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

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(9), 1628-1633. https://doi.org/10.1038/sj.leu.2403866

• Journal Article Type: Article
• Online Publication Date: Jul 14, 2005
• Publication Date: 2005-09
• Deposit Date: Jul 4, 2008
• Journal: Leukemia
• Print ISSN: 0887-6924
• Electronic ISSN: 1476-5551
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 19
• Issue: 9
• 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