Download Cancer Chemotherapy: Targets for selective toxicity

Cancer Chemotherapy Topics
1.
2.
3.
4.
Basic principles: cell cycle, tumor growth
kinetics, log kill, recruitment, drug targets
Mechanisms of drug action
Drug resistance mechanisms
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)
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)
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



fluorouracil
mercaptopurine
methotrexate

Cycle non-specific

• cyclophosphamide,
mechlorethamine,
nitrosoureas


L-asparaginase




paclitaxel
vincristine/vinblastine
alkylating agents:


actinomycin D
daunorubicin, doxorubicin
etoposide, irinotecan
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)
B)
C)
D)
E)
3
4
5
6
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.
B.
C.
D.
E.
3 treatments at one week intervals
8 treatments at two week intervals
50 treatments at three week intervals
5 treatments at one week intervals
none of the above
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)
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)