In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3633-3633
Abstract:
Vascular endothelial growth factor (VEGF-A) is a major mediator in tumor angiogenesis. VEGF-A binds to the receptors VEGFR-1 and VEGFR-2, both known to be overexpressed on tumor endothelial cells. Here we present a highly selective method for the targeting of VEGFRs by PCI of a VEGFR targeting fusion toxin. PCI is a novel drug delivery system for macromolecules that accumulate in the cells endosomes and lysosomes. PCI is based on light sensitive compounds, photosensitizers, which can absorb light at appropriate wavelengths and thereby generate reactive oxygen species (ROS). Photosensitizers utilized for PCI are amphiphilic and localize intracellularly to endocytic vesicles. Light exposure activates the photosensitizer and causes rupture of the vesicles so that drugs trapped within can be released into the cytosol. PCI was employed to deliver VEGF121/rGel, a recombinant VEGFR targeting fusion toxin composted of VEGF121, an isoform of VEGF-A, and gelonin, a type I ribosome inactivating protein toxin. VEGF121/rGel has been shown to be effective in suppressing tumor xenografts. Severe adverse effects may limit the possibilities to obtain complete responses with VEGF121/rGel monotherapy. We evaluated whether PCI could improve the efficacy and thereby reduce the dosage required for VEGF121/rGel to kill tumor vascular endothelial cells. Porcine aortic endothelial cells (PAE) transfected with either VEGFR-1 (PAE/FLT-1) or VEGFR-2 (PAE/KDR) served as a model system for endothelial cells. Clonal cell survival and MTT assay studies showed that PCI treatment resulted in a dramatic reduction in the dosage of VEGF121/rGel to 1/100 as measured by a LD90 of 10nM for the fusion toxin alone compared to 100pM with the PCI treatment in PAE/KDR cells. VEGF121/rGel alone exerted a higher cytotoxicity in PAE/KDR cells than in PAE/FLT-1 cells. Surprisingly, no difference in cytotoxicity was observed between the cell lines after PCI of the fusion toxin. Fluorescent microscopy of Alexa Fluor 488-labeled VEGF121/rGel as well as Western blots of VEGF121/rGel following PCI treatment showed, however, a ∼9 fold higher uptake of the IT in PAE/KDR cells compared to the PAE/FLT-1 cells. The results therefore indicate activation of different intracellular pharmacologic pathways in these cell lines as the cause of similar PCI mediated cytotoxicity. This is the first report on PCI of a tumor vascular targeting drug. In conclusion, the present results indicate PCI of VEGF121/rGel as a highly attractive method for destroying tumor vasculature as it shows high cytotoxicity to both VEGFR-1 and VEGFR-2 expressing cells. An animal study of PCI of VEGF121/rGel is already initiated in mice. The project is supported by the Norwegian Cancer Society. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3633. doi:10.1158/1538-7445.AM2011-3633
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-3633
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
