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Cancer Chemotherapy

Normal cells
Differentiate, grow, mature, divide
Regulated, balanced; cell birth=cell
death
Regulation: intracell signaling

Hyperplasia: new cells prodd w/


growth stimulus via hormones,
endogenous signals
Ex: hyperplasia of endometrial tissue
during menstrual cycle is normal and
necessary
BUT if intense, prolonged
demand
May cell structural, functional
abnormalities
Metaplasia: replacement of one cell type by
another
Thicker cell layer better accommodates
irritation
Ex: bronchial epithelium chronically
irritated ciliated columnar epithelial
cells replaced by sev layers cuboidal
epithelium
Note: Replacement cells normal, just
Dysplasia: replacement cells disordered
in size, shape
Incrd mitosis rate
Somewhat reversible, often precancerous
Neoplasia: abnormal growth/invasion of
cells
New growth
Neoplasm = tumor
Irreversible
Cells replicate, grow w/out control
Neoplasms

= Tumors = groups of neoplastic cells


Two major types: benign, malignant
Benign noncancerous
Local; cells cohesive, well-defined
borders
Push adjacent tissue away
Doesnt spread beyond original site
Often has capsule of fibrous
connective tissue
Malignant grow more rapidly;
often called cancer
Not cohesive; seldom have capsule
Irregular shape; disrupted
architecture
Invade surrounding cells
Can break away to form second tumor
Metastasis from 1o to 2o site
Cancer (Neoplastic) Cells
May be:
Well-differentiated = retain normal
cell function
Mimic normal tissue
Often benign
Poorly differentiated = disorganized
Cant tell tissue of origin
Anaplastic
Oncogenesis = Process of
Tumor Development

Probably multi-step process


Decrd ability to differentiate
and control replication and growth
Steps to Cancer
Initation = impt change introduced into
cell
Probably through DNA alteration
>1 event probably needed for tumor prodn
Reversible unless and until:
Promotion = biochem event encourages
tumor formn
Genly need both initiation and
promotion
Initiators, promoters may be toxins OR
radiation OR viruses)
Genetics vs. Environment
Most tumors arise spontaneously w/out
known carcinogen exposure, AND
Proto-oncogenes can be inherited (ex:
breast cancer gene)
BUT environmental agents are known to
cause DNA mutations, AND
Risk factors known (Ex:
Cigarette smoking lung cancer
UV light exposure skin cancer)
Theory: Genetics loads the gun; the
environment pulls the trigger
Cell Cycle = Growth,
Division
Cell Cycle Phases
Premitotic synth of
structures, mols

Synth DNA precursors,


proteins, etc.
Cycle Checkpoints
Cdks, Cyclins Implement Cycle
Decisions
Brody 42.1 G0
G0
Quiescent phase outside cell cycle
Most adult cells
Cyclin D in low concent
Rb prot hypophosphd
Inhibs expression prots impt to cycle
progression
Binds E2F transcrn factors
Controls genes impt to DNA repln
Growth factor binding actn to G1
Apoptosis Review
In healthy cells, survival factors signal
actn anti-apoptotic mechs
Cytokines, hormones, cell contact factors
Programmed cell death
Cascade of proteases initiate process
Initiator caspases that act on effector
caspases
Effector caspase actn may be
through Tumor Necrosis Factor
Receptor
Second pathway actd by intracell
signals, e.g. DNA damage
Players are p53 gene & prot;
mitochondrial cytochrome c; Apaf-1
(prot); caspase 9
Effector caspases initiate pathway
cleavage cell constituents cluster
membr-bound entities (used to be
cell) that are phagocytosed
Anti-apoptotic genetic lesions nec for
devt cancer
Apoptosis resistance characteristic of
cancer cells
Genes Impt to
Oncogenesis
Code for prots that regulate cell
div/prolifn when turned on/off
Malfunctions, mutations may oncogenesis
Changes w/ viruses, chems: point mutations, gene
amplifications, chromosome translocations
Two impt routes:
Proto-Oncogenes code for prots turning cell div
ON
Mutations overexpression cancer
Tumor suppressor genes code for prots turning
cell div OFF
Mutations repression cancer
50.2 Rang
Uncontrolled Proliferation
Result of actn proto-oncogenes or
inactn tumor suppressor genes
Change in growth factors, receptors
Incrd growth factors prodd
Change in growth factor pathways
2nd messenger cascades (esp tyr-kinase
receptor cascades)
Change in cell cycle transducers
Cyclins, Cdks, Cdk inhibitors
Change in apoptotic mechs
Change in telomerase expression
Change in local blood vessels
angiogenesis
Note: Genes controlling any of
these prots/mechs can be
considered proto-oncogenes or
tumor suppressor genes
Note: Devt malignant cancer
depends on sev transformns
Anticancer Drugs are
Antiproliferative

Affect cell division


Active on rapidly dividing cells
Most effective during S phase of
cell cycle
Many cause DNA damage
Damage DNA initn apoptosis
Side effects greatest in other
rapidly-dividing cells
Bone marrow toxicity
Impaired wound healing
Hair follicle damage
Gi epith damage
Growth in children
Gametes
Fetus
May themselves be carcinogenic
Difficulties in Chemotherapy
Effectiveness
Solid tumors
Growth rate decrs as neoplasm size incrs
Outgrows ability to maintain blood supply AND
Not all cells proliferate continuously
Compartments
Dividing cells (may be ~5% tumor volume)
Only popn susceptible to most anticancer drugs
Resting cells (in G0); can be stimd G1
Not sensitive to chemotherapy, but actd when
therapy ends
Cells unable to divide but add to tumor bulk
Suspended cancer cells (leukemias)
Killing 99.99% of 1011 cancer cell
burden, 107 neoplastic cells remain
Cant rely on host immunological
defense to kill remaining cancer cells
Diagnosis, treatment difficult if
rapidly growing
Ex: Burkitts lymphoma doubles ~24 h
Approx 30 doublings tumor mass of 2
cm (109 cells)
May be detected, if not in deep organ
Approx 10 addl doublings 20 cm
mass (1012 cells) lethal
Therefore, silent for first existence
Drugs Used in Cancer
Chemotherapy
Cytotoxic Agents
Alkylating Agents
Antimetabolites
Cytotoxic antibiotics
Plant derivatives
Hormones
Suppress natl hormone secrn or
antagonize hormone action
Misc (mostly target oncogene
products)
Rand 50.3
Alkylating Agents
Contain chem grps that covalently
bind cell nucleophiles
Impt properties of drugs
Can form carbonium ions
C w/ 6 electrons highly reactive
React w/ -NH2, -OH, -SH
Bifunctional (2 reactive grps)
Allow cross-linking
Impt targets
G N7 strongly nucleophilic
A N1, A N3, C N3 also targets
DNA becomes cross-linked w/ agent
Intra- or inter-strand
Decrd transcrn, repln
Chain scission, so strand breaks
Inappropriate base pairing (alkylated
G w/ T)
Most impt: S phase repln (strands
unwound, more susceptible) G2
block, apoptosis
Rang 50.4
Nitrogen Mustards

42-5 structures

Loss Cl intramolec cyclization of side


chain
Reactive ethylene immonium derivative
Cyclophosphamide
Most common
Prodrug liver metab by CYP P450
MFOs
Effects lymphocytes
Also immunosuppressant
Oral or IV usually
SEs: n/v, bone marrow dpression,
hemorrhagic cystitis
Latter due to acrolein toxicity;
ameliorated w/ SH-donors
42.6 cyclophosph
Nitrosoureas
Also activated in vivo
Alkylate DNA BUT alkn prots
toxicity

42.7 nitrosourea
Temozolomide
Methylates G, A improper G-T base pairing
Cisplatin
Cl- dissocs reactive complex that
reacts w/ H2O and interacts w/ DNA
intrastrand cross-link (G N7 w/
adjacent G O6) denaturation DNA
Nephrotoxic
Severe n/v ameliorated w/ 5-HT3
antagonists (decr gastric motility)
Carboplatin fewer above SEs, but
more myelotoxic
Antimetabolites
Mimic structures of normal
metabolic mols
Inhibit enzs competitively OR
Incd into macromols inappropriate
structures
Kill cells in S phase
Three main groups
Folate antagonists
Pyr analogs
Pur analogs
Folic Acid Analogs
Folic acid essential for synth purines,
and thymidylate
Folate: pteridine ring + PABA +
glutamate
In cells, converted to polyglutamates then
tetrahydrofolate (FH4)
Folate FH4 catd
by dihydrofolate
reductase in 2
steps:
Folate FH2
FH2 FH4
FH4 serves as
methyl grp donor
(1-C unit) to
deoxyuridine
(dUMP dTMP),
also regenerating
FH2
Methotrexate
Higher affinity for enz than does FH2
Addl H or ionic bond forms
Depletion FH4 in cell depln dTMP
thymine-less death
Inhibn DNA synth
Uptake through folate transport system
Resistance through decrd uptake
Metabolites (polyglutamate derivs)
retained for weeks, months
50.8 Rand
Pemetrexed
FYI

45.2 Rand
Pyrimidine Analogs
5-Fluorouracil dUMP analog also
works through dTMP synthesis
pathway
Converted fraudulent nucleotide
FdUMP
Competitive inhibitor for thymidylate
synthetase active site, but cant be
converted to dTMP
Covalently binds thymidylate synthetase
Mech action uses all 3routes decrd DNA
synthesis, also transcrn/transln inhibn
Gemcitabine
Phosphd tri-PO4s
Fraudulent nucleotide
Also inhibs ribonucleotide reductase
decrd nucleotide synth
Capecitabine is prodrug
Converted to 5FU in liver, tumor
Enz impt to conversion overexpressed in
cancer cells (?)
Cytosine arabinoside
Analog of 2dC
Phosphd in vivo cytosine
arabinoside triphosphate
Inhibits DNA polymerase
Gemcitabine araC analog
Fewer SEs
42-11

Gemcitabine

http://www.pfeist.net/ALL/arac/images/spongo2.gif
Purine Analogs
6-Mercaptopurine, 6-Thioguanine
Converted to fraudulent nucleotides
Inhibit enzs nec for purine synth
Fludarabine
Converted to triphosphate
Mech action sim to ara-C
Pentostatin
Inhibits adenosine deaminase
Catalyzes adenosine inosine
Interferes w/ purinemetab, cell prolifn
42-10

Fludarabine Pentostatin
Cytotoxic Antibiotics

Substances of microbial origin that


prevent mammalian cell division
Anthracyclines
Doxorubicin
Intercalates in DNA
Inhibits repln via action at topoisomerase II
Topoisomerase II catalyzes nick in DNA strands
Intercalated strand/topoisomerase complex
stabilized permanently cleaved helix
Epirubicin, mitozantrone structurally
related
SEs: cardiotoxicity (due to free radical
prodn), bone marrow suppression

Mitozantrone

http://www.geocities.com/lubolahchev/Mitoxa4.gif
http://www.farmakoterapi.uio.no/cytostatika/images/16_1_t.gif
Dactinomycin
Intercalates in DNA minor groove between
adjacent GC pairs
Interferes w/ RNA polymerase movement
decrd transcrn
Also may work through topoisomerase II
Bleomycin
Glycopeptide
Chelates Fe, which interacts w/ O2
Genn superoxide and/or hydroxyl radicals
Radicals degrade DNA fragmentation, release
of free bases
Most effective in G2, also active against cells in
G0
Little myelosuppression BUT pulmonary fibrosis
Dactinomycin

Bleomycin
Plant Alkaloids
Work at mitosis
Effect tubulin, therefore microtubule
activity
Prevention spindle formn OR
Stabilize (freeze) polymerized
microtubules
Arrest of mitosis
Other effects due to tubulin defects
Phagocytosis/chemotaxis
Axonal transport in neurons
Vinca Alkaloids

http://biotech.icmb.utexas.edu/botany/gifs/vdes.gif
Taxanes: Paclitaxel, Docetaxel

http://home.caregroup.org/clinical/altmed/interactions/Images/Drugs/docetaxe.gif

http://biotech.icmb.utexas.edu/botany/gifs/tax.gif
Etoposide, teniposide
From mandrake root
Inhibit mitoch function, nucleoside
transport, topoisomerase II
Campothecins: irinotecan, topotecan
Irinotecan requires hydrolysis active
form
Bind, inhibit topoisomerase II
Repair is difficult
Ironotecan

Topotecan

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http://www.cancerquest.org/images/topotecan.gif
http://www.chemheritage.org/EducationalServices/pharm/chemo/readings/ages/ages04.gif
Hormones
Tumors derd from tissues responding
to hormones may be hormone-
dependent
Growth inhibd by hormone antagonists OR
other hormones w/ opposing actions OR
inhibitors of relevant hormone
Glucocorticoids
Inhibitory on lymphocyte prolifn
Used against leukemias, lymphomas
Estrogens
Block androgen effects (ex: fosfestrol)
Used to recruit cells in G0 G1, so
better targets for cytotoxic drugs
Progestogens (ex: megestrol,
medroxyprogesterone)
Used in endometrial, renal tumors
GnRH analogs (ex: goserelin)
Inhibit gonadotropin release decrd
circulating estrogens
Hormone antagonists
Tamoxifen impt in breast cancer
treatment
Competes w/ endogenous estrogens for
receptor
Inhibits transcrn estrogen-responsive genes
Flutamide, cyproterone impt in prostate
tumors
Androgen antagonists
Trilostane, aminoglutethimide inhibit
sex hormone synth at adrenal gland
Formestane inhibits aromatase at
adrenal gland
Trilostane

Formestane
http://img.alibaba.com/photo/50310947/Trilostane.jpg
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http://www.neurosci.pharm.utoledo.edu/MBC3320/images/Flutamide.gif
http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/tamoxifen.gif
Antitumor Agents Working through Cell Signalling

Rang 50.1
Binding Epidermal Growth
Factor Receptors Cell
Prolifn
EGFR present on many solid tumors
Tyr-kinase type receptors
Ligand binding kinase cascade
transcription factor synth
incrd cell prolifn
metastasis
decrd apoptosis
Cells expressing EGFR resistant to
cytotoxins; poor clinical outcome
predicted
Drugs Targeting Growth Factor
Receptors
Cetuximab
Monoclonal Ab directed against EGFR
Erbitux Famous anti-EGFR Ab
Trastuzumab
Humanized mouse
monoclonal Ab
Binds HER2
Membr prot
structurally similar to
EGFR
Has integral tyr
kinase activity
Impt in breast cancer
cells
May also induce p21
and p27
Cell cycle inhibitors
http://www.gene.com/gene/products/information/oncology/herceptin/images/moa.jpg
Imatinib (Gleevec, Glivec)
Small inhibitor of kinases
Inhibits PDGF activity via its tyr kinase
receptor
Inhibits Bcr/Abl kinase
Cytoplasmic kinase impt in signal transduction
Unique to chronic myeloid leukemia
Also used against non-small cell lung
cancer
Gefitinib
Similar to Imatinib
Gefitinib

Imatinib
http://www.chemistrydaily.com/chemistry/upload/thumb/9/9a/200px-Imatinib_mesylate.png
http://dric.sookmyung.ac.kr/NEWS/jul01/gleevecmech.jpg
http://www.wwu.edu/depts/healthyliving/PE511info/cancer/My%20Cancer
%20Webs/Symptoms%20and%20Therapy_files/image001.jpg

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