Abstract B107: Targeting metastatic tumor cell functions by Src signaling interference using the small molecule Src inhibitor, saracatinib (AZD0530)
| العنوان: | Abstract B107: Targeting metastatic tumor cell functions by Src signaling interference using the small molecule Src inhibitor, saracatinib (AZD0530) |
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| المؤلفون: | Dietmar W. Siemann, Meiyu Dong |
| المصدر: | Molecular Cancer Therapeutics. 8:B107-B107 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | Cancer Research, business.industry, Cell growth, In vitro, Oncology, Cell culture, In vivo, Cancer cell, Immunology, Cancer research, Medicine, Phosphorylation, business, Tyrosine kinase, Proto-oncogene tyrosine-protein kinase Src |
| الوصف: | Introduction: The metastatic spread of cancer cells remains the principal cause of treatment failure. Src is a non-receptor tyrosine kinase that is frequently over-expressed in malignances, and increased Src activity may be associated with poor patient prognosis. Src tyrosine kinase plays an important role in tumor cell survival, proliferation, migration and invasion. Since these cellular functions are key components of the metastatic cascade, Src may be a novel target for cancer therapy. The present studies were undertaken to investigate whether molecular intervention in Src associated signaling could reduce the metastatic spread of tumor cells. Specifically, the efficacy of saracatinib a potent, selective and orally available Src inhibitor, was evaluated in the highly metastatic rodent KHT sarcoma cell line. Methods: The effect of saracatinib treatment on tumor cell functions, including viability, migration, invasion, and attachment, were examined by clonogenicity, migration/invasion and attachment assays, respectively. To assess saracatinib therapeutic effects on metastatic growth, tumor cells were either pretreated with saracatinib prior to intravenous injection or injected intravenously and then the mice were treated with saracatinib. In the latter case three protocols commencing immediately after tumor cell inoculation were investigated: a single 10 mg/kg dose of saracatinib; four 10 mg/kg doses of saracatinib given at 24 hr intervals; daily 10 mg/kg doses of saracatinib administered over a period of 3 weeks; in all protocols saracatinib was administered p.o. Twenty-one days after cell injection the number of lung metastases were determined. Results: In vitro saracatinib doses ranging from 0.5–5.0 µM significantly reduced Src phosphorylation and functionally inhibited KHT cell proliferation, migration, invasion and adhesion. Pretreating KHT cells with saracatinib (1 or 5 µM, 24 hr) also reduced (2–4-fold) the ability of these cells to form lung metastases when injected into C3H mice via the tail vein. In vivo, daily doses of saracatinib (10 mg/kg) reduced the number of metastases formed at the end of a 3 week period by a factor of ∼2. A similar reduction in lung colonies was achieved with four 10 mg/kg doses of saracatinib given daily commencing immediately after tumor cell injection, or even a single 10 mg/kg treatment administered immediately after tumor cell inoculation. Conclusions: The present studies explored the possibility of utilizing a molecular targeting strategy directed against key aspects of the metastatic cascade. The present findings demonstrate that saracatinib treatment significantly inhibits the ability of the cancer cells to escape the blood stream and invade at a secondary site supporting the notion that Src signal inhibition may hold considerable promise in impairing metastases formation. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B107. |
| تدمد: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.targ-09-b107 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::712d92c23185c3628ac7f481faab43df https://doi.org/10.1158/1535-7163.targ-09-b107 |
| رقم الانضمام: | edsair.doi...........712d92c23185c3628ac7f481faab43df |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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| DOI: | 10.1158/1535-7163.targ-09-b107 |