 or Ionizing Radiation.
R. Hlushchuk, O. Riesterer, O. Baum, J. Wood, G. Gruber, M. Pruschy, and V. Djonov (2008)
Am. J. Pathol. 173, 1173-1185
   Abstract »    Full Text »    PDF »
The renin-angiotensin system and malignancy.
E. I. Ager, J. Neo, and C. Christophi (2008)
Carcinogenesis 29, 1675-1684
   Abstract »    Full Text »    PDF »
Paclitaxel Encapsulated in Cationic Liposomes Increases Tumor Microvessel Leakiness and Improves Therapeutic Efficacy in Combination with Cisplatin.
S. Strieth, M. E. Eichhorn, A. Werner, B. Sauer, M. Teifel, U. Michaelis, A. Berghaus, and M. Dellian (2008)
Clin. Cancer Res. 14, 4603-4611
   Abstract »    Full Text »    PDF »
Tumor Angiogenesis.
R. S. Kerbel (2008)
N. Engl. J. Med. 358, 2039-2049
   Full Text »    PDF »
Antiangiogenic Therapy with Mammalian Target of Rapamycin Inhibitor RAD001 (Everolimus) Increases Radiosensitivity in Solid Cancer.
P. C. Manegold, C. Paringer, U. Kulka, K. Krimmel, M. E. Eichhorn, R. Wilkowski, K.-W. Jauch, M. Guba, and C. J. Bruns (2008)
Clin. Cancer Res. 14, 892-900
   Abstract »    Full Text »    PDF »
Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib.
J. Ma and D. J. Waxman (2008)
Mol. Cancer Ther. 7, 79-89
   Abstract »    Full Text »    PDF »
Oncogene addiction: setting the stage for molecularly targeted cancer therapy.
S. V. Sharma and J. Settleman (2007)
Genes & Dev. 21, 3214-3231
   Abstract »    Full Text »    PDF »
[18F]Galacto-RGD Positron Emission Tomography for Imaging of {alpha}v{beta}3 Expression on the Neovasculature in Patients with Squamous Cell Carcinoma of the Head and Neck.
A. J. Beer, A.-L. Grosu, J. Carlsen, A. Kolk, M. Sarbia, I. Stangier, P. Watzlowik, H.-J. Wester, R. Haubner, and M. Schwaiger (2007)
Clin. Cancer Res. 13, 6610-6616
   Abstract »    Full Text »    PDF »
Bcl-2 Orchestrates a Cross-talk between Endothelial and Tumor Cells that Promotes Tumor Growth.
T. Kaneko, Z. Zhang, M. G. Mantellini, E. Karl, B. Zeitlin, M. Verhaegen, M. S. Soengas, M. Lingen, R. M. Strieter, G. Nunez, et al. (2007)
Cancer Res. 67, 9685-9693
   Abstract »    Full Text »    PDF »
Antiangiogenics: The Potential Role of Integrating This Novel Treatment Modality With Chemoradiation for Solid Cancers.
D. G. Duda, R. K. Jain, and C. G. Willett (2007)
J. Clin. Oncol. 25, 4033-4042
   Abstract »    Full Text »    PDF »
Antiangiogenic Strategies on Defense: On the Possibility of Blocking Rebounds by the Tumor Vasculature after Chemotherapy.
Y. Shaked and R. S. Kerbel (2007)
Cancer Res. 67, 7055-7058
   Abstract »    Full Text »    PDF »
Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice.
U. Emmenegger, Y. Shaked, S. Man, G. Bocci, I. Spasojevic, G. Francia, A. Kouri, R. Coke, W. Cruz-Munoz, S. M. Ludeman, et al. (2007)
Mol. Cancer Ther. 6, 2280-2289
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor Trap Blocks Tumor Growth, Metastasis Formation, and Vascular Leakage in an Orthotopic Murine Renal Cell Cancer Model.
H. M.W. Verheul, H. Hammers, K. van Erp, Y. Wei, T. Sanni, B. Salumbides, D. Z. Qian, G. D. Yancopoulos, and R. Pili (2007)
Clin. Cancer Res. 13, 4201-4208
   Abstract »    Full Text »    PDF »
Molecular Basis of the Synergistic Antiangiogenic Activity of Bevacizumab and Mithramycin A.
Z. Jia, J. Zhang, D. Wei, L. Wang, P. Yuan, X. Le, Q. Li, J. Yao, and K. Xie (2007)
Cancer Res. 67, 4878-4885
   Abstract »    Full Text »    PDF »
An Orally Available Small-Molecule Inhibitor of c-Met, PF-2341066, Exhibits Cytoreductive Antitumor Efficacy through Antiproliferative and Antiangiogenic Mechanisms.
H. Y. Zou, Q. Li, J. H. Lee, M. E. Arango, S. R. McDonnell, S. Yamazaki, T. B. Koudriakova, G. Alton, J. J. Cui, P.-P. Kung, et al. (2007)
Cancer Res. 67, 4408-4417
   Abstract »    Full Text »    PDF »
Anticancer Therapies Combining Antiangiogenic and Tumor Cell Cytotoxic Effects Reduce the Tumor Stem-Like Cell Fraction in Glioma Xenograft Tumors.
C. Folkins, S. Man, P. Xu, Y. Shaked, D. J. Hicklin, and R. S. Kerbel (2007)
Cancer Res. 67, 3560-3564
   Abstract »    Full Text »    PDF »
Target Practice: Lessons from Phase III Trials with Bevacizumab and Vatalanib in the Treatment of Advanced Colorectal Cancer.
M. Los, J. M. L. Roodhart, and E. E. Voest (2007)
Oncologist 12, 443-450
   Abstract »    Full Text »    PDF »
Design of Clinical Trials of Radiation Combined with Antiangiogenic Therapy.
S. Senan and E. F. Smit (2007)
Oncologist 12, 465-477
   Abstract »    Full Text »    PDF »
Functional Neoangiogenesis Imaging of Genetically Engineered Mouse Prostate Cancer Using Three-Dimensional Power Doppler Ultrasound.
J. W. Xuan, M. Bygrave, H. Jiang, F. Valiyeva, J. Dunmore-Buyze, D. W. Holdsworth, J. I. Izawa, G. Bauman, M. Moussa, S. F. Winter, et al. (2007)
Cancer Res. 67, 2830-2839
   Abstract »    Full Text »    PDF »
Mice expressing a humanized form of VEGF-A may provide insights into the safety and efficacy of anti-VEGF antibodies.
H.-P. Gerber, X. Wu, L. Yu, C. Wiesmann, X. H. Liang, C. V. Lee, G. Fuh, C. Olsson, L. Damico, D. Xie, et al. (2007)
PNAS 104, 3478-3483
   Abstract »    Full Text »    PDF »
Thrombospondin-1 Peptide ABT-510 Combined with Valproic Acid Is an Effective Antiangiogenesis Strategy in Neuroblastoma.
Q. Yang, Y. Tian, S. Liu, R. Zeine, A. Chlenski, H. R. Salwen, J. Henkin, and S. L. Cohn (2007)
Cancer Res. 67, 1716-1724
   Abstract »    Full Text »    PDF »
Alternative Vascularization Mechanisms in Cancer: Pathology and Therapeutic Implications.
B. Dome, M. J.C. Hendrix, S. Paku, J. Tovari, and J. Timar (2007)
Am. J. Pathol. 170, 1-15
   Abstract »    Full Text »    PDF »



To Advertise     Find Products


Science. ISSN 0036-8075 (print), 1095-9203 (online)