Tyrosine kinases inhibitors

Certain chemotherapy agents do not fall into one of the categories addressed above. These miscellaneous drugs are listed in Table 36-7, and are described briefly below. 

Arsenic trioxide. Arsenic is a heavy metal that can exert toxic, poisonous effects. Therapeutic dosages of arsenic trioxide (Trisenox), however, may limit the growth of certain leukemias such as acute promyelo-cytic leukemia.11 However, because of its potential toxicity, arsenic trioxide is not usually an initial treatment, but is reserved for patients who relapse or who are resistant to other treatments. Although the exact mechanism of action is unclear, this drug apparently induces several cytotoxic effects by directly damaging DNA and proteins that regulate DNA synthesis and replication. 

Bortezomib. Bortezomib (Velcade) inhibits pro-teasome activity in mammalian cells.11 Mammalian proteasome is responsible for degrading certain cellular proteins affecting cell function and division. By prolonging the activity of these proteins, bortezomib brings about complex changes in cell function that lead to cell dysfunction and death. Certain types of cancer, such as multiple myeloma, are more sensitive to impaired proteasome regulation, hence the use of this drug in these cancers. 

Denileukin Diftitox. Denileukin Diftitox (Ontak) is formulated by combining interleukin-2 with diphtheria toxin.11 Certain leukemia and lymphoma cells have a surface receptor that has a high affinity for interleukin-2, thus attracting this drug directly to these cells. Upon binding with tbe receptor, the diphtheria toxin component of the drug inhibits cellular protein synthesis, which ultimately results in cell death. This 

Drug Arsenic trioxide (Trisenox] Primary Antineoplastic Indication(s) Acute promyelocytic leukemia Common Adverse Effects Dyspnea Gl distress (nausea, vomiting, diarrhea] headache fatigue others 

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Tyrosine Kinase Inhibitors/Receptor Associated Tyrosine Kinase Inhibitors (RTK-I)... 

BCR-ABL tyrosine kinase that is essential for malignant transformation. Cytogenetic responses to IFN-a therapy were seen in 30-40% of the treated patients with complete responses in about 10%. Long term survival can therefore be expected in these patients. In 2000, the BCR-ABL tyrosine kinase inhibitor Imatinib has been introduced for CML therapy and meanwhile has proven more efficient than IFN-a therapy. 

Tyrosine Kinase Inhibitors Protein Kinase Inhibitors... 

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. 

Targeted Cancer Therapy. Table 2 Main differences between monoclonal antibodies and small-molecule tyrosine kinase inhibitors... 

Monoclonal antibodies Small-molecule tyrosine kinase inhibitors... 

TKIs (tyrosine kinase inhibitors) Kinase inhibitors Monoclonal antibodies... 

Tyrosine kinase inhibitors interfere with the function of tyrosine kinases that catalyze the transfer of the y-phosphate group of ATP to tyrosine residues of protein substrates. Tyrosine kinases can be subdivided into two large families, receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (NRTKs see corresponding chapter). The human genome... 

Tyrosine Kinase Inhibitors. Figure 1 Pharmacological strategies to target tyrosine kinases. 

Tyrosine Kinase Inhibitors. Table 1 Tyrosine kinase inhibitors approved for clinical use (by July 2007)... 

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. 

Levitzki A (2000) Protein Tyrosine Kinase Inhibitors as Therapeutic Agents. 211 1-15 Li G, Gouzy M-F, Fuhrhop J-H (2002) Recognition Processes with Amphiphilic Carbohydrates in Water. 218 133-158 Li X, see Paldus J (1999) 203 1-20... 

The photo-Arbuzov rearrangement of allyl-, benzyl- and naphtylmethyl-phosphites (Scheme 13), first developed by Bentrude et al. [20], found applications in the preparation of phosphonates (70-90%) [38]. Arylphosphonates have been shown to act as protein tyrosine kinase inhibitors [39] or non-hy-drolyzable analogs of phosphorylated tyrosine residues [40]. 

Akin C. Brockow K. D Ambrosio C. et al Effects of tyrosine kinase inhibitor SXI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hem-atol 2003 31 686-692. 

ATLURU s, ATLURU D (1991) Evidence that genistein, a protein-tyrosine kinase inhibitor, inhibits CD28 monoclonal antibody stimulated human T-cell proliferation. Transplantation. 51 448-50. 

MARKOVITS J, LINASSIER C, FOSSE P, COUPRIE J, PIERRE J, JACQUEMIN-SABLON A, SAUCIER J M, LE PECQ J B, LARSEN A K (1989) Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II. Cancer Res. 49 5111-17. 

SPINOZZI F, PAGLIACCI M C, MIGLIORATI G, MORACA R, GRIGANI F, RICCARDI C, NICOLETTI I (1994) The natural tyrosine kinase inhibitor genistein produces cell cycle arrest and apoptosis in Jurkat T-leukemia cells. LeukRes. 18 431-9. 

TWADDLE G M, TURBOV J, LIU N, MURTHY s (1999) Tyrosine kinase inhibitors as antiprohferative agents against estrogen-dependent breast cancer cell line in vitro. JSurg Oncol. 70 ... 

ILLEK B, FISCHER H, SANTOS G F, WIDDICOMBE J H, MACHEN T E and REENSTRA W W (1995) cAMP-independent activation of CFTR Cl channels by the tyrosine kinase inhibitor genistein. ./Physiol. 268 (4 Ptl) C886-C893. 

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