1. 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

2. Cellular Pathways to Malignancy

3. Tumor Suppressor Genes
apc=binds beta catenin
p53 = transcription and DNA synthesis
WT-1 = zinc finger transcription factor

4. Cancer Molecular Pathways
apoptosis pathway important
TGFbeta= anti-growth pathway
GPCR= activation of PKA pathway
RTK=receptor tyrosine kinases (e.g. EGF receptor)

5. History of Cancer Chemotherapy
Goodman and Gilman: first to use nitrogen mustard (alkylating agent) to treat cancer

6. 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
not all cancer cells have escaped normal growth control

7. stem cells, proliferation in the lumen of gut

8. many tumors are quite slow growing and often more difficult to treat with drugs

9. 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)
ErbB = epidermal growth factor receptors
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)

10. 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

11. 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
cell cycle 8hr to 100 days

12. Restriction point: cells traverse R by expression and activation of cyclin/CDK complexes and then are committed to continue through S phase.
cyclin/cdks discovered by Lee Hartwell (Nobel 2001)
time in G1 is big variable
once past R--tend to complete cycle
R regulated by the cyclin cdk complexes

13. Cell Cycle Specificity of Selected Drugs
fluorouracil
mercaptopurine
methotrexate
L-asparaginase
paclitaxel
vincristine/vinblastine
Cycle non-specific
alkylating agents:
cyclophosphamide, mechlorethamine, nitrosoureas
actinomycin D
daunorubicin, doxorubicin
etoposide, irinotecan
cisplatin
bleomycin
drugs are phase specific as well….mitosis, or S
based on mechanism
some work better in G2 because there is less time to repair damage (bleomycin)

14. Tumor growth kinetics Based on Gompertz--German insurance salesman
tumors develop from a single cell---clonal
the initial tumor cells display stem cell like properties cancer stem cells

15. 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

16. log kill = - log fraction surviving

17. must get last cell (10 to the 0) to cure.

18. 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

19. 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

20. 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)

21. Hypoxia in tumor induces expression of angiogenic genes
VEGF and Ang1, Ang2 stimulate angiogenesis
diffusion limit for O2 is um
more later
bevacizumab (Avastin) antibody to
VEGF

22. 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
DNA is major target (synthesis and function)
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)