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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 384-392
Stimulation of   T cells by aminobisphosphonates and
induction of antiplasma cell activity in multiple myeloma
Volker Kunzmann,
Eva Bauer,
Juliane Feurle,
Florian Weißinger, Hans-Peter Tony, and
Martin Wilhelm
From the Medizinische Poliklinik Wuerzburg, Julius-Maximilians
Universität Wuerzburg, Wuerzburg, Germany.
Bisphosphonates are well-known inhibitors of osteoclastic bone
resorption, but recent clinical reports support the possibility of
direct or indirect antitumor effects by these compounds. Because bisphosphonates share structural homologies with recently
identified   T-cell ligands, we examined the stimulatory capacity
of bisphosphonates to T cells and determined whether
T-cell stimulation by bisphosphonates could be exploited to generate
antiplasma cell activity in multiple myeloma (MM). All tested
aminobisphosphonates (alendronate, ibandronate, and pamidronate)
induced significant expansion of T cells (V9V2 subset) in
peripheral blood mononuclear cell cultures of healthy donors at
clinically relevant concentrations (half-maximal activity, 0.9-4 µmol/L). The proliferative response of T
cells to aminobisphosphonates was IL-2 dependent, whereas activation of T cells (up-regulation of CD25 and CD69) occurred in the absence of exogenous cytokines. Pamidronate-activated T
cells produced cytokines (ie, interferon [IFN]-) and exhibited specific cytotoxicity against lymphoma (Daudi) and myeloma cell lines
(RPMI 8226, U266). Pamidronate-treated bone marrow (BM) cultures of 24 patients with MM showed significantly reduced plasma cell survival compared with untreated cultures, especially in cultures
in which activation of BM- T cells was evident (14 of 24 patients with MM). T-cell depletion from BM cultures completely
abrogated the cytoreductive effect on myeloma cells in 2 of 3 tested
patients with MM. These results show that aminobisphosphonates stimulating T cells have pronounced effects on the immune
system, which might contribute to the antitumor effects of these drugs.
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Inhibition of Caspases Maintains the Antineoplastic Function of {{gamma}}{{delta}} T Cells Repeatedly Challenged with Lymphoma Cells
Cancer Res.,
April 1, 2001;
61(7):
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[Abstract]
[Full Text]
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O. Teronen, M. Laitinen, T. Salo, R. Hanemaaijer, P. Heikkila, Y. T. Konttinen, and T. Sorsa
Inhibition of matrix metalloproteinases by bisphosphonates may in part explain their effects in the treatment of multiple myeloma
Blood,
December 1, 2000;
96(12):
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[Full Text]
[PDF]
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N. Raje and K. C. Anderson
Introduction: the evolving role of bisphosphonate therapy in multiple myeloma
Blood,
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381 - 383.
[Full Text]
[PDF]
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K. C. Anderson, R. A. Kyle, W. S. Dalton, T. Landowski, K. Shain, R. Jove, L. Hazlehurst, and J. Berenson
Multiple Myeloma: New Insights and Therapeutic Approaches
Hematology,
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[Abstract]
[Full Text]
[PDF]
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