1.Cilengitide targeting of alpha(v)beta(3) integrin receptor synergizes with radioimmunotherapy to increase efficacy and apoptosis in breast cancer xenografts.
Burke PA;DeNardo SJ;Miers LA;Lamborn KR;Matzku S;DeNardo GL Cancer Res. 2002 Aug 1;62(15):4263-72.
Although metastatic breast cancer is responsive to radioimmunotherapy (RIT), a systemic targeted 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(v)beta(3) 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 mu Ci (90)Y-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 microg/dose; n = 41). Tumor size, survival, body weight, and blood counts were monitored for efficacy and toxicity of therapy.
2.The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model.
Ten Hagen TL;Seynhaeve AL;de Wiel-Ambagtsheer Ga;de Bruijn EA;van Tiel ST;Ruegg C;Meyring M;Grell M;Goodman SL;Eggermont AM Int J Cancer. 2013 Jun 1;132(11):2694-704. doi: 10.1002/ijc.27940. Epub 2012 Dec 5.
Isolated limb perfusion (ILP) with melphalan and tumor necrosis factor (TNF)-α is used to treat bulky, locally advanced melanoma and sarcoma. However, TNF toxicity suggests a need for better-tolerated drugs. Cilengitide (EMD 121974), a novel cyclic inhibitor of alpha-V integrins, has both anti-angiogenic and direct anti-tumor effects and is a possible alternative to TNF in ILP. In this study, rats bearing a hind limb soft tissue sarcoma underwent ILP using different combinations of melphalan, TNF and cilengitide in the perfusate. Further groups had intra-peritoneal (i.p.) injections of cilengitide or saline 2 hr before and 3 hr after ILP. A 77% response rate (RR) was seen in animals treated i.p. with cilengitide and perfused with melphalan plus cilengitide. The RR was 85% in animals treated i.p. with cilengitide and ILP using melphalan plus both TNF and cilengitide. Both RRs were significantly greater than those seen with melphalan or cilengitide alone. Histopathology showed that high RRs were accompanied by disruption of tumor vascular endothelium and tumor necrosis. Compared with ILP using melphalan alone, the addition of cilengitide resulted in a three to sevenfold increase in melphalan concentration in tumor but not in muscle in the perfused limb.
3.Longitudinal microPET imaging of brain tumor growth with F-18-labeled RGD peptide.
Chen X;Park R;Khankaldyyan V;Gonzales-Gomez I;Tohme M;Moats RA;Bading JR;Laug WE;Conti PS Mol Imaging Biol. 2006 Jan-Feb;8(1):9-15.
PURPOSE: ;EMD 121974, a potent cyclic RGD peptide inhibitor of alphav-integrins, demonstrated effectiveness in suppressing brain tumor growth in both preclinical models and phases I/II clinical trials. The ability to non-invasively evaluate alphav-integrin expression provides a novel and unique way to better understand brain tumor angiogenesis in relationship to alphav-integrin expression, and allow for direct assessment of anti-integrin treatment efficacy.;PROCEDURES: ;We developed a F-18-labeled RGD peptide [F-18]FB-RGD and performed serial microPET imaging scans to follow brain tumor growth and angiogenesis as a function of time in an orthotopic U87MG glioblastoma xenograft model in athymic nude mice.;RESULTS: ;The tumor was barely visible on microPET at the size of