Cancer Research The Future of Cancer Research: Science and Patient Impact Translational Medicine Conference in Israel
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lin, B.
Right arrow Articles by Anderson, K. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lin, B.
Right arrow Articles by Anderson, K. C.
[Cancer Research 62, 5019-5026, September 1, 2002]
© 2002 American Association for Cancer Research

Experimental Therapeutics

The Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor PTK787/ZK222584 Inhibits Growth and Migration of Multiple Myeloma Cells in the Bone Marrow Microenvironment1

Boris Lin, Klaus Podar, Deepak Gupta, Yu-Tzu Tai, Sigui Li, Edie Weller, Teru Hideshima, Suzanne Lentzsch, Faith Davies, Cheng Li, Ellen Weisberg, Robert L. Schlossman, Paul G. Richardson, James D. Griffin, Jeanette Wood, Nikhil C. Munshi and Kenneth C. Anderson2

Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology [B. L., K. P., D. G., Y. T., T. H., S. L., F. D., R. L. S., P. G. R., J. D. G., N. C. M., K. C. A.], and Department of Biostatistical Science [S. L., E. W., C. L.], Dana-Farber Cancer Institute, Boston, Massachusetts 02115; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115 [B. L., K. P., D. G., Y. T., T. H., S. L., F. D., R. L. S., P. G. R., J. D. G., N. C. M., K. C. A.]; and Department of Oncology Research, Novartis Pharma AG, CH-4002 Basel, Switzerland [J. W.]

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 µM) inhibits proliferation of MM cells by 50%, as assayed by [3H]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 µM) 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.




This article has been cited by other articles:


Home page
 BloodHome page
A. M. L. Coluccia, T. Cirulli, P. Neri, D. Mangieri, M. C. Colanardi, A. Gnoni, N. Di Renzo, F. Dammacco, P. Tassone, D. Ribatti, et al.
Validation of PDGFR{beta} and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: preclinical efficacy of the novel, orally available inhibitor dasatinib
Blood, August 15, 2008; 112(4): 1346 - 1356.
[Abstract] [Full Text] [PDF]

Home page
 Ann. N. Y. Acad. Sci.Home page
D. CILLONI, E. MESSA, F. MESSA, S. CARTURAN, I. DEFILIPPI, F. ARRUGA, V. ROSSO, R. CATALANO, E. BRACCO, P. NICOLI, et al.
Genetic Abnormalities as Targets for Molecular Therapies in Myelodysplastic Syndromes
Ann. N.Y. Acad. Sci., November 1, 2006; 1089(1): 411 - 423.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
Z. F. Yang, R. T.P. Poon, Y. Liu, C. K. Lau, D. W. Ho, K. H. Tam, C. T. Lam, and S. T. Fan
High doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: dual effects on cancer cell and angiogenesis.
Mol. Cancer Ther., September 1, 2006; 5(9): 2261 - 2270.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
G. Bisping, M. Kropff, D. Wenning, B. Dreyer, S. Bessonov, F. Hilberg, G. J. Roth, G. Munzert, M. Stefanic, M. Stelljes, et al.
Targeting receptor kinases by a novel indolinone derivative in multiple myeloma: abrogation of stroma-derived interleukin-6 secretion and induction of apoptosis in cytogenetically defined subgroups
Blood, March 1, 2006; 107(5): 2079 - 2089.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
A. Arora and E. M. Scholar
Role of Tyrosine Kinase Inhibitors in Cancer Therapy
J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 971 - 979.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
T. Hideshima, D. Chauhan, P. Richardson, and K. C. Anderson
Identification and Validation of Novel Therapeutic Targets for Multiple Myeloma
J. Clin. Oncol., September 10, 2005; 23(26): 6345 - 6350.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. Hamasaki, T. Hideshima, P. Tassone, P. Neri, K. Ishitsuka, H. Yasui, N. Shiraishi, N. Raje, S. Kumar, D. H. Picker, et al.
Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo
Blood, June 1, 2005; 105(11): 4470 - 4476.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. Liu, R. T. Poon, Q. Li, T. W. Kok, C. Lau, and S. T. Fan
Both Antiangiogenesis- and Angiogenesis-Independent Effects Are Responsible for Hepatocellular Carcinoma Growth Arrest by Tyrosine Kinase Inhibitor PTK787/ZK222584
Cancer Res., May 1, 2005; 65(9): 3691 - 3699.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Vincent, D. K. Jin, M. A. Karajannis, K. Shido, A. T. Hooper, W. K. Rashbaum, B. Pytowski, Y. Wu, D. J. Hicklin, Z. Zhu, et al.
Fetal Stromal-Dependent Paracrine and Intracrine Vascular Endothelial Growth Factor-A/Vascular Endothelial Growth Factor Receptor-1 Signaling Promotes Proliferation and Motility of Human Primary Myeloma Cells
Cancer Res., April 15, 2005; 65(8): 3185 - 3192.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
K. Podar and K. C. Anderson
The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications
Blood, February 15, 2005; 105(4): 1383 - 1395.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
B. Lin, L. Catley, R. LeBlanc, C. Mitsiades, R. Burger, Y.-T. Tai, K. Podar, M. Wartmann, D. Chauhan, J. D. Griffin, et al.
Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo
Blood, January 1, 2005; 105(1): 350 - 357.
[Abstract] [Full Text] [PDF]

Home page
 Ann. N. Y. Acad. Sci.Home page
G. PAGNUCCO, G. CARDINALE, and F. GERVASI
Targeting Multiple Myeloma Cells and Their Bone Marrow Microenvironment
Ann. N.Y. Acad. Sci., December 1, 2004; 1028(1): 390 - 399.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
S. Le Gouill, K. Podar, M. Amiot, T. Hideshima, D. Chauhan, K. Ishitsuka, S. Kumar, N. Raje, P. G. Richardson, J.-L. Harousseau, et al.
VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis
Blood, November 1, 2004; 104(9): 2886 - 2892.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
K. Podar, R. Shringarpure, Y.-T. Tai, M. Simoncini, M. Sattler, K. Ishitsuka, P. G. Richardson, T. Hideshima, D. Chauhan, and K. C. Anderson
Caveolin-1 Is Required for Vascular Endothelial Growth Factor-Triggered Multiple Myeloma Cell Migration and Is Targeted by Bortezomib
Cancer Res., October 15, 2004; 64(20): 7500 - 7506.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson
Advances in biology of multiple myeloma: clinical applications
Blood, August 1, 2004; 104(3): 607 - 618.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. H. Kropff and J. Kienast
Myeloma: targeted therapies march on
Blood, May 1, 2004; 103(9): 3247 - 3248.
[Full Text] [PDF]

Home page
 BloodHome page
K. Podar, L. P. Catley, Y.-T. Tai, R. Shringarpure, P. Carvalho, T. Hayashi, R. Burger, R. L. Schlossman, P. G. Richardson, L. N. Pandite, et al.
GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment
Blood, May 1, 2004; 103(9): 3474 - 3479.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. Zangari, E. Anaissie, A. Stopeck, A. Morimoto, N. Tan, J. Lancet, M. Cooper, A. Hannah, G. Garcia-Manero, S. Faderl, et al.
Phase II Study of SU5416, a Small Molecule Vascular Endothelial Growth Factor Tyrosine Kinase Receptor Inhibitor, in Patients with Refractory Multiple Myeloma
Clin. Cancer Res., January 1, 2004; 10(1): 88 - 95.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
C. A. London, A. L. Hannah, R. Zadovoskaya, M. B. Chien, C. Kollias-Baker, M. Rosenberg, S. Downing, G. Post, J. Boucher, N. Shenoy, et al.
Phase I Dose-Escalating Study of SU11654, a Small Molecule Receptor Tyrosine Kinase Inhibitor, in Dogs with Spontaneous Malignancies
Clin. Cancer Res., July 1, 2003; 9(7): 2755 - 2768.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
G. Bisping, R. Leo, D. Wenning, B. Dankbar, T. Padro, M. Kropff, C. Scheffold, M. Kroger, R. M. Mesters, W. E. Berdel, et al.
Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma
Blood, April 1, 2003; 101(7): 2775 - 2783.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Podar, Y.-T. Tai, C. E. Cole, T. Hideshima, M. Sattler, A. Hamblin, N. Mitsiades, R. L. Schlossman, F. E. Davies, G. J. Morgan, et al.
Essential Role of Caveolae in Interleukin-6- and Insulin-like Growth Factor I-triggered Akt-1-mediated Survival of Multiple Myeloma Cells
J. Biol. Chem., February 14, 2003; 278(8): 5794 - 5801.
[Abstract] [Full Text] [PDF]

Home page
 ASH Education BookHome page
F. J. Giles, A. Keating, A. H. Goldstone, I. Avivi, C. L. Willman, and H. M. Kantarjian
Acute Myeloid Leukemia
Hematology, January 1, 2002; 2002(1): 73 - 110.
[Abstract] [Full Text]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2002 by the American Association for Cancer Research.