Preclinical studies in support of defibrotide for the treatment of multiple myeloma and other neoplasias.
OBJECTIVE
Defibrotide, an orally bioavailable polydisperse oligonucleotide, has promising activity in hepatic veno-occlusive disease, a stem cell transplantation-related 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.


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.


CONCLUSIONS
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.
Mitsiades
Constantine S
CS
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. constantine_mitsiades@dfci.harvard.edu
Rouleau
Cecile
C
Echart
Cinara
C
Menon
Krishna
K
Teicher
Beverly
B
Distaso
Maria
M
Palumbo
Antonio
A
Boccadoro
Mario
M
Anderson
Kenneth C
KC
Iacobelli
Massimo
M
Richardson
Paul G
PG
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005260:Female; D005966:Glucuronidase / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D011089:Polydeoxyribonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D017154:Stromal Cells / Q000187:drug effects / Q000502:physiology; D000099175:Heparanase
D000970:Antineoplastic Agents; D005966:Glucuronidase; D011089:Polydeoxyribonucleotides; D000099175:Heparanase; C036901:defibrotide