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)-a 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.Since the continued growth of solid tumors requires angiogenesis, an anti-angiogenic approach to cancer therapy is logical. Since angiogenesis is mediated in part by adhesion receptors of the integrin family, including the alpha-V (aV) integrins, 1,2 there is a strong rationale for assessing the effects of integrin inhibitors in cancer treatment. Cilengitide (EMD

Integrins as Therapeutic Targets: Successes and Cancers

“…Cilengitide is rapidly cleared from serum (t 1/2 = 3–5 h) [ 147 ], but continuous perfusion studies over 4 weeks with cilengitide at the limits of solubility (40 mg/h), attaining a steady state concentration of ~10 µM, also failed to improve the clinical outcome, without dose-limiting toxicity [ 148 ]. Preclinical studies suggested that nanomolar concentrations of cilengitide could on one hand activate αvβ3 and enhance angiogenesis and tumor growth [ 27 ], and on the other, enhance intratumoral vascular permeability and increase drug delivery [ 149 ]. This lead to much active debate about the role of αvβ3 and αvβ5 in tumor development (e.g., [ 150 ]).…”

The natural compound atraric acid suppresses androgen-regulated neo-angiogenesis of castration-resistant prostate cancer through angiopoietin 2

“…ATN-161 in combination with chemotherapy reduces metastasis and improves survival in mice with colon cancer [ 42 ]. Since integrins compensate for each other, in our study we have used a combination of two anti-angiogenic compounds cilengitide, which inhibits α v β 3 and α v β 5 [ 43 ] and ATN-161 which blocks integrin α 5 β 1 and binds integrin α v β 3 [ 44 ]. The combination treatment with both small molecule compounds revealed a significant reduction in endothelial cell sprouting but no synergistic effect indicating a maximal blockage of ANGPT2-mediated sprouting, perhaps through the overlapping target of both compounds, the integrin α v β 3 .…”

Are Integrins Still Practicable Targets for Anti-Cancer Therapy?

“…High-affinity inhibitors disrupt the Vascular Endothelial (VE)–cadherin junction, and increase permeability through αVβ3 activation and FAK–SRC signaling in vitro [153]. These effects translated into increased vascular permeability of αVβ3-positive tumor vessels in tumor-bearing mice treated with cilengitide, resulting in increased chemotherapy delivery to the tumor relative to healthy tissue [154]. Interesting, the αVβ3 function appears to be modulated by inflammatory factors.…”