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

• Published in: Leukemia Vol. 19; no. 9; pp. 1628 - 1633
• Main Authors: VAN VALCKENBORGH, E, MINCHER, D, DI SALVO, A, VAN RIET, I, YOUNG, L, VAN CAMP, B, VANDERKERKEN, K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01.09.2005; Nature Publishing Group
• Subjects: Animal diseases; Animals; Biological and medical sciences; Biotransformation; Bone marrow; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Cell Line; Cell proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs; Fluorescein; Fluorescein isothiocyanate; Fluoresceins - chemical synthesis; Fluoresceins - metabolism; Fluoresceins - therapeutic use; Fluorescence; Gelatinase A; Gelatinase B; Hematologic and hematopoietic diseases; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Injection; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocytes B; Matrix metalloproteinase; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - metabolism; Matrix metalloproteinases; Medical sciences; Mice; Mice, Inbred C57BL; Molecular Conformation; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Oligopeptides - chemical synthesis; Oligopeptides - metabolism; Oligopeptides - therapeutic use; Organ Specificity - drug effects; Organs; Prodrugs; Prodrugs - chemical synthesis; Prodrugs - metabolism; Prodrugs - therapeutic use; Spleen; Spleen - cytology; Spleen - drug effects; Spleen - metabolism; Tumors; Immunopathology; Animal model; multiple myeloma; Targeting; Hematology; Enzyme; 5T33; Rodentia; Metalloendopeptidases; Malignant hemopathy; Prodrug; Myeloma; Gelatinase B; Peptidases; Vertebrata; Mammalia; Immunoglobulinopathy; Mouse; Lymphoproliferative syndrome; Bone marrow; Hydrolases; MMP-9; matrix metalloproteinases
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2403866

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 non-tumour-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.