Induction therapy in a multiple myeloma mouse model using a combination of AS101 and melphalan, and the activity of AS101 in a tumor microenvironment model.
OBJECTIVE
We previously showed that the organotellurium compound, ammonium trichloro (dioxyethylene-0-0') tellurate (AS101), has antitumoral activity in multiple myeloma (MM) cell lines. Here, we evaluated the antimyeloma activity of AS101 combined with low-dose melphalan, and also examined the activity of AS101 in the myeloma tumor microenvironment.


METHODS
Isobologram analysis was performed to determine the interactions of AS101 and melphalan as a combination therapy. Growth arrest, apoptosis, and CD81 antigen were detected by flow cytometry. Using the 5T33MM mouse model, we evaluated mouse survival and serum levels of vascular endothelial growth factor (VEGF) and IgG(2b) paraprotein. We established cocultures of MS-5 bone marrow stromal cells and 5T33 MM cells in order to examine AS101 activity in a myeloma microenvironment model.


RESULTS
Combined treatment of AS101 with melphalan in vitro resulted in a synergistic inhibitory effect on growth, G(2)/M phase growth arrest, reduced IgG(2b) secretion, apoptotic cell death, and reduced fibronectin-mediated adhesion of MM cells. AS101 reduced VEGF secretion and protein expression in myeloma and cocultured cells, downregulated production of the matrix metalloproteinases (MMPs), MMP-9 and MMP-2, and also inhibited growth of the treated myeloma coculture. Combined treatment using AS101 and low dose of melphalan in vivo resulted in modest survival improvement of myeloma-bearing mice and in reduced IgG(2b) and VEGF serum levels.


CONCLUSIONS
AS101 in combination with a subtherapeutic dose of melphalan had increased beneficial effect relative to each agent alone in a mouse MM model. In addition, AS101 might be useful for targeting interactions between myeloma cells and the bone marrow microenvironment.
Safdié Institute for AIDS and Immunology Research, The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Michal
M
Hayun
Hagar
H
Saida
Michael
M
Albeck
Alpha
A
Peled
Nechama
N
Haran-Ghera
Benjamin
B
Sredni
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005030:Ethylenes / Q000819:agonists / Q000494:pharmacology / Q000627:therapeutic use; D005353:Fibronectins; D016195:G2 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007074:Immunoglobulin G / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008558:Melphalan / Q000819:agonists / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010266:Paraproteins / Q000096:biosynthesis; D060225:Tetraspanin 28; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D015703:Antigens, CD; C554799:Cd81 protein, mouse; D005030:Ethylenes; D005353:Fibronectins; D007074:Immunoglobulin G; D009363:Neoplasm Proteins; D010266:Paraproteins; D060225:Tetraspanin 28; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D008558:Melphalan