Kinase cancer patients

The unbound fraction of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib has been extensively studied in cancer patients [39]. The drug was found to bind to serum albumin, oq-acid glycoprotein, and red blood cells with a mean unbound fraction of 3.4% which was constant over 28 days of dosing. Unbound fraction ranged from 2.2% to 5.4% and was inversely correlated with pre-treatment levels of oq-acid glycoprotein. 

The Ras to Raf to Erk signaling pathway depicted in fignre 24.1 is important but it is not the most important signaling pathway associated with development of human tumors, particularly those tumors that are most frequently fatal to cancer patients. That honor goes to the phosphatidylinositol-3-kinase, P13K, signaling pathway. This pathway is complex and 1 shall not describe it. 

UCN-01 is currently being explored in cancer patients in Phase I/II clinical trials, both as a single agent and in combination with conventional chemotherapeutic drugs (e.g., cytarabine, topotecan). In this last scenario, results from a Phase I clinical trial in combination with topotecan showed antitumor activity in 12 patients with advanced solid tumor with one partial response and three cases of stable disease. However, and due to the low selectivity of UCN-01, it is unclear which inhibited kinase(s) are suppressing growth and survival of cancer cells in these clinical studies. 

Through collaboration with Clinomics Biosciences, Inc., we obtained access to their breast cancer patient database containing clinical information and immunohistochem-istry tissue array data. We developed an integrative profile for breast cancer survival and treatment response predictions, which composed the expression profile of several major activated protein kinases as well as several traditional clinical parameters (39). 

Amler LC, Goddard AD, Hillan KJ. Predicting clinical benefit in non-small-cell lung cancer patients treated with epidermal growth factor tyrosine kinase inhibitors. Cold Spring Harb Symp Quant Biol... 

Man A, Fabbro D, Harris A, Balkwill F. The protein kinase C 95. inhibitor CGP41251 suppresses cytokine release and extracellular signal-regulated kinase 2 expression in cancer patients. Cancer Res. 1999 59 3980-3984. 

Li J, Cusatis G, Brahmer J, Sparreboom A, Robey RW, Bates SE, Hidalgo M, Baker SD (2007) Association of variant ABCG2 and the pharmacokinetics of epidermal growth factor receptor tyrosine kinase inhibitors in cancer patients. Cancer Biol Ther 6 432 438... 

Taguchi, F. et al., Mass spectrometry to classify non-small-cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors A multicohort cross-institutional study, J. Natl. Cancer Inst., 99(11), 838, 2007. 

I thank my present and former colleagues for their outstanding work and dedication to identify and develop kinase inhibitors, bringing hope to cancer patients and their families. 

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