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.