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Imatinib mesylate (STI-571) reduces Bcr-Abl-mediated vascular endothelial growth factor secretion in chronic myelogenous leukemia.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Ebos, John M. L. Tran, Jennifer Master, Zubin Dumont, D. Melo, Junia V. Buchdunger, Elisabeth Kerbel, Robert S. |
| Copyright Year | 2002 |
| Abstract | A large and diverse spectrum of oncogenes has been implicated as a contributor to angiogenesis in solid tumors based, in part, on its ability to induce proangiogenic growth factors such as vascular endothelial growth factor (VEGF), and the fact that various anti-oncogenic signaling inhibitor drugs have been shown to reverse such proangiogenic effects both in vitro and in vivo. Because leukemias are now also considered to be angiogenesis-dependent malignancies, we asked whether a similar paradigm might exist for the BCR-ABL oncogene and the Bcr-Abl targeting drug, STI-571 (imatinib mesylate), in the context of chronic myelogenous leukemia (CML) cells. We found that levels of VEGF expression in BCR-ABL-positive K562 cells were reduced in vitro by treatment with STI-571 in a dose-dependent fashion. Transfection of BCR-ABL into murine myeloid 32D and human megakaryocyte MO7e hematopoietic cells resulted in enhanced VEGF expression, which could be further elevated by the exposure to cytokines such as interleukin 3 and granulocyte macrophage colony-stimulating factor. We also found that conditioned media taken from 32D-p210-transfected cells could stimulate human umbilical vein endothelial cells by increasing phosphorylation of VEGF-R2/KDR and the downstream serine/threonine kinase PKB/Akt, an important regulator of endothelial cell survival. Moreover, amplification of BCR-ABL in STI-571-resistant cells was associated with elevated VEGF expression levels which could be reversed by treatment with higher concentrations of STI-571. Taken together, our results implicate BCR-ABL as a possible regulator of CML angiogenesis and raise the possibility that STI-571 could mediate some of its anti-CML properties in vivo through an angiogenesis-dependent mechanism. |
| Starting Page | 89 |
| Ending Page | 95 |
| Page Count | 7 |
| File Format | PDF HTM / HTML |
| PubMed reference number | 12496355 |
| Journal | Medline |
| Volume Number | 1 |
| Issue Number | 2 |
| Alternate Webpage(s) | http://mcr.aacrjournals.org/content/molcanres/1/2/89.full.pdf |
| Journal | Molecular cancer research : MCR |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
