In vitro
 and
 in vivo
 studies of a VEGF
 121
 /rGelonin chimeric fusion toxin targeting the neovasculature of solid tumors

Veenendaal, Liesbeth M.; Jin, Hangqing; Ran, Sophia; Cheung, Lawrence H.; Navone, Nora M.; Marks, John W.; Waltenberger, Johannes; Rosenblum, Michael G.

doi:10.1073/pnas.122157899

Cited by 135 publications

(136 citation statements)

References 47 publications

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“…Of all the tumor lines tested, three MCL cell lines (JeKo-1, Mino, and SP53) expressing all three distinct BLyS receptors were found to be the most sensitive to the fusion toxin (targeting index = 27,500 -80,000), whereas nontargeted rGel itself or CTP/ rGel (non-B cell -targeting chemical conjugate) showed no specific cytotoxic activity against these three cell lines. As our previous findings (20), this result suggests that the rGel has impressive cytotoxic effects when delivered to cells using growth factor ligands. Interestingly, BCL-1 a mouse B lymphoma showed the highest targeting index (187,500) of all lines examined so far.…”

Section: Discussionsupporting

confidence: 85%

“…The proapoptotic nature of this fusion toxin seems to be related to the cell targets rather than the rGel toxin itself. In previous studies (20,26), we have found that rGel-containing fusion constructs targeting solid tumor cells and tumor vascular endothelium seem to be cytotoxic through a nonapoptotic (necrotic) mechanism that involves inhibition of protein synthesis. The protein synthesis inhibitory properties of rGel are similar to that of ricin A-chain and depend on ribosomal inactivation through enzymatic (n-glycosidase) activity of the toxin molecule (27).…”

Section: Discussionmentioning

confidence: 91%

“…20, 23 -26). rGel has shown impressive cytotoxic effects when delivered to cells using growth factor ligands (20), as chemical conjugates with monoclonal antibodies (23 -25), or fused to singlechain antibodies (26). This toxin is an n-glycosidase that disrupts cellular protein synthesis at the ribosomal level in a manner similar to that of ricin A-chain (27).…”

Section: Introductionmentioning

confidence: 99%

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The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA

Lyu

Cheung

Hittelman

et al. 2007

Molecular Cancer Therapeutics

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B lymphocyte stimulator (BLyS) is crucial for B-cell survival, and the biological effects of BLyS are mediated by three cell surface receptors designated B cellactivating factor receptor (BAFF-R), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antibody (BCMA). Increased expression of BLyS and its receptors has been identified in numerous B-cell malignancies. We generated a fusion toxin designated rGel/BLyS for receptor-mediated delivery of the recombinant gelonin (rGel) toxin to neoplastic B cells, and we characterized its activity against various B-cell tumor lines. Three mantle cell lymphoma (MCL) cell lines (JeKo-1, Mino, and SP53) and two diffuse large B-cell lymphoma (DLBCL) cell lines (SUDHL-6 and OCI-Ly3) expressing all three distinct BLyS receptors were found to be the most sensitive to the fusion toxin (IC 50 = 2 -5 pmol/L and 0.001 -5 nmol/L for MCL and DLBCL, respectively). The rGel/BLyS fusion toxin showed specific binding to cells expressing BLyS receptors and rapid internalization of the rGel component into target cells. The cytotoxic effects of rGel/BLyS were inhibited by pretreatment with free BLyS or with soluble BAFF-R, TACI, and BCMA decoy receptors. This suggests that the cytotoxic effects of the fusion toxin are mediated through BLyS receptors. The rGel/BLyS fusion toxin inhibited MCL cell growth through induction of apoptosis associated with caspase-3 activation and poly (ADP-ribose) polymerase cleavage. Our results suggest that BLyS has the potential to serve as an excellent targeting ligand for the specific delivery of cytotoxic molecules to neoplastic B cells expressing the BLyS receptors, and that the rGel/ BLyS fusion toxin may be an excellent candidate for the treatment of B-cell malignancies especially MCL and DLBCL. [Mol Cancer Ther 2007;6(2):460 -70]

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA

Lyu

Cheung

Hittelman

et al. 2007

Molecular Cancer Therapeutics

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“…Some of these determinants, including endoglin (Burrows, 1995;Seon, 2002), vascular endothelial growth factor (VEGF) receptors (Brekken and Thorpe, 2001;Veenendaal, 2002), a v b 3 -integrins (Arap, 1998;Brooks, 1994), the fibronectin EDB domain (Nilsson, 2001), the prostate-specific membrane antigen (Chang, 1999) and specific aminopeptidases (Arap, 1998;Marchio, 2004;Taylor, 1993) have been identified as targets for ligand-directed approaches involving VDAs. Preclinical investigations employing such liganddirected VDAs have shown not only the homing of the therapeutic moieties to tumour vessels but also the selective destruction of tumour vasculature (Pastorino, 2003a;Thorpe, 2004).…”

Section: Loi Et Almentioning

confidence: 99%

The use of the orthotopic model to validate antivascular therapies for cancer

Loi¹,

Paolo²,

Becherini³

et al. 2011

Int. J. Dev. Biol.

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The orthotopic model reproduces aspects of the tumour microenvironment and emulates a number of important biological features of cancer progression, angiogenesis, metastasis and resistance. Due to its parallels with human cancer, the model can be used to evaluate therapeutic responses to various therapies. This review outlines the importance of using the orthotopic implantation of tumour cells in mice models for evaluating the effectiveness of antivascular therapies. KEY WORDS: orthotopic model, vascular disrupting agent, antivascular therapy, cancer Tumour vasculature and antivascular therapiesA functioning and continuously expanding vascular network is essential for tumour development, growth, survival and metastasis (Hanahan and Folkman, 1996). Given its pivotal role in these processes, tumour vasculature is a highly attractive target in anticancer therapy. Compared with the vasculature in normal tissue, the tumour vasculature is strikingly disorganized and tortuous (Eberhard, 2000;Konerding, 2001;McDonald and Choyke, 2003), its wall is poorly developed, often with discontinuous endothelial-cell lining, has relatively poor investiture with vascular smooth muscle cells, poor connections between pericytes and endothelial cells (Dvorak, 1988;Eberhard, 2000;Hashizume, 2000;Kobayashi, 1993) and an irregular, structurally abnormal basement membrane (Baluk, 2003;Paku and Paweletz, 1991). Endothelial cells themselves are often irregularly shaped, forming an uneven luminal layer, with loose interconnections and focal intercellular openings (Hashizume, 2000). These features contribute to a high intrinsic vascular permeability of macromolecules into the vasculature (Dvorak, 1991;Jain, 1987) and the consequent development of high interstitial fluid pressure (Boucher, 1990), which is augmented by inadequate lymphatic drainage. Tumour vascular networks are chaotic, featuring complex branching patterns and lack of hierarchy (Gillies, 1999;Konerding, 1999;Less, 1991). Vessel diameters are irregular and lengths between branching points are often very long. The result is a high geometrical resistance to blood flow, that such as small decreases in perfusion pressure, which have little Int. J. Dev. Biol. 55: [547][548][549][550][551][552][553][554][555] doi: 10.1387/ijdb.103230ml www.intjdevbiol.com *Address correspondence to: Mirco Ponzoni or Fabio Pastorino. Experimental Therapies Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, 16148-Genoa, Italy. Tel: +39-010-5636342. Fax: +39-010-3779820. e-mail: mircoponzoni@ospedale-gaslini.ge.it or fabiopastorino@ospedale-gaslini.ge.it # These Authors share the last co-authorship. effect in normal tissues, can be catastrophic in tumours (Sevick and Jain, 1989). Capillary blood contains abnormally high levels of deoxygenated blood (Mueller-Klieser, 1981), which, combined with heterogeneous blood flow and large intercapillary distances, contributes to micro-regional hypoxia in tumours (Vaupel and Hockel, 2000). The tumour is also starved of nutrient, under acidic cond...

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“…distant metastasis or EGFR expressing normal cells, may be subjected to growth and survival signals. However, growth stimulating effects have not been reported using other ligands, as VEGF (Veenendaal et al 2002) and IL-2 (Foss 2006), as targeting moieties in targeted toxins, and EGF fused to DAB389 has been investigated in a clinical phase I/II trial against lung cancer (Kreitman 1999). Using cetuximab as the targeting ligand in EGFR targeted toxins will, on the other hand, block EGFR signalling and reduce growth and survival of the cells.…”

Section: Egf Versus Cetuximab As a Targeting Ligandmentioning

confidence: 99%

Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin

Weyergang

Selbo

Berg

2006

Journal of Controlled Release

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In vitro and in vivo studies of a VEGF ₁₂₁ /rGelonin chimeric fusion toxin targeting the neovasculature of solid tumors

Cited by 135 publications

References 47 publications

The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA

The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA

The use of the orthotopic model to validate antivascular therapies for cancer

Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin

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In vitro and in vivo studies of a VEGF 121 /rGelonin chimeric fusion toxin targeting the neovasculature of solid tumors

Cited by 135 publications

References 47 publications

The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA

The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA

The use of the orthotopic model to validate antivascular therapies for cancer

Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin

Contact Info

Product

Resources

About

In vitro and in vivo studies of a VEGF ₁₂₁ /rGelonin chimeric fusion toxin targeting the neovasculature of solid tumors