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Types of chemotherapies
- Alkylating agents
- Topoisomerase inhibitors
- 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
- Drugs: 5-fluorouracil
- Work by: Act as purine or pyrimidine analogs and are incorporated into dividing DNA, causing damage and eventual cell death
- Drugs: taxol, docetaxel
- Work by: stabilizing microtubules duing cell divison, thus inhibiting the normal function of the mitotic spindle
- Drugs: etoposide
- Work by: Inhibit topoisomerase proteins. This prevents the unwinding of DNA during replication, leading to DNA damage and eventual cell death.
- Drugs: doxorubicin
- Works by: Intercalates DNA, inducing DNA damage that is more problematic for rapidly dividing cells.
Problem with traditional chemotherapeutics
Since they target rapidly dividing cells, a variety of non-cancer cells are harmed.
Focus with new chemotherapeutics
Selective elimination of cancer cells using some function that sets them apart from normal cells.
Target of Gleevec
Bcr-Abl kinase in chronic myelogenous leukemia (CML)
Most successful new chemotherapeutics to date (besides Gleevec)
- EGFR inhibition: lung tumors with getfitinib
- ErbB2 inhibition: breast tumors with Herceptin
- 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)
1 Primary tumor formation
Carcinomas begin in epithelial cells
2 localized invasion
cancer cells can breach the basement membrane and interact w/ the surrounding stromal cells. Now classified as malignant
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.
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
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.
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
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.)
relatively low rate of success for forming a macroscopic metastasis
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
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
- 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
EMT protein markers