Research Output

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

  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.

  • Type:

    Article

  • Date:

    14 July 2005

  • Publication Status:

    Published

  • Publisher

    Nature Publishing Group

  • DOI:

    10.1038/sj.leu.2403866

  • ISSN:

    0887-6924

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. doi:10.1038/sj.leu.2403866. ISSN 0887-6924

Authors

Keywords

Matrix metalloproteinases; Multiple myeloma; 5T33, prodrug, MMP-9

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