Preferential Susceptibility of Brain Tumors to the Antiangiogenic Effects of an αv Integrin Antagonist

MacDonald, Tobey J.; Taga, Takashi; Shimada, Hiroyuki; Tabrizi, Peyman; Zloković, Berislav V.; Cheresh, David A.; Laug, Walter E.

doi:10.1227/00006123-200101000-00026

Cited by 56 publications

(62 citation statements)

References 39 publications

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“…2,4 We have recently shown that the cyclic RGD pentapeptide EMD 121974, a specific ␣v-integrin antagonist, inhibited growth of brain tumor cell lines xenotransplanted into the forebrain of nu/nu mice, resulting in long-term survival. 8 In the present study, we investigated in more detail the mechanisms responsible for this growthinhibitory effect. Our data demonstrate that EMD 121974 detaches both the ␣v-integrin-expressing brain capillary and brain tumor cells from the matrix proteins vitronectin and tenascin, resulting in significant apoptosis of both cell types.…”

Section: Abstract: Brain Tumor; Xenograft; Anti-angiogenesis; ␣V-intmentioning

confidence: 96%

αv‐Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin

Taga

Suzuki

González-Gómez

et al. 2002

Intl Journal of Cancer

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182

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Orthotopic brain tumor growth is inhibited in athymic mice by the daily systemic administration of the ␣v-integrin antagonist EMD 121974. This compound, a cyclic RGDpenta-peptide, is a potent inhibitor of angiogenesis, which induces apoptosis of growing endothelial cells through inhibition of their ␣v-integrin interaction with the matrix proteins vitronectin and tenascin. Here we show that EMD 121974 also induces apoptosis in the ␣v-integrin-expressing tumor cell lines U87 MG and DAOY by detaching them from vitronectin and tenascin, matrix proteins known to be essential for brain tumor growth and invasion. These matrix proteins are shown to be produced by the brain tumor cells in vitro and in vivo. Key words: brain tumor; xenograft; anti-angiogenesis; ␣v-integrins; apoptosisAngiogenesis, the recruitment of new blood vessels from existing capillaries, is essential for tumor growth and progression. 1 This complex process is characterized by proliferation, migration and invasion of capillary endothelial cells, as well as functional features that depend on their interactions with the surrounding extracellular matrix components. The expression of the integrin adhesion molecules ␣v␤3 and ␣v␤5 on sprouting capillary cells and their interaction with specific matrix ligands has been shown to play a key role in angiogenesis. [2][3][4] Although vitronectin is the only matrix ligand for ␣v␤5, the promiscuous ␣v␤3 receptor interacts with various matrix proteins including vitronectin, tenascin, fibronectin, fibrinogen, etc. 5 Ligand binding to these receptors through specific RGD motifs leads to complex intracellular signaling resulting in endothelial cell survival. 3,6,7 Consequently, blocking of these receptors with specific antibodies or RGD peptides results in endothelial cell apoptosis in vitro and suppression of angiogenesis in vivo, with subsequent suppression of tumor growth. 2,4 We have recently shown that the cyclic RGD pentapeptide EMD 121974, a specific ␣v-integrin antagonist, inhibited growth of brain tumor cell lines xenotransplanted into the forebrain of nu/nu mice, resulting in long-term survival. 8 In the present study, we investigated in more detail the mechanisms responsible for this growthinhibitory effect. Our data demonstrate that EMD 121974 detaches both the ␣v-integrin-expressing brain capillary and brain tumor cells from the matrix proteins vitronectin and tenascin, resulting in significant apoptosis of both cell types. We also show that the brain tumor cells produce these matrix proteins in vitro and in vivo. Furthermore, we found that only ␣v-integrin-expressing tumor cells responded in vivo to the treatment with EMD 121974. Taken together, these data suggest that EMD 121974 not only inhibits angiogenesis but is also cytotoxic for brain tumor cells. MATERIAL AND METHODS Cell linesThe human brain tumor cell lines DAOY (medulloblastoma) and U87MG (glioblastoma) were purchased from ATCC (Manassas, VA) and grown in RPMI-1640 medium with 10% FBS in 5% CO 2 at 37°C. Primary human and mouse brain capillar...

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Section: Abstract: Brain Tumor; Xenograft; Anti-angiogenesis; ␣V-intmentioning

confidence: 96%

αv‐Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin

Taga

Suzuki

González-Gómez

et al. 2002

Intl Journal of Cancer

Self Cite

182

110

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“…3,[7][8][9]43 Agents directed at these integrins should therefore have a degree of tumor specificity in their effects. Cilengitide inhibits cell-matrix contact and angiogenesis in a tumor-induced CAM assay 23 and increases apoptosis of activated endothelial cells in tumor neovasculature and of tumor cells themselves in animal models. 24,26 Exploratory in vivo studies demonstrated that cilengitide disrupts cell adhesion mediated by aVb3 and aVb5 integrins.…”

Section: Discussionmentioning

confidence: 99%

“…8,9,[44][45][46][47][48] It is therefore plausible that inhibiting aVintegrin-ligand interaction should reduce tumor progression. As a single agent, cilengitide inhibits growth of brain tumors 23 and has modest activity in recurrent clinical glioblastoma, 36 an activity which appears to be amplified by co-therapy with ionizing radiation. 25,49 In the present study, as in others such as that of Mikkelsen et al, 25 cilengitide alone did not reduce tumor growth but it is possible that this was because our model involved only a single short exposure to the drug.…”

Section: Discussionmentioning

confidence: 99%

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The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model

Hagen

Seynhaeve

Wiel-Ambagtsheer

et al. 2012

Intl Journal of Cancer

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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

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“…39 Phase I clinical trials of anti-angiogenic agents are underway. 38 Cilenglitide (EMD 121974), an anti-angiogenic integrin receptor antagonist in preclinical trials, 40 is currently being evaluated in a phase I trial for children with recurrent brain tumors. Preliminary results suggest some efficacy for brain tumors; a likely future strategy will be to combine anti-angiogenic drugs with other adjuvant therapies.…”

Section: Therapeutic Modalitiesmentioning

confidence: 99%

Advances in treatment of pediatric brain tumors

Robertson

2006

NeuroRX

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Summary:The long-term survival of children with brain tumor has improved considerably in the last three decades, owing to advances in neuroimaging, neurosurgical, and radiation therapy modalities, coupled with the application of conventional chemotherapy. MRI, MR spectroscopy and diffusion-weighted MRI have contributed to more accurate diagnosis, prognostication and better treatment planning. Neurosurgical treatment has been advanced by the use of functional MRI, and intraoperative image-guided stereotactic techniques and electrophysiologic monitoring. The use of 3-D conformal and intensitymodulated radiation therapy, stereotactic radiosurgery, and radiosensitizing agents has made radiation therapy safer and more effective. Conventional chemotherapy, administered either alone or combined with radiation therapy has improved survival and quality of life of children with brain tumors. These improved outcomes have also occurred, due, in part, to their treatment on collaborative national and international studies. Recent promising diagnostic and therapeutic strategies have resulted from advances in understanding molecular brain tumor biology. Important new approaches include the refinement of drug-delivery strategies, the evaluation of biologic markers to stratify patients for optimal treatment and to exploit these molecular differences using "targeted" therapeutic strategies. These approaches include blocking tumor cell drug resistance mechanisms, immunotherapy, inhibition of molecular signal transduction pathways important in tumorigenesis, anti-angiogenic therapy, and gene therapy. The thrust of such approaches for children with brain tumors is especially directed at reducing the toxicity of therapy and improving quality-of-life, as well as increasing disease-free survival.

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Preferential Susceptibility of Brain Tumors to the Antiangiogenic Effects of an αv Integrin Antagonist

Cited by 56 publications

References 39 publications

αv‐Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin

αv‐Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin

The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model

Advances in treatment of pediatric brain tumors

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