Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins
- 26 May 1998
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 95 (11), 6448-6453
- https://doi.org/10.1073/pnas.95.11.6448
Abstract
Vascular disrupting agents (VDA) offer a strategy to starve solid tumors of nutrients and oxygen concomitant with tumor shrinkage. Several VDAs have progressed into early clinical trials, but their therapeutic value seems to be compromised by systemic toxicity. In this report, we describe the design and characterization of a novel VDA, ICT2588, that is nontoxic until activated specifically in the tumor by membrane-type 1 matrix metalloproteinase (MT1-MMP). HT1080 cancer cells expressing MT1-MMP were selectively chemosensitive to ICT2588, whereas MCF7 cells that did not express MT1-MMP were nonresponsive. Preferential hydrolysis of ICT2588 to its active metabolite (ICT2552) was observed in tumor homogenates of HT1080 relative to MCF7 homogenates, mouse plasma, and liver homogenate. ICT2588 activation was inhibited by the MMP inhibitor ilomastat. In HT1080 tumor–bearing mice, ICT2588 administration resulted in the formation of the active metabolite, diminution of tumor vasculature, and hemorrhagic necrosis of the tumor. The antitumor activity of ICT2588 was superior to its active metabolite, exhibiting reduced toxicity, improved therapeutic index, enhanced pharmacodynamic effect, and greater efficacy. Coadministration of ICT2588 with doxorubicin resulted in a significant antitumor response (22.6 d growth delay), which was superior to the administration of ICT2588 or doxorubicin as a single agent, including complete tumor regressions. Our findings support the clinical development of ICT2588, which achieves selective VDA targeting based on MT-MMP activation in the tumor microenvironment. Cancer Res; 70(17); 6902–12. ©2010 AACR.Keywords
This publication has 69 references indexed in Scilit:
- CNS neuronal focal adhesion kinase forms clusters that co-localize with vinculinJournal of Neuroscience Research, 1996
- RAGE and amyloid-β peptide neurotoxicity in Alzheimer's diseaseNature, 1996
- Protein kinase C and F‐actin are essential for stimulation of neuronal FAK tyrosine phosphorylation by G‐proteins and amyloid beta proteinFEBS Letters, 1996
- The nanometer-scale structure of amyloid-Β visualized by atomic force microscopyProtein Journal, 1996
- Soluble multimeric Alzheimer β(1–40) pre-amyloid complexes in dilute solutionNeurobiology of Aging, 1995
- fyn tyrosine kinase is involved in keratinocyte differentiation control.Genes & Development, 1995
- Development of kainic acid and N-methyl-d-aspartic acid toxicity in organotypic hippocampal culturesExperimental Neurology, 1995
- Purification and Characterization of Brain ClusterinBiochemical and Biophysical Research Communications, 1994
- β/A4‐evoked degeneration of differentiated SH‐SY5Y human neuroblastoma cellsJournal of Neuroscience Research, 1994
- Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease.Proceedings of the National Academy of Sciences of the United States of America, 1993