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Bondage: crosslinking agents
Nitrogen mustards: mustard
gas used first during WWI.
Leukopenia and GI ulceration
noted in survivors
Spontaneous activation of mechlorethamine
Bifunctional crosslinking between G
residues in the DNA
Other alkylating agents and intermediates
parent compound
mechlorethamine
cyclophosphamide
carmustine
procarbazine
reactive intermediate
Cyclophosphamide (Cytoxan)
requires P450 activation in liver
Cisplatin: chloro to hydroxyl conversion in cell
G
H2O
G residue
in DNA
Vaporization: Bleomycin, radiation
Bleomycin chelates iron/catalyzes formation of
hydroxyl radicals
Confusion
Actinomycin D
Actinomycin D:
-intercalates into the
DNA duplex
-blocks RNA synthesis
and DNA replication
Topoisomerase inhibitors
 Topo

II inhibitors
doxorubicin (daunorubicin, idarubicin, etoposide)
bind to DNA/topo II complex and prevents resealing of DNA breaks made by topo II
• also act to inhibit DNA and RNA synthesis
• etoposide (similar to above) causes DNA strand
breaks and cell death
 Topo

I inhibitors
camptothecins (irinotecan, topotecan) bind the
Topo I/DNA complex and prevent religation
Pharmacogenetics
Starvation for substrates
 Methotrexate:

inhibitor of human DHFR
 5-fluorouracil:

inhibits thymidylate synthetase and
misincorporated into RNA
Methotrexate and 5-fluorouracil
5-FU first--> then MTX = antagonism
MTX first--> (hrs) then 5-FU = synergism
dTMP
5-FU
5-FdUMP
purines
dUMP
FH2
thymidine
synthetase
MTX
DHFR
FH4
purines/amino
acids
Starvation for substrates

Methotrexate:


5-fluorouracil:


inhibits purine biosynthesis
cytosine arabinoside, difluorodeoxycytidine
(gemcitabine):


inhibits thymidylate synthetase and misincorporated into RNA
6 thioguanine:


inhibitor of human DHFR
inhibits DNA polymerase and gets misincorporated
hydroxyurea:

inhibits ribonucleotide reductase and therefore DNA synthesis
Regulation
 Hormone



therapy:
breast cancer
prostate cancer
ovarian, endometrial cancer
Risk of breast CA
in BRCA1/2
carriers

BRCA mutations in about 7% of
Caucasian breast CA pts.
 BRCAs are tumor suppressor
proteins
 loss of heterozygosity leads to
tumor formation
 exercise, normal weight, and
child bearing delays onset
 other variables (environment?)
seem to be speeding onset
BRCA protein function?

BRCA proteins have unique
domain structures that bind
phosphorylated regulatory
proteins
 BRCA1 is an E3 ubiquitin
ligase that participates in
DNA repair and BRCA2
seems to be involved in
homologous recombination.
Both are required for
genomic stability
Position of mutation in BRCA determines
risk for breast versus ovarian cancer
Tamoxifen antagonizes estrogen action
in breast cancer cells and affects growth
factor synthesis

Tamoxifen





IGF-1
TGFa
plasminogen
activator
laminin
receptors
TGFb
Emergence of Immunotherapy
• Paul Ehrlich (1904) hypothesized that antibodies could be
used as ‘magic bullets’ to treat cancer
• Köhler and Milstein (1979) described a method to develop
antibodies with defined specificity
• Rituximab is approved by FDA in 1997 for the treatment of
B-cell non-Hodgkin’s lymphoma
• Addition of rituximab to standard CHOP chemotherapy
provided the first improvement in survival in diffuse large
cell lymphoma (2002) in 25 years
Antibodies in Cancer
Chemotherapy
 Herceptin

humanized monoclonal antibody against
HER2 (human epidermal growth factor
receptor 2)
 Avastin

(trastuzumab)
(bevacizumab)
humanized monoclonal against VEGF
(vascular endothelial growth factor)
 Cetuximab

antibody against the EGF receptor
Clinical trial of herceptin
Induction of VEGF and angiogenesis



HIF = hypoxia inducible
factor
oxygen dependent
proline hydroxylation
regulates degradation of
HIF-a by proteasome
low oxygen leads to
increased HIF and
induction of VEGF and
other genes
Tumor vasculature regrowth after
anti-VEGF therapy stopped?
Avastin (bevacizumab)
benefits may not persist
Assembly of tubulin
into microtubules
Vinca alkaloids (vincristine,
vinblastine, vindesine)
inhibit polymerization
Taxol: binds microtubules and
prevents depolymerization.
Microtubules do more than just help segregate chromosomes
at mitosis: for example, they are involved in vesicle
transport in neurons.
Gleevec (imatinib) is
a specific inhibitor
Imatinib (Gleevec) highly effective in
treatment of CML
5000 pts
develop CML
each year in US
2.1 billion $ for
Novartis
Protein kinase inhibitors on the
market and in development
Many new drugs targeted to the
EGF and VEGFR pathways
FDA
Avastin
Tarceva
Tarceva (erlotinib) is an EGFR tyrosine kinase inhibitor that also promotes regeneration
HDAC inhibitors:promising
Proteasome inhibitor:
Bortezomib



small molecule inhibitor of
the 26S proteasome
approved by FDA for
relapsed multiple myeloma
one-year survival rate was
80 percent among patients
taking bortezomib and 66
percent among patients
taking dexamethasone