Blood, 1 December 2000, Vol. 96, No. 12, pp. 4006-4007
CORRESPONDENCE
To the editor:
Inhibition of matrix metalloproteinases by bisphosphonates may
in part explain their effects in the treatment of multiple myeloma
The recent Blood focus on hematology describing the
role of bisphosphonates in the therapy of multiple myeloma, and the
stimulation of 
T cells by bisphosphonates and the induction of
antiplasma cell activity in multiple myeloma,1,2 also
cites several possible mechanisms for the beneficial effects observed
in the treatment of human malignancies by
bisphosphonates.3,4 These include the inhibition
of cellular functions, induction of apoptosis, and change in the local
concentrations and expressions of growth factors, cytokines, adhesion
molecules, and so forth. But we propose that another mechanism may be
involved, namely, the inhibition of matrix metalloproteinase (MMP)
activity by bisphosphonates.5 There may also be other
MMP-related mechanisms involved, such as TIMP- or substrate-related
mechanisms, as shown by Farina et al6 and Makowski et
al,7 respectively.
Recently, Diehl et al8 reported on significant decrease of
breast cancer metastases both in bone and in soft tissues of patients
receiving adjunctive clodronate therapy. Extensive literature supports
a role for various MMPs in cancer growth and metastasis, especially
collagenases-1 and -3 (MMP-1 and MMP-13),9 the
gelatinases (MMP-2 and MMP-9), and the membrane-type MMPs (MT-MMPs);
futhermore, several MMPs have been shown to be expressed by
multiple myeloma. MMPs can collectively degrade the extracellular
matrix and basement membrane, which act as barriers to tumor spread and
growth. Therefore, identification of pharmacologically potential agents
that might inhibit human cell-derived MMPs has long seemed a
reasonable therapeutic goal for modulation and down-regulation of
metastases formation and bone destruction in these pathological
states.1,2,10
Our data show (Figure 1) that clodronate
(and several other bisphosphonates; data not shown) can inhibit in
vitro the activities of cancer-related enzymes MMP-2, MMP-9, MMP-13,
and MT1-MMP (and several other MMPs).5,11,12 These drugs
also inhibit reconstituted basement membrane-invasion of
malignant cell lines (capable of expressing these MMPs) in a
dose-dependent manner and at concentrations attainable in
vivo.5 In our study with patients receiving clodronate therapy, a slight but significant decrease in the salivary collagenase levels was observed after 3 weeks, demonstrating a down-regulating effect of MMPs by clodronate in vivo.13 We propose that
the beneficial effects of the bisphosphonates on the metastatic process may be related to inhibition and down-regulation of various genetically distinct MMPs that are crucial in the escape of malignant
cells into and out of circulation, and destruction of local tissue at a
metastatic site.
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| Figure 1.
Representative data demonstrating dose-dependent
inhibition of various MMP activities by clodronate.
The activity of MMPs were assayed by a urokinase-based activity
assay.5
|
|
Olli Teronen
Department of Oral and Maxillofacial Surgery Faculty of
Medicine, Institute of Medical Technology University of Tampere
Tampere, Finland
Minna Laitinen
Department of Surgery Tampere University
Hospital Institute of Medical Technology University of
Tampere Tampere, Finland
Tuula Salo
Institute of Dentistry University of Oulu Oulu, Finland
Roeland Hanemaaijer
TNO Pharma Leiden, Holland
Pia Heikkilä, Yrjö T. Konttinen, and Timo Sorsa
University of Helsinki Helsinki, Finland
References
1.
Raje N, Anderson KC.
Introduction: the evolving role of bisphosphonate therapy in multiple myeloma.
Blood.
2000;96:381-383[Free Full Text].
2.
Kunzmann V, Bauer E, Feurle J, Wei
inger F, Tony H-P, Wilhelm M.
Stimulation of T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma.
Blood.
2000;96:384-392[Abstract/Free Full Text].
3.
Bataille R.
Management of myeloma with bisphosphonates [editorial].
N Engl J Med.
1996;334:529-530[Free Full Text].
4.
Hortobagyi GN, Theriault RL, Porter L, et al.
Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases.
N Engl J Med.
1996;335:1785-1791[Abstract/Free Full Text].
5.
Teronen O, Heikkila P, Konttinen YT, et al.
MMP inhibition by bisphosphonates.
Ann N Y Acad Sci.
1999;878:453-465[Abstract/Free Full Text].
6.
Farina AR, Tacconelli A, Teti A, Gulino A, Mackay AR.
Tissue inhibitor of metalloproteinase-2 protection of matrix metalloproteinase-2 from degradation by plasmin is reversed by divalent cation chelator EDTA and the bisphosphonate alendronate.
Cancer Res.
1998;15:2957-2960.
7.
Makowski GS, Ramsby ML.
Amorphous calcium phosphate-mediated binding of matrix metalloproteinase-9 to fibrin is inhibited by pyrophosphate and bisphosphonate.
Inflammation.
1999;23:333-360[Medline]
[Order article via Infotrieve].
8.
Diel IJ, Solomayer EF, Costa SD, et al.
Reduction in new metastases in breast cancer with adjuvant clodronate treatment.
N Engl J Med.
1998;339:357-363[Abstract/Free Full Text].
9.
Chambers AF, Matrisian LM.
Changing views of the role of matrix metalloproteinases in metastasis.
J Natl Cancer Inst.
1997;89:1260-1270[Abstract/Free Full Text].
10.
Kahari VM, Saarialho-Kere U.
Matrix metalloproteinases and their inhibitors in tumour growth and invasion.
Ann Med.
1999;31:34-45[Medline]
[Order article via Infotrieve].
11.
Teronen O, Konttinen YT, Lindqvist C, et al.
Inhibition of matrix metalloproteinase-1 by dichloromethylene bisphosphonate (clodronate).
Calcif Tissue Int.
1997;61:59-61[Medline]
[Order article via Infotrieve].
12.
Konttinen YT, Salo T, Hanemaaijer R, et al.
Collagenase-3 (MMP-13) and its activators in rheumatoid arthritis: localization in the pannus-hard tissue junction and inhibition by alendronate.
Matrix.
1999;18:401-412.
13.
Valleala H, Teronen O, Friman C, Sorsa T, Solovieva SA, Konttinen YT.
Inhibition of collagenase by a bisphosphonate-group drug in rheumatoid arthritis patients.
J Rheumatol.
2000;27:1570-1572[Medline]
[Order article via Infotrieve].
