Cancer Chemotherapy Topics

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Cancer Chemotherapy Topics

• Basic principles cell cycle, tumor growth
  kinetics, log kill, recruitment, drug targets
• Mechanisms of drug action
• Drug resistance mechanisms
• Toxicity and new approaches

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Cellular Pathways to Malignancy
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Tumor Suppressor Genes
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Cancer Molecular Pathways
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History of Cancer Chemotherapy
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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

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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)

• cell surface receptors (e.g. trastuzumab
  (Herceptin) blocks HER2 (ErbB) in breast cancer)

• specific hormonal 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)

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Remissions and complete cures are obtained with
specific cancers

• Hodgkins lymphoma
• choriocarcinoma
• acute leukemias in children
• Wilms tumor (kidney)
• testicular cancer
• breast, prostate CA

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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
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Restriction point cells traverse R by expression
and activation of cyclin/CDK complexes and then
are committed to continue through S phase.
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Cell Cycle Specificity of Selected Drugs

• Cell Cycle Specific
• fluorouracil
• mercaptopurine
• methotrexate
• L-asparaginase
• paclitaxel
• vincristine/vinblastine

• Cycle non-specific
• alkylating agents
• cyclophosphamide, mechlorethamine, nitrosoureas
• actinomycin D
• daunorubicin, doxorubicin
• etoposide, irinotecan
• cisplatin
• bleomycin

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Tumor growth kinetics
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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

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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
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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 dont 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
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Recruitment
non-dividing cells (insensitive to many drugs)
rapidly dividing cells (sensitive to drugs)

• increase nutrient supply
• increase perfusion
• reduce crowding
• surgery
• radiation
• chemo with cycle non-specific drugs
• (e.g. alkylating agents)

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Hypoxia in tumor induces expression of angiogenic
genes
bevacizumab (Avastin) antibody to VEGF
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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)