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[Cancer Research 62, 4263-4272, August 1, 2002]
© 2002 American Association for Cancer Research

Experimental Therapeutics

Cilengitide Targeting of {alpha}vß3 Integrin Receptor Synergizes with Radioimmunotherapy to Increase Efficacy and Apoptosis in Breast Cancer Xenografts1

Patricia A. Burke, Sally J. DeNardo2, Laird A. Miers, Kathleen R. Lamborn, Siegfried Matzku and Gerald L. DeNardo

University of California at Davis, Sacramento Medical Center, Radiodiagnosis and Therapy/Internal Medicine, Sacramento, California 95816 [P. A. B., S. J. D., L. A. M., G. L. D.]; University of California at San Francisco, Department of Neurological Surgery, San Francisco, California 94143 [K. R. L.]; and Merck KGaA, Department of Preclinical Oncology, 64271 Darmstadt, Germany [S. M.]

Although metastatic breast cancer is responsive to radioimmunotherapy (RIT), a systemictargeted radiation modality, complete and permanent remissions are not typical with single-modality treatment. Antiangiogenic agents, which target normal, proliferating endothelial cells, have the potential to provide relatively nontoxic continuous inhibition of tumor growth by blocking new blood vessel growth and may synergize with RIT to increase efficacy. This study was designed to determine whether, and how, the cyclic Arg-Gly-Asp peptide Cilengitide (EMD 121974), which targets the {alpha}vß3 integrin receptor expressed on neovasculature, could increase systemic RIT efficacy of therapy in a human breast cancer tumor model having mutant p53 and expressing bcl-2. HBT 3477 breast cancer tumor response in nude mice was compared between groups of untreated mice (n = 24), Cilengitide-treated mice (n = 18), RIT (200–260 µCi 90Y-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-peptide ChL6; n = 46), and combined modality RIT (CMRIT) using RIT and six doses of Cilengitide (250 µg/dose; n = 41). Tumor size, survival, body weight, and blood counts were monitored for efficacy and toxicity of therapy. To clarify the mechanism of synergistic effect, tumors were evaluated at selected time points through 6 days for apoptosis, proliferation, and microvessel density. Cilengitide alone did not alter tumor growth when compared with untreated mice, but CMRIT with Cilengitide increased efficacy of treatment, with the cure rate for mice that received 260 µCi RIT increasing from 15 to 53% (P = 0.011). Lower-dose RIT (200 µCi) combined with Cilengitide resulted in less increase in cures (36 compared with 25% for RIT alone; P = 0.514). Combined analysis for high- and low-dose groups demonstrated increased efficacy of CMRIT (P = 0.020). Analysis of tumors from CMRIT mice indicated significantly increased apoptosis of tumor and endothelial cells 5 days after RIT compared with tumors from mice given RIT alone. Proliferation was decreased in CMRIT tumors compared with RIT tumors at 6 days (ANOVA, P < 0.05). Microvessel density in tumors from RIT and CMRIT mice was not different. No increased toxicity attributable to Cilengitide was observed based upon pooled blood sample and no statistical increase in mortality. In conclusion, CMRIT, combining Cilengitide and RIT, significantly increased the efficacy of therapy and increased apoptosis compared with single-modality therapy with either agent, in an aggressive, well-studied breast cancer model. The enhanced therapeutic synergy is of particular note, having been achieved without additional toxicity.




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