Abstract | PURPOSE OF THE STUDY: 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 myeloma-bone marrow stromal cell adhesion and its sequelae, including nuclear factor-kappaB 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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Authors | Constantine S Mitsiades, Cecile Rouleau, Cinara Echart, Krishna Menon, Beverly Teicher, Maria Distaso, Antonio Palumbo, Mario Boccadoro, Kenneth C Anderson, Massimo Iacobelli, Paul G Richardson |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 15
Issue 4
Pg. 1210-21
(Feb 15 2009)
ISSN: 1078-0432 [Print] United States |
PMID | 19228727
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Polydeoxyribonucleotides
- defibrotide
- heparanase
- Glucuronidase
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Topics |
- Animals
- Antineoplastic Agents
(therapeutic use)
- Cell Line, Tumor
- Cell Survival
(drug effects)
- Coculture Techniques
- Endothelial Cells
(drug effects, physiology)
- Female
- Glucuronidase
(physiology)
- Humans
- Male
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Multiple Myeloma
(drug therapy, pathology)
- Polydeoxyribonucleotides
(administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
- Rats
- Rats, Inbred F344
- Stromal Cells
(drug effects, physiology)
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