This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gorski, D. H. Articles by Weichselbaum, R. R. Search for Related Content PubMed PubMed Citation Articles by Gorski, D. H. Articles by Weichselbaum, R. R.

Potentiation of the Antitumor Effect of Ionizing Radiation by Brief Concomitant Exposures to Angiostatin¹

Departments of Radiation and Cellular Oncology [D. H. G., H. J. M., S. H., M. A. B., R. R. W.] and Surgery [R. M. S.], University of Chicago, Chicago, Illinois 60637; Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, Illinois 60611 [S. G., G. A. S.]; Renal Division, Beth Israel Deaconness Medical Center, [V. P. S.]; and Dana Farber Cancer Institute, Harvard Medical School [D. W. K.], Boston, Massachusetts 02115

Angiostatin, a proteolytic fragment of plasminogen, inhibits the growth of primary and metastatic tumors by suppressing angiogenesis. When used in combination with ionizing radiation (IR), angiostatin demonstrates potent antitumor synergism, largely caused by inhibition of the tumor microvasculature. We report here the temporal interaction of angiostatin and IR in Lewis lung carcinoma (LLC) tumors growing in the hind limbs of syngeneic mice. Tumors with an initial mean volume of 510 ± 151 mm³ were treated with IR alone (20 Gy x 2 doses on days 0 and 1), angiostatin alone (25 mg/kg/day divided twice daily) on days 0 through 13, or a combination of the two as follows: (a) IR plus angiostatin (days 0 through 13); (b) IR plus angiostatin (days 0 and 1); and (c) IR followed by angiostatin beginning on the day after IR completion and given daily thereafter (days 2 through 13). By day 14, tumors in untreated control mice had grown to 6110 ± 582 mm³, whereas in mice treated with: (a) IR alone, tumors had grown to 2854 ± 338 mm³ (P < 0.05 compared with untreated controls); and (b) angiostatin alone, tumors had grown to 3666 ± 453 mm³ (P < 0.05 compared with untreated controls). In combined-treatment groups, in mice treated with: (a) IR plus longer-course angiostatin, tumors reached 2022 ± 282 mm³ (P = 0.036 compared with IR alone); (b) IR followed by angiostatin, tumors reached 2677 ± 469 mm³ (P > 0.05 compared with IR alone); and (c) IR plus short-course angiostatin, tumors reached 1032 ± 78 mm³ (P < 0.001 compared with IR alone). These findings demonstrate that the efficacy of experimental radiation therapy is potentiated by brief concomitant exposure of the tumor vasculature to angiostatin.

¹ Supported in part by National Cancer Institute Grant CA42596.

² To whom requests for reprints should be addressed, at Department of Radiation and Cellular Oncology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637. Phone: (773) 702-0817; Fax: (773) 834-7233; E-mail: rrw@rover.uchicago.edu.

Received 9/ 1/98. Accepted 10/27/98.

This article has been cited by other articles:

				C. Oehler-Janne, W. Jochum, O. Riesterer, A. Broggini-Tenzer, G. Caravatti, V. Vuong, and M. Pruschy Hypoxia modulation and radiosensitization by the novel dual EGFR and VEGFR inhibitor AEE788 in spontaneous and related allograft tumor models Mol. Cancer Ther., September 1, 2007; 6(9): 2496 - 2504. [Abstract] [Full Text] [PDF]

				R. P.M. Dings, M. Loren, H. Heun, E. McNiel, A. W. Griffioen, K. H. Mayo, and R. J. Griffin Scheduling of Radiation with Angiogenesis Inhibitors Anginex and Avastin Improves Therapeutic Outcome via Vessel Normalization Clin. Cancer Res., June 1, 2007; 13(11): 3395 - 3402. [Abstract] [Full Text] [PDF]

				M. R. Horsman and D. W. Siemann Pathophysiologic Effects of Vascular-Targeting Agents and the Implications for Combination with Conventional Therapies Cancer Res., December 15, 2006; 66(24): 11520 - 11539. [Abstract] [Full Text] [PDF]

				D. W. N. Kim, J. Huamani, K. J. Niermann, H. Lee, L. Geng, L. L. Leavitt, R. A. Baheza, C. C. Jones, S. Tumkur, T. E. Yankeelov, et al. Noninvasive Assessment of Tumor Vasculature Response to Radiation-Mediated, Vasculature-Targeted Therapy Using Quantified Power Doppler Sonography: Implications for Improvement of Therapy Schedules. J. Ultrasound Med., December 1, 2006; 25(12): 1507 - 1517. [Abstract] [Full Text] [PDF]

				O. Riesterer, M. Honer, W. Jochum, C. Oehler, S. Ametamey, and M. Pruschy Ionizing radiation antagonizes tumor hypoxia induced by antiangiogenic treatment. Clin. Cancer Res., June 1, 2006; 12(11): 3518 - 3524. [Abstract] [Full Text] [PDF]

				R. S. Herbst, A. Onn, and A. Sandler Angiogenesis and Lung Cancer: Prognostic and Therapeutic Implications J. Clin. Oncol., May 10, 2005; 23(14): 3243 - 3256. [Abstract] [Full Text] [PDF]

				R. Ansiaux, C. Baudelet, B. F. Jordan, N. Beghein, P. Sonveaux, J. De Wever, P. Martinive, V. Gregoire, O. Feron, and B. Gallez Thalidomide Radiosensitizes Tumors through Early Changes in the Tumor Microenvironment Clin. Cancer Res., January 15, 2005; 11(2): 743 - 750. [Abstract] [Full Text] [PDF]

				B. M. Fenton, S. F. Paoni, and I. Ding Pathophysiological Effects of Vascular Endothelial Growth Factor Receptor-2-Blocking Antibody plus Fractionated Radiotherapy on Murine Mammary Tumors Cancer Res., August 15, 2004; 64(16): 5712 - 5719. [Abstract] [Full Text] [PDF]

				N. Ferrara Vascular Endothelial Growth Factor as a Target for Anticancer Therapy Oncologist, June 1, 2004; 9(suppl_1): 2 - 10. [Abstract] [Full Text] [PDF]

				M. E. Daly, A. Makris, M. Reed, and C. E. Lewis Hemostatic Regulators of Tumor Angiogenesis: A Source of Antiangiogenic Agents for Cancer Treatment? J Natl Cancer Inst, November 19, 2003; 95(22): 1660 - 1673. [Abstract] [Full Text] [PDF]

				H. Choy and L. Milas Enhancing Radiotherapy With Cyclooxygenase-2 Enzyme Inhibitors: A Rational Advance? J Natl Cancer Inst, October 1, 2003; 95(19): 1440 - 1452. [Abstract] [Full Text] [PDF]

				A. J. Schueneman, E. Himmelfarb, L. Geng, J. Tan, E. Donnelly, D. Mendel, G. McMahon, and D. E. Hallahan SU11248 Maintenance Therapy Prevents Tumor Regrowth after Fractionated Irradiation of Murine Tumor Models Cancer Res., July 15, 2003; 63(14): 4009 - 4016. [Abstract] [Full Text] [PDF]

				E. K. Rofstad, K. Henriksen, K. Galappathi, and B. Mathiesen Antiangiogenic Treatment with Thrombospondin-1 Enhances Primary Tumor Radiation Response and Prevents Growth of Dormant Pulmonary Micrometastases after Curative Radiation Therapy in Human Melanoma Xenografts Cancer Res., July 15, 2003; 63(14): 4055 - 4061. [Abstract] [Full Text] [PDF]

				B. B.Y. Ma, R. G. Bristow, J. Kim, and L. L. Siu Combined-Modality Treatment of Solid Tumors Using Radiotherapy and Molecular Targeted Agents J. Clin. Oncol., July 15, 2003; 21(14): 2760 - 2776. [Abstract] [Full Text] [PDF]

				C. N. Coleman Linking Radiation Oncology and Imaging through Molecular Biology (or Now That Therapy and Diagnosis Have Separated, It's Time to Get Together Again!) Radiology, July 1, 2003; 228(1): 29 - 35. [Abstract] [Full Text] [PDF]

				P. Wachsberger, R. Burd, and A. P. Dicker Tumor Response to Ionizing Radiation Combined with Antiangiogenesis or Vascular Targeting Agents: Exploring Mechanisms of Interaction Clin. Cancer Res., June 1, 2003; 9(6): 1957 - 1971. [Abstract] [Full Text] [PDF]

				P. Sonveaux, A. Brouet, X. Havaux, V. Gregoire, C. Dessy, J.-L. Balligand, and O. Feron Irradiation-induced Angiogenesis through the Up-Regulation of the Nitric Oxide Pathway: Implications for Tumor Radiotherapy Cancer Res., March 1, 2003; 63(5): 1012 - 1019. [Abstract] [Full Text] [PDF]

				D. H. Gorski, H. J. Mauceri, R. M. Salloum, A. Halpern, S. Seetharam, and R. R. Weichselbaum Prolonged Treatment with Angiostatin Reduces Metastatic Burden during Radiation Therapy Cancer Res., January 15, 2003; 63(2): 308 - 311. [Abstract] [Full Text] [PDF]

				R. P. M. Dings, Y. Yokoyama, S. Ramakrishnan, A. W. Griffioen, and K. H. Mayo The Designed Angiostatic Peptide Anginex Synergistically Improves Chemotherapy and Antiangiogenesis Therapy with Angiostatin Cancer Res., January 15, 2003; 63(2): 382 - 385. [Abstract] [Full Text] [PDF]

				F. A. Scappaticci Mechanisms and Future Directions for Angiogenesis-Based Cancer Therapies J. Clin. Oncol., September 15, 2002; 20(18): 3906 - 3927. [Abstract] [Full Text] [PDF]

				P. A. Burke, S. J. DeNardo, L. A. Miers, K. R. Lamborn, S. Matzku, and G. L. DeNardo Cilengitide Targeting of {alpha}v{beta}3 Integrin Receptor Synergizes with Radioimmunotherapy to Increase Efficacy and Apoptosis in Breast Cancer Xenografts Cancer Res., August 1, 2002; 62(15): 4263 - 4272. [Abstract] [Full Text] [PDF]

				L. Hlatky, P. Hahnfeldt, and J. Folkman Clinical Application of Antiangiogenic Therapy: Microvessel Density, What It Does and Doesn't Tell Us J Natl Cancer Inst, June 19, 2002; 94(12): 883 - 893. [Full Text] [PDF]

				K. Camphausen, M. A. Moses, W.-D. Beecken, M. K. Khan, J. Folkman, and M. S. O’Reilly Radiation Therapy to a Primary Tumor Accelerates Metastatic Growth in Mice Cancer Res., March 1, 2001; 61(5): 2207 - 2211. [Abstract] [Full Text]

				R. Z. Renno, F. C. Delori, R. A. Holzer, E. S. Gragoudas, and J. W. Miller Photodynamic Therapy Using Lu-Tex Induces Apoptosis In Vitro, and Its Effect Is Potentiated by Angiostatin in Retinal Capillary Endothelial Cells Invest. Ophthalmol. Vis. Sci., November 1, 2000; 41(12): 3963 - 3971. [Abstract] [Full Text]

				C.-G. Lee, M. Heijn, E. di Tomaso, G. Griffon-Etienne, M. Ancukiewicz, C. Koike, K. R. Park, N. Ferrara, R. K. Jain, H. D. Suit, et al. Anti-Vascular Endothelial Growth Factor Treatment Augments Tumor Radiation Response under Normoxic or Hypoxic Conditions Cancer Res., October 1, 2000; 60(19): 5565 - 5570. [Abstract] [Full Text]

				C. Petersen, S. Petersen, L. Milas, F. F. Lang, and P. J. Tofilon Enhancement of Intrinsic Tumor Cell Radiosensitivity Induced by a Selective Cyclooxygenase-2 Inhibitor Clin. Cancer Res., June 1, 2000; 6(6): 2513 - 2520. [Abstract] [Full Text]

				A. C. Hartford, T. Gohongi, D. Fukumura, and R. K. Jain Irradiation of a Primary Tumor, Unlike Surgical Removal, Enhances Angiogenesis Suppression at a Distal Site: Potential Role of Host-Tumor Interaction Cancer Res., April 1, 2000; 60(8): 2128 - 2131. [Abstract] [Full Text]

				Y. Yokoyama, M. Dhanabal, A. W. Griffioen, V. P. Sukhatme, and S. Ramakrishnan Synergy between Angiostatin and Endostatin: Inhibition of Ovarian Cancer Growth Cancer Res., April 1, 2000; 60(8): 2190 - 2196. [Abstract] [Full Text]

				, , , , , J. , P. , and Preferential Enhancement of Tumor Radioresponse by a Cyclooxygenase-2 Cancer Res., March 1, 2000; 60(5): 1326 - 1331. [Abstract] [Full Text] [PDF]

				L. Milas, K. A. Mason, and P. J. Tofilon RESPONSE: Re: Enhancement of Tumor Response to {gamma}-Radiation by an Inhibitor of Cyclooxygenase-2 Enzyme J Natl Cancer Inst, February 16, 2000; 92(4): 346a - 347a. [Full Text] [PDF]

				L. Milas, K. Mason, N. Hunter, S. Petersen, M. Yamakawa, K. Ang, J. Mendelsohn, and Z. Fan In Vivo Enhancement of Tumor Radioresponse by C225 Antiepidermal Growth Factor Receptor Antibody Clin. Cancer Res., February 1, 2000; 6(2): 701 - 708. [Abstract] [Full Text]

				L. Milas, K. Kishi, N. Hunter, K. Mason, J. L. Masferrer, and P. J. Tofilon Enhancement of Tumor Response to {gamma}-Radiation by an Inhibitor of Cyclooxygenase-2 Enzyme J Natl Cancer Inst, September 1, 1999; 91(17): 1501 - 1504. [Full Text] [PDF]

				D. H. Gorski, M. A. Beckett, N. T. Jaskowiak, D. P. Calvin, H. J. Mauceri, R. M. Salloum, S. Seetharam, A. Koons, D. M. Hari, D. W. Kufe, et al. Blockade of the Vascular Endothelial Growth Factor Stress Response Increases the Antitumor Effects of Ionizing Radiation Cancer Res., July 1, 1999; 59(14): 3374 - 3378. [Abstract] [Full Text] [PDF]