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. Supportive in vitro studies indicate that cilengitide both 
inhibits tumor cell attachment and increases endothelial permeability. Since 
cilengitide has low toxicity, these data suggest the agent is a good alternative 
to TNF in the ILP setting.