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Myeloma

Targeting an MMP-9-activated prodrug to multiple myeloma-diseased bone marrow: a proof of principle in the 5T33MM mouse model

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.

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Acknowledgements

This work was financially supported by the Stichting Emmanuel Vander Scheuren, Onderzoeksraad-Vrije Universiteit Brussel (OZR-VUB), Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Kom op tegen Kanker, Belgische Federatie tegen Kanker, Fortis, VIVA and VIS. Karin Vanderkerken is a postdoctoral fellow of the ‘Fonds voor Wetenschappelijk Onderzoek-Vlaanderen’ (FWO-Vl). The financial support of BTG International plc (ADS and DM) and assistance of the EPSRC Mass Spectrometry Service Centre, Swansea, UK, are gratefully acknowledged.

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Correspondence to K Vanderkerken.

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Van Valckenborgh, E., Mincher, D., Di Salvo, A. et al. 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 (2005). https://doi.org/10.1038/sj.leu.2403866

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