Site of action of targeted agents. Signals proceeding from growth factor– related receptor tyrosine kinases (RTKs) such as EGF-R, erbB2, or c-kit can be interrupted by lapatinib, erlotinib, gefitinib, and imatinib, acting at the ATP binding site; or by cetuximab, trastuzumab, or panitumomab. Tyrosine kinases (TKs) that are not directly stimulated by growth factors such as p210 bcr-abl or src can be inhibited by imatinib, dasatinib, or nilotinib. Signals projected downstream from growth factor receptors can be affected by the multitargeted kinase inhibitor sorafenib, acting on c-raf, and, upon arrival at the nucleus, affect gene expression, which can be. | Chapter 081. Principles of Cancer Treatment Part 18 Site of action of targeted agents. Signals proceeding from growth factor-related receptor tyrosine kinases RTKs such as EGF-R erbB2 or c-kit can be interrupted by lapatinib erlotinib gefitinib and imatinib acting at the ATP binding site or by cetuximab trastuzumab or panitumomab. Tyrosine kinases TKs that are not directly stimulated by growth factors such as p210 bcr-abl or src can be inhibited by imatinib dasatinib or nilotinib. Signals projected downstream from growth factor receptors can be affected by the multitargeted kinase inhibitor sorafenib acting on c-raf and upon arrival at the nucleus affect gene expression which can be affected by the targeted transcriptional modulators vorinostat targeting histone deacetylase azacytidine derivatives targeting DNA methyltransferase or retinoid receptor modulators all- wm-retinoic acid ATRA or bexarotene. Cytokine receptors CkRs are one stimulus for degradation of the inhibitory subunit of the NFkB transcription factor by the proteosome. Bortezomib inhibits this process and can prevent activation of NFkB-dependent genes among other growth-related effects. Sorafenib and sunitinib acting as inhibitors of VEGF receptors can modulate tumor blood vessel function through their action on endothelial cells while bevacizumab targets the same process by combining with VEGF itself. Hematopoietic Neoplasms Imatinib targets the ATP binding site of the p210bcr-abl protein tyrosine kinase that is formed as the result of the chromosome 9 22 translocation producing the Philadelphia chromosome in CML. Imatinib is superior to interferon plus chemotherapy in the initial treatment of the chronic phase of this disorder. It has lesser activity in the blast phase of CML where the cells may have acquired additional mutations in p210bcr-abl itself or other genetic lesions. Its side effects are relatively tolerable in most patients and include hepatic dysfunction diarrhea and fluid retention. .
