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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 and 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. ISSN 0887-6924

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Abstract/Description

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.

Item Type: Article
Print ISSN: 0887-6924
Electronic ISSN: 1467-5551
Uncontrolled Keywords: Matrix metalloproteinases; Multiple myeloma; 5T33, prodrug, MMP-9
University Divisions/Research Centres: Faculty of Health, Life & Social Sciences > School of Life Sciences
Dewey Decimal Subjects: 600 Technology > 610 Medicine & health > 615 Pharmacology & therapeutics
600 Technology > 610 Medicine & health > 616 Diseases
Library of Congress Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Item ID: 1677
Depositing User: RAE Import
Date Deposited: 04 Jul 2008 09:30
Last Modified: 26 Jul 2010 11:59
URI: http://researchrepository.napier.ac.uk/id/eprint/1677

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