IV - Transplantation and Immunology - 24 25

  1. Classify immunosuppressants.
    • 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.
  2. Mode of action of cyclosporine?
    • o Cyclosporine is a calcineurin inhibitor; binds cyclophilin.
    • o Blocks T cell activation  by preventing IL-2 transcription.
  3. 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)
  4. What is ErbB family?
    The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR)

    • 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

    EGFR inhibitors - 

    ErbB-1 inhibitor - panitumumab, cetuximab, gefitinib, erlotinib, afatinib

    HER-2 receptor blocker - trastuzumab

    Imatinib works by stopping the Bcr-Abl tyrosine-kinase.
  5. 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.
  6. 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
  7. 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
  8. 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
  9. 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.
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IV - Transplantation and Immunology - 24 25