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82 - Tyrosine-kinase inhibitors in oncology
- from Part 4 - Pharmacologic targeting of oncogenic pathways
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- By Anne S. Tsao, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, Vassiliki Papadimitrakopoulou, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, Roy S. Herbst, Yale University School of Medicine, New Haven, CT
- Edited by Edward P. Gelmann, Columbia University, New York, Charles L. Sawyers, Memorial Sloan-Kettering Cancer Center, New York, Frank J. Rauscher, III
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- Book:
- Molecular Oncology
- Published online:
- 05 February 2015
- Print publication:
- 19 December 2013, pp 872-883
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Summary
Introduction
In the past decade, delivering personalized medicine via molecularly targeted therapies has become a major focus in the field of cancer therapeutics. Tyrosine kinases regulate angiogenesis and cell proliferation, invasion, and apoptosis. Tyrosine-kinase inhibitors (TKIs) are small-molecule inhibitors that permeate through the cell membrane and target specific portions of kinase receptors in cancer cells and/or the surrounding endothelium and vasculature. In this chapter, we review the TKIs currently used to treat cancer, including targeted agents, angiogenesis inhibitors, and Her family inhibitors (Figure 82.1).
Imatinib mesylate
Imatinib mesylate (STI-571; Gleevec/Glivec, Novartis Pharmaceuticals), the first TKI developed for Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia (CML), specifically targets the translocation that encodes the breakpoint cluster region–Abelson (BCR–ABL) tyrosine kinase (Figure 82.2). Imatinib also inhibits normal ABL. The BCR–ABL fusion gene is found in 90% of patients with CML and 15–30% of patients with acute lymphoblastic leukemia (ALL; 1). BCR–ABL activates multiple cytoplasmic and nuclear signal-transduction pathways, including Ras, phosphatidylinositol-3 kinase (PI3K), protein kinase B (AKT), and Jak/Stat, and up-regulates interleukin-3 and focal adhesion kinase. BCR–ABL is associated with an impaired DNA-repair response that promotes genetic abnormalities (2–10). In addition, imatinib inhibits c-Kit receptor and platelet-derived growth-factor receptor (PDGFR)-α and -β.
24 - Head and neck cancer
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- By Merrill S. Kies, U.T. M.D. Anderson Cancer Center, Houston, Roy S. Herbst, U.T. M.D. Anderson Cancer Center, Houston
- Edited by Michael J. Fisch, University of Texas, M. D. Anderson Cancer Center, Eduardo Bruera, University of Texas, M. D. Anderson Cancer Center
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- Book:
- Handbook of Advanced Cancer Care
- Published online:
- 04 August 2010
- Print publication:
- 27 March 2003, pp 207-216
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Summary
Introduction
Head and neck cancers constitute a broad spectrum of disease processes with varying histology, natural history, and treatment outcomes. In this chapter we discuss squamous cell cancers of the oral cavity, pharynx, and larynx constituting about 80% of head and neck malignancies. The annual incidence of such cancers is approximately 45 000 cases per year in the US. This is the fifth most common cancer in the world today. Median age at presentation is 60 years and two-thirds of patients are men. There is a strong association with alcohol and/or tobacco use, and most patients present with local or regionally advanced disease.
There exists a dose–response relationship between exposure to tobacco and cancers of the head and neck. Smoking is the preferred method of tobacco use in the United States, and is most strongly associated with malignancies of the floor of mouth, oropharynx, and larynx., Other practices, for example chewing tobacco or dipping snuff, tend to be associated with malignancies of the buccal mucosa., Alcohol use is an independent risk factor and there appear to be synergistic carcinogenic effects for persons who both smoke and drink, especially for cancers of the larynx. There is an inverse relationship between the consumption of fruits and vegetables and head and neck squamous cell cancers. Viral exposures have also been implicated in the causation of some uncommon head and neck malignancies. In the Orient, there is a clear etiologic relationship between Epstein–Barr virus and nasopharyngeal carcinoma.