E Van Valckenborgh
Targeting an MMP-9-activated prodrug to multiple myeloma diseased bone marrow: a proof of principle in the 5T33MM mouse model.
Van Valckenborgh, E; Mincher, David; Di Salvo, A; Van Riet, I; Young, Lesley; Van Camp, B; Vanderkerken, K
Authors
Dr David Mincher D.Mincher@napier.ac.uk
Senior Lecturer
A Di Salvo
I Van Riet
Dr Lesley Young LE.Young@napier.ac.uk
Senior Technician
B Van Camp
K Vanderkerken
Abstract
Multiple myeloma (MM) is an incurable B-cell cancer characterised by the monoclonal proliferation of tumour cells in the bone marrow (BM). It has been described that matrix metalloproteinases (MMPs) and especially MMP-9 is secreted by MM cells. In this study, we investigated the possibility to exploit MMP-9 activity to activate prodrugs and to target MM cells as a new tumour-specific therapy. Cleavage of the prodrug EV1-FITC by MMP-9 resulted in release of fluorescence which can be used as a measure of prodrug activation. The 5T33MM mouse model was used in this proof-of-principle study. The prodrug was activated in a higher amount by addition to MMP-9-producing 5T33MMvv cells, homogenates from tumour-bearing organs (BM, spleen) and isolated 5T33MM-diseased BM and spleen cells compared to non-MMP-9-producing 5T33MMvt cells and homogenates/cells from nontumour-bearing organs/mice, as measured by fluorescence release. This fluorescence release could be inhibited by the MMP-2/MMP-9-specific inhibitor, CTT. Activation of the prodrug in the 5T33MM spleen and BM homogenates was confirmed by chromatography. EV1-fluorescein isothiocyanate injection into 5T33MM-diseased animals resulted in a higher fluorescence release by the isolated BM and spleen cells compared to injection into healthy animals. In conclusion, MMP-9 activity can be used to activate prodrugs that target MM.
Citation
Van Valckenborgh, E., Mincher, D., Di Salvo, A., Van Riet, I., Young, L., Van Camp, B., & Vanderkerken, K. (2005). Targeting an MMP-9-activated prodrug to multiple myeloma diseased bone marrow: a proof of principle in the 5T33MM mouse model. Leukemia, 19, 1628-1633. https://doi.org/10.1038/sj.leu.2403866
Journal Article Type | Article |
---|---|
Publication Date | Jul 14, 2005 |
Deposit Date | Jul 4, 2008 |
Print ISSN | 0887-6924 |
Electronic ISSN | 1467-5551 |
Publisher | Nature Publishing Group |
Peer Reviewed | Peer Reviewed |
Volume | 19 |
Pages | 1628-1633 |
DOI | https://doi.org/10.1038/sj.leu.2403866 |
Keywords | Matrix metalloproteinases; Multiple myeloma; 5T33, prodrug, MMP-9 |
Public URL | http://researchrepository.napier.ac.uk/id/eprint/1677 |
Publisher URL | http://www.nature.com/leu/journal/v19/n9/abs/2403866a.html |
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