Tyrosine kinase inhibitors in cancer therapy

Adjej, A. (2001). Epidermal growth factor receptor tyrosine kinase inhibitors in cancer therapy. Drugs Future 26(11), 1087-1092. 

Shawver, L. K., Slamon, D., Ullrich, A. Smart drugs tyrosine kinase inhibitors in cancer therapy. Cancer Cell 2002, 1, 117-123. 

Smith, J. K., Mamoon, N. M., Duhe, R. J. (2004). Emerging roles of targeted small molecule protein-tyrosine kinase inhibitors in cancer therapy. Oncol. Res. 14, 175-225. 

Arora A, Scholar EM (2005) Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther 315 971-979... 

Massarelli E et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clinical Cancer Research 2007 13 2890-2896. 

Sorafenib is a multitargeted cancer therapy that inhibits VEGFR, PDGFR, KIT, fetal liver tyrosine kinase 3 (FLT-3), and the serine/threonine kinase RAF. RAF kinase is a key downstream effector of Ras in the MAPK/Ras signal-transduction pathway that has been linked to various cancers. Sorafenib is both a tyrosine kinase inhibitor and serine/threonine signal-transduction inhibitor. Sorafenib has been approved in renal cancer. 

Note that application in the particular indications is usually restricted either to patients expressing the target (e.g. trastuzumab, cetuximab, lapatinib, imatinib) and/or after failure of prior therapies (e.g. cetuximab, erlotinib, lapatinib, sutinib, dasatinib). Furthermore, for cancer treatment most tyrosine kinase inhibitors are applied in combination with conventional chemotherapeutic drugs, such as fluorouracil, taxanes, platin-based regimens, anthracylines and irinotecan or radiotherapy. 

Oxindole derivatives, (III), prepared by Harris (3) were effective as Trk family protein tyrosine kinase inhibitors and were useful in cancer therapy. 

Abnormal activation of specific protein tyrosine kinases has been demonstrated in many human neoplasms, making them attractive molecular targets for cancer therapy. There currently are 3 smaU-molecular-weight protein tyrosine kinase inhibitors that are FDA-approved and many others in clinical trials. 

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