The new development is described in abstarcts on Her-2/neu inhibitor(AstaM program) and MMP-9,-2 regulation by bFGFr/VEGFr inhibition.
#456 VEGFR and bFGFR antagonists SU9902 and SU9803 inhibit growth and MMP-9 expression in human glioma cell lines. Shravan K. Chintala, Jasti S. Rao, Peter A. Steck*, T.J. Liu, Gerald McMahon†, and WK Alfred Yung*. Departments of Neurosurgery and *Neuro-Oncology, UT M.D. Anderson Cancer Center, Houston, TX 77030, and †SUGEN Inc, 230 East Grand Avenue, South San Francisco, CA 94080.
Glioblastomas are highly aggressive tumors that extensively invade the surrounding normal brain. Compared to normal brain and low-grade gliomas, glioblastomas express increased levels of VEGF, bFGF, and matrix metalloproteinases (MMPs). Our long-term interest is to understand the cellular and molecular mechanisms that underlie glioma growth progression and invasion. In this study we investigated the effect of two compounds (SU9902 and SU9803) that are antagonists of VEGFR-, and bFGFR- mediated tyrosine kinase activities, on cell growth and on the expression of VEGF, MMP-2, and MMP-9 in several human glioma cell lines. Treatment of U87 and U251 glioma cells, cell lines that both express high levels of VEGF and bFGF, with both compounds showed growth inhibition with an IC50 of 20-30 µM. Similar treatment of SNB19 glioma cells resulted in the inhibition of MMP-9 but not of MMP-2. In vitro invasiveness of SNB19 cells was inhibited by both compounds as determined using a 3-dimensional spheroid assay system. These preliminary results suggest that blockade of VEGFR and bFGFR activities with synthetic inhibitors may provide a means to effect the growth and invasion of human glioma cells.
#4819 Blockade of the EGF receptor tyrosine kinase prevents tumorigenesis in MMTV/neu + TGF[alpha] bigenic mice. Lenferink AEG, Busse D, Shawver LK, Bogatcheva G, Coffey RJ, Simpson JF, Forbes JT and Arteaga CL. Departments of Medicine, Cell Biology, and Pathology, Vanderbilt University School of Medicine, Vanderbilt Cancer Center, Nashville, TN; Sugen, Inc., South San Francisco, CA.
The combined overexpression of the ErbB-2/Neu receptor and the EGFR ligand TGF[alpha] results in accelerated mammary tumor formation. Here we show that treatment of virgin MMTV/Neu + MMTV/TGF[alpha] bigenic mice with the EGFR tyrosine kinase inhibitor AG1478 (50 mg/kg i.p. daily) results in a remarkable delay in mammary tumor formation. After 6 months of uninterrupted treatment without any signs of toxicity, 9/10 control but only 2/10 AG1478 treated mice had detectable mammary tumors. By histology, these were ductal hyperplasias and carcinoma in situ. Tumor-free glands in mice treated with the kinase inhibitor exhibited no ductal hyperplasia. Upon cessation of AG1478, 6/8 mice developed palpable tumors within 2 months. In addition, mammary gland whole mount preparations from the 2 remaining tumor-free 1 year old animals showed epithelial hyperplasia, suggesting that the full impact of EGFR-kinase inhibition on transformation may require more prolonged treatment. Western blot analyses of tumor tissue taken from bigenic mice with established carcinomas following 5 days of AG1478 administration, showed a significant loss of phosphorylation of precipitated EGFR and Neu without loss of receptor proteins, a decrease in MAP-kinase phosphorylation, up-regulation of the Cdk inhibitor p27, and down-regulation of Cyclin D1. Studies addressing G1 arrest and apoptosis in vivo are in progress. These data suggest that chronic inhibition of ErbB tyrosine kinase(s) can prolong latency and/or prevent oncogene mediated mammary transformation. |
