title: The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model.
abstract: 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.
authors.affiliation: Department of Surgery, Section Surgical Oncology, Laboratory Experimental Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands. t.l.m.tenhagen@erasmusmc.nl
authors.forename: Timo L M
authors.initials: TL
authors.lastname: Ten Hagen
authors.forename: Ann L B
authors.initials: AL
authors.lastname: Seynhaeve
authors.forename: Gisela aan
authors.initials: Ga
authors.lastname: de Wiel-Ambagtsheer
authors.forename: Ernst A
authors.initials: EA
authors.lastname: de Bruijn
authors.forename: Sandra T
authors.initials: ST
authors.lastname: van Tiel
authors.forename: Curzio
authors.initials: C
authors.lastname: Ruegg
authors.forename: Michael
authors.initials: M
authors.lastname: Meyring
authors.forename: Matthias
authors.initials: M
authors.lastname: Grell
authors.forename: Simon L
authors.initials: SL
authors.lastname: Goodman
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D010478:Chemotherapy, Cancer, Regional Perfusion; D004195:Disease Models, Animal; D004357:Drug Synergism; D023821:Limb Salvage; D008297:Male; D008558:Melphalan / Q000627:therapeutic use*; D051381:Rats; D011914:Rats, Inbred BN; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D012513:Sarcoma, Experimental / Q000378:metabolism / Q000517:prevention & control*; D012910:Snake Venoms / Q000627:therapeutic use*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019030:Receptors, Vitronectin; D012910:Snake Venoms; C064660:integrin alphaVbeta5; C422910:Cilengitide; D008558:Melphalan