- I. Specific T cell inhibitors - Cyclosporine, Tacrolimus
- II. Cytotoxic drugs - Azathioprine, Cyclophosphamide, Methotrexate, Chlorambucil
- III. Glucocorticoids - Prednisolone
- IV. Antibiotics - Muromonab CD3, Antithymocyte globulin (ATG), Rhe immunoglobulin
Leflunomide is an immunosuppressive drug capable of inhibiting T and B cell response in vivo.
Mode of action of cyclosporine?
- o Cyclosporine is a calcineurin inhibitor; binds cyclophilin.
- o Blocks T cell activation by preventing IL-2 transcription.
Receptor tyrosine kinase?
- Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones.
- Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer.
Approximately 20 different RTK classes have been identified.
- RTK class I (epidermal growth factor receptor (EGFR) family) (ErbB family)
- RTK class II (Insulin receptor family)
- RTK class III (Platelet-derived growth factor receptors (PDGF-R) family)
- RTK class IV (Vascular endothelial growth factor (VEGF) receptors family)
- RTK class XIV (RET receptor family)
What is ErbB family?
The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR)
EGFR inhibitors -
- The ErbB protein family consists of 4 members
- ErbB-1, also named epidermal growth factor receptor (EGFR)
- ErbB-2, also named HER2 in humans and neu in rodents
- ErbB-3, also named HER3
- ErbB-4, also named HER4
ErbB-1 inhibitor - panitumumab, cetuximab, gefitinib, erlotinib, afatinib
HER-2 receptor blocker - trastuzumab
Imatinib works by stopping the Bcr-Abl tyrosine-kinase.
What is Cetuximab
- Cetuximab is a chimeric (mouse-human) monoclonal antibody; panitumumab, a fully human monoclonal antibody, binds to and inhibits the EGFR, which is overexpressed in 60% to 80% of colorectal cancers and is associated with a shorter survival time.
- Cetuximab and panitumumab are effective only on tumors that do not have a mutation of the KRAS gene.
- Accordingly, genetic testing is now recommended to confirm the absence of KRAS mutations (indicating the presence of the KRAS wild-type gene) before the use of these EGFR inhibitors is recommended.
Platelet-derived growth factor (PDGF)?
Platelet-derived growth factor (PDGF) is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation (angiogenesis), the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled angiogenesis is a characteristic of cancer
Vascular endothelial growth factor (VEGF)?
Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis.
VEGF inhibitors - aflibercept, bevacizumab, and ranibizumab
Small molecule inhibitors and monoclonal antibodies (approved by the US Food and Drug Administration) against RTKs for cancer therapy?
Small Molecule // Target // Disease
Imatinib (Gleevec) // PDGFR, KIT, Abl, Arg // SML, GIST
Gefitinib (Iressa) // EGFR // Esophageal cancer, Glioma
Erlotinib (Tarceva) // EGFR // Esophageal cancer, Glioma
Sorafenib (Nexavar) // Raf, VEGFR, PDGFR, Flt3, KIT // Renal cell carcinoma
Sunitinib (Sutent) // KIT, VEGFR, PDGFR, Flt3 // Renal cell carcinoma, GIST, Endocrine pancreatic cancer
Desatinib (Sprycel) // Abl, Arg, KIT, PDGFR, Src // Gleevec-resistant CML
Nilotinib (Tasigna) // Abl, Arg, KIT, PDGFR // Gleevec-resistant CML
Lapatinib (Tykerb) // EGFR, ErbB2 // Mammary carcinoma
Trastuzumab (Herceptin) // ErbB2 // Mammary carcinoma
Cetuximab (Erbitux) // EGFR // Colorectal cancer, Head and neck cancer
Bevacizumab (Avastin) // VEGF // Lung cancer, Colorectal cancer
Panitumumab (Vectibix) // EGFR // Colorectal cancer
Significance of K-ras gene with EGFR receptor inhibitors?
EGFR blockers are effective only on the tumors that do not have a mutation of K-ras gene. Genetic testing is now recommended to confirm the absence of K-ras mutation (indicating the presence of K-ras wild type gene) before the use of EGFR inhibitors.