FQPD, a novel immunomodulatory drug, has significant in vitro activity in multiple myeloma.
Multiple myeloma (MM) is a plasma cell malignancy that claims thousands of lives each year and has considerable morbidity. The disease remains incurable despite recent advances in the understanding of the disease biology and the introduction of more effective drugs is needed. This study evaluated the anti-MM activity of 3-(7-fluoro-4H-quinazolin-3-yl)-piperidine-2,6-dione, hydrochloride (FQPD), a novel immunomodulatory drug. FQPD inhibited the proliferation of multiple MM cell lines, including those resistant to conventional treatments, such as dexamethasone. It induced apoptosis in MM cell lines, as well as freshly isolated patient MM cells, without cytotoxicity on normal human lymphocytes. Moreover, it induced apoptosis in MM cells adherent to bone marrow (BM) stromal cells or in the presence of cytokines, such as interleukin-6 and vascular endothelial growth factor, confirming its ability to overcome the protective effects of the BM milieu. Apoptosis in the MM cells was mediated via poly-ADP ribose polymerase cleavage as well as cleavage of caspase 8 and caspase 9. Our studies therefore demonstrated in vitro anti-MM activity of FQPD and provide the rationale for its in vivo evaluation in animal models and derived clinical trials.
Division of Hematology, Mayo Clinic, Rochester, MN, USA.
Shaji
S
Kumar
Noopur
N
Raje
Teru
T
Hideshima
Kenji
K
Ishitsuka
Klaus
K
Podar
Steven
S
Le Gouille
Dharminder
D
Chauhan
Paul
P
Richardson
Nikhil C
NC
Munshi
Kenneth
K
Anderson
D015121:6-Ketoprostaglandin F1 alpha / Q000276:immunology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000096:biosynthesis; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000276:immunology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology; D013002:Somatomedins / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology; D042442:Vascular Endothelial Growth Factors / Q000276:immunology
D004273:DNA, Neoplasm; D007155:Immunologic Factors; D015850:Interleukin-6; D013002:Somatomedins; D042442:Vascular Endothelial Growth Factors; D015121:6-Ketoprostaglandin F1 alpha