Preclinical Studies in Support of Defibrotide for the Treatment of Multiple Myeloma and Other Neoplasias
Purpose of the Study: Defibrotide, an orally bioavailable polydisperse oligonucleotide, has promising activity in hepatic veno-occlusive disease, a stem cell transplantationârelated toxicity characterized by microangiopathy. The antithrombotic properties of defibrotide and its minimal hemorrhagic...
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Veröffentlicht in: | Clinical cancer research 2009-02, Vol.15 (4), p.1210-1221 |
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Zusammenfassung: | Purpose of the Study: Defibrotide, an orally bioavailable polydisperse oligonucleotide, has promising activity in hepatic veno-occlusive disease,
a stem cell transplantationârelated toxicity characterized by microangiopathy. The antithrombotic properties of defibrotide
and its minimal hemorrhagic risk could serve for treatment of cancer-associated thrombotic complications. Given its cytoprotective
effect on endothelium, we investigated whether defibrotide protects tumor cells from cytotoxic antitumor agents. Further,
given its antiadhesive properties, we evaluated whether defibrotide modulates the protection conferred to multiple myeloma
cells by bone marrow stromal cells.
Methods-Results: Defibrotide lacks significant single-agent in vitro cytotoxicity on multiple myeloma or solid tumor cells and does not attenuate their in vitro response to dexamethasone, bortezomib, immunomodulatory thalidomide derivatives, and conventional chemotherapeutics, including
melphalan and cyclophosphamide. Importantly, defibrotide enhances in vivo chemosensitivity of multiple myeloma and mammary carcinoma xenografts in animal models. In cocultures of multiple myeloma
cells with bone marrow stromal cells in vitro , defibrotide enhances the multiple myeloma cell sensitivity to melphalan and dexamethasone, and decreases multiple myelomaâbone
marrow stromal cell adhesion and its sequelae, including nuclear factor-κB activation in multiple myeloma and bone marrow
stromal cells, and associated cytokine production. Moreover, defibrotide inhibits expression and/or function of key mediators
of multiple myeloma interaction with bone marrow stromal cell and endothelium, including heparanase, angiogenic cytokines,
and adhesion molecules.
Conclusion: Defibrotide's in vivo chemosensitizing properties and lack of direct in vitro activity against tumor cells suggest that it favorably modulates antitumor interactions between bone marrow stromal cells
and endothelia in the tumor microenvironment. These data support clinical studies of defibrotide in combination with conventional
and novel therapies to potentially improve patient outcome in multiple myeloma and other malignancies. |
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ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-08-1270 |