TCB Final.txt

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TCB Final.txt
2011-05-11 07:06:00
TCB final

TCB Final
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  1. Types of chemotherapies
    • Alkylating agents
    • Anti-metabolites
    • Taxanes
    • Topoisomerase inhibitors
    • Antineoplastics
  2. Alkylating agents
    • Drugs: cisplatin, carboplatin
    • Work by: damaging DNA, causing the cells to undergo apoptosis.
    • Theory: Rapidly dividing cells (like tumor cells) are not as efficient at fixing DNA damage
  3. Anti-metabolites
    • Drugs: 5-fluorouracil
    • Work by: Act as purine or pyrimidine analogs and are incorporated into dividing DNA, causing damage and eventual cell death
  4. Taxanes
    • Drugs: taxol, docetaxel
    • Work by: stabilizing microtubules duing cell divison, thus inhibiting the normal function of the mitotic spindle
  5. Topoisomerase inhibitors
    • Drugs: etoposide
    • Work by: Inhibit topoisomerase proteins. This prevents the unwinding of DNA during replication, leading to DNA damage and eventual cell death.
  6. Antineoplastics
    • Drugs: doxorubicin
    • Works by: Intercalates DNA, inducing DNA damage that is more problematic for rapidly dividing cells.
  7. Problem with traditional chemotherapeutics
    Since they target rapidly dividing cells, a variety of non-cancer cells are harmed.
  8. Focus with new chemotherapeutics
    Selective elimination of cancer cells using some function that sets them apart from normal cells.

    Ex: Gleevec
  9. Target of Gleevec
    Bcr-Abl kinase in chronic myelogenous leukemia (CML)
  10. Most successful new chemotherapeutics to date (besides Gleevec)
    • EGFR inhibition: lung tumors with getfitinib
    • ErbB2 inhibition: breast tumors with Herceptin
  11. Metastasis cascade
    • 1 Primary tumor formation
    • 2 localized invasion
    • 3 intravasation
    • 4 transport through circulation
    • 5 arrest in microvessels of various organs
    • 6 extravasation
    • 7 formation of a micrometastasis
    • 8 colonization - formation of a macrometastasis
    • (Prim & Proper staged a Local Invasion with a conVasation about Transpahtation. If Arrested, Exit conVasations would be Formed on Micro- and Macro- fiche)

  12. 1 Primary tumor formation
    Carcinomas begin in epithelial cells
  13. 2 localized invasion
    cancer cells can breach the basement membrane and interact w/ the surrounding stromal cells. Now classified as malignant
  14. 3 intravasation
    carcinoma cells now have direct access to the blood vessels and lymphatics. invasive properties can allow for cancer cells to move into the lumen of these vessels.
  15. 4 transport through circulation
    individual cells can transport to other areas of the body, but may be susceptible to anoikis and have no stromal support
  16. 5 arrest in microvessels of various organs
    Cancer cells typically lodge in the first capillaries they contact - the lungs. Cancer cells typically too large to pass through capillaries

    Cancer cells can avoid the capillaries and use the larger arterial or venous shunts.
  17. 6 extravasation
    Cancer cells escape blood vessels

    • One strategy:
    • platelets attach to cancer cell in capillary forming a microthrombus.

    This allows the cancer cell to push aside an endothelial cell and come into contact w/ the capillary basement membrane.

    This provides a source of ECM attachment.

    Microthrombus is dissolved by proteases that typically remove blood clots.

    The cancer cell can proliferate -> mass of cells becomes large enough to break through the basement membrane

  18. 7 formation of micrometastasis
    8 colonization - formation of a macrometastasis
    Micro - small clumps of cancer cells that don't increase in size, usually far outnumber macrometastases

    Macro - often mean a very poor outcome for patient

    Colonization the rate limiting step! Most difficult step b/c cancer cells are w/o growth & survival factors of primary tumor. (experiemnts show micrometastases could persist w/o any proliferation for sustained periods of time.)
  19. metastatic inefficiency
    relatively low rate of success for forming a macroscopic metastasis
  20. epithelial-mesencymal transition (EMT)
    • Epithelial cells shed epithelial characteristics and gene expression and adopt those of mesenchymal cells.
    • Used during wound healing and embryonic development
    • Required for cancer cells to become invasive
    • Signals from the stroma are heavily involved in EMT induction
  21. EMT protein marker functions
    • E-cadherin: loss = decreased cell adhesion
    • (beta)-catenin: freed by loss of E-cadherin, translocates to nucleus and activates genes further facilitating EMT
    • N-cadherin: gain = binding of cancer cells to surrounding fibroblasts, facilitates integration into stromal environment
  22. MET
    • Reversion from EMT.
    • Ex: EMT facilitates migration, MET at secondary site causes metastasis to look like the primary tumor as in ErbB2 and ER breast cancer metastases

  23. EMT protein markers
    • Epithelial:
    • ---E-cadherin
    • ---(alpha)-catenin
    • ---(beta)-catenin
    • ---(gamma)-catenin

    • Mesenchymal
    • ---fibronectin
    • ---vimentin
    • ---N-cadherin
    • ---(alpha)-sm-actin