The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment.
Our prior studies show that multiple myeloma (MM) cell lines and patient cells express high-affinity vascular endothelial growth factor (VEGF) receptor (VEGFR) Flt-1 but not Flk-1/KDR. Moreover, these studies have shown that VEGF induces proliferation and migration of MM cells, and we have begun to delineate the signaling cascades mediating those sequelae. In this study, we examined the activity of PTK787/ZK 222584 (PTK787), a molecule designed to bind specifically to the tyrosine kinase domain of VEGFR and inhibit angiogenesis. We show that PTK787 acts both directly on MM cells and in the bone marrow microenvironment. Specifically, PTK787 (1-5 micro M) inhibits proliferation of MM cells by 50%, as assayed by [(3)H]thymidine uptake. This effect of PTK787 is dose dependent in both MM cell lines and patient cells that are both sensitive and resistant to conventional therapy. PTK787 enhances the inhibitory effect of dexamethasone on growth of MM cells and can overcome the protective effect of interleukin 6 (IL-6) against dexamethasone-induced apoptosis. PTK787 (1 micro M) also blocks VEGF-induced migration of MM cells across an extracellular matrix. Importantly, PTK787 also inhibits the increased MM cell proliferation and increased IL-6 and VEGF secretion in cultures of MM cells adherent to bone marrow stem cells. These findings therefore demonstrate that PTK787 both acts directly on MM cells and inhibits paracrine IL-6-mediated MM cell growth in the bone marrow milieu. The demonstrated anti-MM activity of PTK787, coupled with its antiangiogenic effects, provides the framework for clinical trials of this agent to overcome drug resistance and improve outcome in MM.
Lin
Boris
B
Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Podar
Klaus
K
Gupta
Deepak
D
Tai
Yu-Tzu
YT
Li
Sigui
S
Weller
Edie
E
Hideshima
Teru
T
Lentzsch
Suzanne
S
Davies
Faith
F
Li
Cheng
C
Weisberg
Ellen
E
Schlossman
Robert L
RL
Richardson
Paul G
PG
Griffin
James D
JD
Wood
Jeanette
J
Munshi
Nikhil C
NC
Anderson
Kenneth C
KC
D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D010793:Phthalazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D011725:Pyridines; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017978:Receptors, Growth Factor / Q000096:biosynthesis; D040262:Receptors, Vascular Endothelial Growth Factor; D014407:Tumor Cells, Cultured; D040281:Vascular Endothelial Growth Factor Receptor-1; D040321:Vascular Endothelial Growth Factor Receptor-3
D016326:Extracellular Matrix Proteins; D015850:Interleukin-6; D010793:Phthalazines; D011725:Pyridines; D017978:Receptors, Growth Factor; C404768:vatalanib; D003907:Dexamethasone; C501162:FLT1 protein, human; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040321:Vascular Endothelial Growth Factor Receptor-3