Cancer Chemotherapy Topics - courseswashingtonedu courses .ppt

Document Sample
Cancer Chemotherapy Topics - courseswashingtonedu courses .ppt Powered By Docstoc
					      Cancer Chemotherapy Topics

1.   Basic principles: cell cycle, tumor growth
     kinetics, log kill, recruitment, drug targets
2.   Mechanisms of drug action
3.   Drug resistance mechanisms
4.   Toxicity and new approaches
Cellular
Pathways to
Malignancy
Tumor Suppressor Genes
Cancer Molecular Pathways
History of Cancer Chemotherapy
      Cancer Chemotherapy:
    Targets for selective toxicity
   target rapidly dividing cells?
       cancer cells are not the only replicating cells
         • e.g. intestinal epithelia, bone marrow, mucosal, hair follicle
           cells are all rapidly dividing as well
       not all cells in a tumor are replicating
      Cancer Chemotherapy:
    Targets for selective toxicity
   target rapidly dividing cells?
        cancer cells are not the only replicating cells
          • e.g. intestinal epithelia, bone marrow, mucosal, hair follicle cells are all
            rapidly dividing as well
        not all cells in a tumor are replicating

altered metabolic enzymes (e.g. L-asparaginase to kill cells that can not
synthesize asparagine)
cellsurface receptors (e.g. trastuzumab (Herceptin) blocks HER2
(ErbB) in breast cancer)
specifichormonal requirements (e.g. steroid receptor antagonists for
breast CA, prostate CA)

altered intracellular signaling (e.g. imatinib (Gleevec) targets the Abl
kinase which is turned on in chronic myelocytic leukemia)
Remissions and complete cures are
  obtained with specific cancers
        Hodgkin’s   lymphoma
        choriocarcinoma
        acute leukemias in children
        Wilm’s tumor (kidney)
        testicular cancer
        breast, prostate CA
                  The cell cycle
G1: growth, protein
synthesis, RNA synthesis
S: DNA synthesis,
replication, RNA & protein
synthesis
G2: DNA repair,
chromosome
     condensation
M:   mitosis, nuclear division
Restriction point: cells traverse R by expression and
 activation of cyclin/CDK complexes and then are
      committed to continue through S phase.
             Cell Cycle Specificity of
                  Selected Drugs
   Cell Cycle Specific              Cycle non-specific
       fluorouracil                     alkylating agents:
                                           • cyclophosphamide,
       mercaptopurine                       mechlorethamine,
       methotrexate                         nitrosoureas


                                         actinomycin D
       L-asparaginase                   daunorubicin, doxorubicin
                                         etoposide, irinotecan
       paclitaxel
       vincristine/vinblastine          cisplatin
                                         bleomycin
Tumor growth kinetics
           Log Kill hypothesis
 Dr.   Howard Skipper
     1960s
     postulated that cell death follows 1st order
      kinetics with anti cancer drugs
     experiment: treat mouse leukemia with
      cytosine arabinose
        • 24 hr of ara-C--mice died
        • 3 treatment every 4 days--mice lived
     developed concept of Log Kill
               Easy Exam Question
As part of your research project you are experimenting with
the treatment of mice injected with 1012 leukemia cells.
You are using a combination of mechlorethamine and
vincristine with a log kill of 4. The leukemia grows at
a rate of 1 log per week. If you start treatment immediately
and give a treatment every 2 weeks, what is the minimum
number of treatments required to theoretically cure your
mouse patients?

                    A)     3
                    B)     4
                    C)     5
                    D)     6
                    E)     7
                    Harder Exam question
The initial tumor burden is 1010 cells and the drug combination
used is known to give a log kill of 3. Assuming a 1 log re-growth
per week between treatments and that all the cells are sensitive,
which of the following treatment schedules would be expected
to give a complete cure (ignoring the fact that cancers don’t
always behave predictably)?


      A.   3 treatments at one week intervals
      B.   8 treatments at two week intervals
      C.   50 treatments at three week intervals
      D.   5 treatments at one week intervals
      E.   none of the above
                   Recruitment

  non-dividing cells
                                        rapidly dividing
(insensitive to many                          cells
       drugs)                             (sensitive to
                                             drugs)
    •increase nutrient supply
    •increase perfusion
    •reduce crowding:
           surgery
           radiation
           chemo with cycle non-specific drugs
                   (e.g. alkylating agents)
Hypoxia in tumor induces expression of
           angiogenic genes




                               bevacizumab
                               (Avastin)
                               antibody to
                               VEGF
        Drug Targets in Cancer Chemotherapy
1. DNA
    a) bondage--alkylating agents (mechlorethamine,
    cyclophosphamide), cisplatin
    b) vaporization--bleomycin
    c) confusion--actinomycin D, doxorubicin, etoposide,
           irinotecan
    d) starvation--methotrexate, 6-thioguanine,
           5-fluorouracil, cytosine arabinoside,hydroxyurea
    e) regulation--tamoxifen, aromatase inhibitors
2. Protein synthesis: L-asparaginase
3. Mitotic Apparatus: vincristine, vinblastine, paclitaxel
4. Specific antigens: therapeutic antibodies (e.g.
Herceptin, Avastin)
5. Protein kinase inhibitors: Gleevec (imatinib) inhibits
       BCR-ABL which causes CML(chronic myeloid leukemia)

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:119
posted:5/16/2012
language:English
pages:22
tongxiamy tongxiamy http://
About