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GKA deel 1 college 14
 

GKA deel 1 college 14

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  • GK 2009 a.a.m.thomas@uu.nl
  • GK 2009 a.a.m.thomas@uu.nl
  • GK 2009 a.a.m.thomas@uu.nl

GKA deel 1 college 14 GKA deel 1 college 14 Presentation Transcript

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  • Angiogenesis inhibitors Folkman Sci Am 275-3, 1996
    • Phase I: small trial, toxicity, maximum safe dose
    • Phase II: small trials for efficacy
    • Phase III: large trials that compare new therapy with best available treatment
    • Endostatin
    • Angiostatin
      • Fragment plasminogen
    • Aimed against non-tumor cells
        •  Prevents resistence
    GK 2009 Drug Possible mechanism of action Current status CAI Inhibits Ca²+ influx, suppresses endothelial cells Phases I and II CM101 Induces inflammation in tumors, destroying growing capillaries Phase I Interferon  Decreases FGF production (made by tumor cells) Phase II Interleukin-1,2 Increases production of angiogenic inhibitor Phase I Marimastat Inhibits enzymes that destroy ECM Phases II and III Thalidomide Unknown? Phases I and II TNP-470 Inhibits proliferation endothelial cells Phases I and II Platelet factor 4 Inhibits proliferation endothelial cells Phases I and II Pentosan polysulfate Blocks effect of growth factors on endothelial cells Phases I
  • Angiogenesis inhibitors Folkman Sci Am 275-3, 1996
    • Mechanisms of angiogenesis drugs
      • Becker, Nature Biotechnol 2004, 22, 15-18
      • VEGF: vascular endothelial growth factor
        • Mitogen for endothelial cells, just as FGF
    GK 2009 VEGF FGF
  • Surgery of primary tumor allows metastasis to grow Folkman Sci Am 275-3, 1996
    • Surgery removes
      • Primary tumor
      • Source of angiostatin  growth metastasis
    GK 2009 =============== http://angiogenesis.amgen.com/
  • From bench top to bedside Barinaga, Science 278, 1997, 1036-1039
    • Newer version: Nature Biotech 2004, 22, 15-18
      • Copy in reader
    GK 2009
  • From bench top to bedside Barinaga, Science 278, 1997, 1036-1039
    • Newer version: Nature Biotech 2004, 22, 15-18
      • Copy in reader
    GK 2009 Herceptine ONYX-015 Gleevec Farnesyl
  • Fatty anchor of Ras Barinaga, Science 278, 1997, 1036-1039
    • Ras has farnesyl = lipid modification
    • FT: farnesyl transferase
    • FT-inhibitor inhibits
      • All types of tumors
      • ???
    GK 2009                                       
  • Effect van ONYX-015 Barinaga, Science 278, 1997, 1036-1039 GK 2009 The ‘adeno-trick’: Ellisen en Haber
  • Cancer drug: Gleevec=Glivec=imatinib=STI-571
    • ATP-analogue, small organic molecule
    • Binds ATP-binding site of
      • PDGF-R, a tyrosine kinase
        • Some tumors
      • BCR-ABL
        • Leukemia by translocation ABL to BCR
        • Philadelphia chromosome
      • c-KIT
        • Regulates immune system
    • Gleevec inhibits some tumors
      • In spite of (!) -effect on c-KIT
      • C-KIT overexpression in gastro-intestinal tumor
      • Resistance against Gleevec: Y253F
    • Comparable: Iressa blocks EGF-receptor
            • N Engl J Med 347, 2002, 462-463
            • Nature 416, 2002, 470-474
    GK 2009
  • Gleevec
    • Fits ATP-binding site of some tyrosine kinases
    • “ Promiscuous”
      • ‘ Playing dirty’
        • Frantz, Nature 437, 2005, 942-43
    GK 2009 ============== Becker, Nature Biotechnol 2004, 22, 15-18
    • CML: Chronic myelogenous leukemia
  • Targeting Tyrosine Kinases in Cancer: The Second Wave Jose Baselga, Science 2006, 312, 1175-1178
    • Tumor types, genetics
      • Elements that lead to improved drugs
    GK 2009 ===============
  • The hallmarks of cancer Hanahan & Weinberg, Cell 100, 2000, 57-70 GK 2009
  • The hallmarks of cancer Hanahan & Weinberg, Cell 100, 2000, 57-70 GK 2009 Mantovani Nature 457, 36-37(2009)