| Autor: |
Dool, Carly Jade, Mashhedi, Haider, Zakikhani, Mahvash, David, Stéphanie, Zhao, Yunhua, Birman, Elena, Carboni, Joan M., Gottardis, Marco, Blouin, Marie-José, Pollak, Michael |
| Předmět: |
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| Zdroj: |
Endocrine-Related Cancer; Dec2011, Vol. 18 Issue 6, p699-709, 11p |
| Abstrakt: |
Epidemiologic and experimental evidence suggest that a subset of breast cancer is insulin responsive, but it is unclear whether safe and effective therapies that target the insulin receptor (IR), which is homologous to oncogenes of the tyrosine kinase class, can be developed. We demonstrate that both pharmacologic inhibition of IRfamily tyrosine kinase activity and insulin deficiency have antineoplastic activity in amodel of insulin-responsive breast cancer. Unexpectedly, in contrast to insulin deficiency, pharmacologic IR family inhibition does not lead to significant hyperglycemia and is well tolerated. We show that pharmacokinetic factors explain the tolerability of receptor inhibition relative to insulin deficiency, as the small molecule receptor kinase inhibitor BMS-536924 does not accumulate inmuscle at levels sufficient to block insulin-stimulated glucose uptake.Metformin, which lowers insulin levels only in settings of hyperinsulinemia, hadminimal activity in this normoinsulinemic model. These findings highlight the importance of tissue-specific drug accumulation as a determinant of efficacy and toxicity of tyrosine kinase inhibitors and suggest that therapeutic targeting of the IR family for cancer treatment is practical. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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