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INTRODUCTION

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Many new agents are available to block the fundamental mutations that cause specific cancers: aberrant growth factor receptors, dysregulated intracellular signaling pathways, defective DNA repair and apoptosis, and tumor angiogenesis. The primary tools for inhibiting these targets are monoclonal antibodies that attack cell surface receptors and antigens, and synthetic small molecules that enter cells and engage critical enzymes. These 2 classes of drugs have very different pharmacological properties.

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Monoclonal antibodies kill tumor cells by blocking cell surface receptor function and by recruiting immune cells and complement to the antigen–antibody complex. They may be armed to carry toxins or radionuclides to the cells of interest, thereby enhancing their cytotoxic effects. They generally are specific for a single receptor, have a long plasma t1/2, and require only intermittent administration. Small molecules may attack the same targets and pathways as the monoclonals, but may also exert their effect by entering cells and inhibiting enzymatic functions (usually tyrosine kinase reactions). The small molecules often inhibit multiple enzymatic sites, have a broad spectrum of target kinases, and tend to be substrates of hepatic CYPs with a t1/2 of 12-24 h, and thus require daily oral administration.

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These 2 drug classes, when targeted against the same pathway, may have significantly different spectra of antitumor activity. Thus, monoclonal antibodies to the epidermal growth factor receptor (EGFR) are effective in the treatment of head and neck and colon cancers, while small molecules, such as erlotinib and gefitinib, attack the intracellular tyrosine kinase function of the same receptor and have a different spectrum of antitumor activity (non–small cell lung cancer). The specific drug target is of central importance in cancer chemotherapy and forms the organizational basis for the discussion below.

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PROTEIN TYROSINE KINASE INHIBITORS

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There are 3 basic types of protein kinases (see Chapter 3):

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  • Kinases that specifically phosphorylate tyrosine residues

  • Kinases that phosphorylate serine and threonine residues

  • Kinases with activity toward all 3 residues

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Tyrosine kinases can be further subdivided into those with an extracellular ligand-binding domain (receptor tyrosine kinases, associated with growth factor receptors, Figure 62-1) and intracellular enzymes (nonreceptor tyrosine kinases, e.g., src, abl, jak, fak, srm). In a number of human malignancies, mutations that constitutively activate protein tyrosine kinases are implicated in malignant transformation.

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figure 62–1

Growth factor signaling. Binding of agonist ligands to growth factor receptors (monospanning membrane proteins) causes receptor dimerization and activation of cytosolic protein kinase domains, leading to activation of multiple signaling pathways. Shown here are the RAS/MAPK/ERK, PI3K, and SMAD pathways, each of which is activated by receptors or cross-talk from adjacent pathways. Their signals regulate proliferation, metabolism, survival, and the synthesis of other growth factors, such as the vascular endothelial growth factor (VEGF).

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INHIBITORS OF THE ...

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