Download Decr`d ability to differentiate and control replication and growth

Cancer Chemotherapy
Chapter 42
Normal cells…
•Differentiate, grow, mature, divide
–Regulated, balanced; cell birth=cell death
•Regulation: intracell signaling
–Hyperplasia: new cells prod’d 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
different
» Reversible
– Dysplasia: replacement cells disordered in size,
shape
• Incr’d 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
– Doesn’t 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
• Can’t tell tissue of origin
• “Anaplastic”
Oncogenesis = Process of
Tumor Development
• Probably multi-step process
•  Decr’d 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 prod’n
– Reversible unless and until:
• Promotion = biochem event encourages
tumor form’n
• Gen’ly 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
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Cell Cycle Phases
Premitotic 18_02_four_phases.jpg
synth of
structures, mol’s
Synth DNA precursors,
proteins, etc.
Cycle Checkpoints
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Cdk’s, Cyclins Implement Cycle Decisions
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Brody 42.1 – G0
G0
• Quiescent phase outside cell cycle
• Most adult cells
• Cyclin D in low concent
• Rb prot hypophosph’d
– Inhib’s expression prot’s impt to cycle
progression
– Binds E2F transcr’n factors
• Controls genes impt to DNA repl’n
• Growth factor binding  act’n to G1
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18_23_02_mitogens.jpg
Apoptosis Review
• In healthy cells, survival factors signal
act’n anti-apoptotic mech’s
– Cytokines, hormones, cell contact factors
• Programmed cell death
• Cascade of proteases initiate process
– Initiator caspases that act on effector
caspases
• Effector caspase act’n may be through
Tumor Necrosis Factor Receptor
• Second pathway act’d 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
dev’t cancer
– Apoptosis resistance characteristic of cancer
cells
Genes Impt to Oncogenesis
• Code for prot’s that regulate cell div/prolif’n
when turned on/off
– Malfunctions, mutations may  oncogenesis
– Changes w/ viruses, chem’s: point mutations, gene
amplifications, chromosome translocations
• Two impt routes:
– Proto-Oncogenes – code for prot’s turning cell div ON
• Mutations  overexpression  cancer
– Tumor suppressor genes – code for prot’s turning cell
div OFF
• Mutations  repression  cancer
50.2 Rang
Uncontrolled Proliferation
• Result of act’n proto-oncogenes or
inact’n tumor suppressor genes
– Change in growth factors, receptors
• Incr’d growth factors prod’d
– Change in growth factor pathways
• 2nd messenger cascades (esp tyr-kinase receptor
cascades)
– Change in cell cycle transducers
• Cyclins, Cdk’s, Cdk inhibitors
– Change in apoptotic mech’s
– Change in telomerase expression
– Change in local blood vessels 
angiogenesis
• Note: Genes controlling any of these
prot’s/mech’s can be considered protooncogenes or tumor suppressor genes
• Note: Dev’t malignant cancer depends
on sev transform’ns
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  init’n apoptosis
• Side effects greatest in other rapidlydividing cells
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–
–
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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 decr’s as neoplasm size incr’s
• Outgrows ability to maintain blood supply AND
• Not all cells proliferate continuously
– Compartments
• Dividing cells (may be ~5% tumor volume)
– Only pop’n susceptible to most anticancer drugs
• Resting cells (in G0); can be stim’d  G1
– Not sensitive to chemotherapy, but act’d 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
– Can’t rely on host immunological defense to
kill remaining cancer cells
• Diagnosis, treatment difficult if rapidly
growing
– Ex: Burkitt’s lymphoma doubles ~24 h
– Approx 30 doublings  tumor mass of 2 cm
(109 cells)
• May be detected, if not in deep organ
– Approx 10 add’l doublings  20 cm mass
(1012 cells) – lethal
– Therefore, “silent” for first ¾ existence
Drugs Used in Cancer Chemotherapy
• Cytotoxic Agents
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–
–
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Alkylating Agents
Antimetabolites
Cytotoxic antibiotics
Plant derivatives
• Hormones
– Suppress nat’l hormone secr’n 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
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–
–
–
Intra- or inter-strand
 Decr’d transcr’n, repl’n
 Chain scission, so strand breaks
 Inappropriate base pairing (alkylated G
w/ T)
• Most impt: S phase repl’n (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
MFO’s
• Effects lymphocytes
– Also immunosuppressant
• Oral or IV usually
• SE’s: 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 alk’n prot’s  toxicity
42.7 nitrosourea
Temozolomide
•Methylates G, A  improper G-T base pairing
Cisplatin
• Cl- dissoc’s  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 SE’s, but more
myelotoxic
Antimetabolites
• Mimic structures of normal metabolic
mol’s
– Inhibit enz’s competitively OR
– Inc’d into macromol’s  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 cat’d
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
– Add’l H or ionic bond forms
•  Depletion FH4 in cell  depl’n dTMP 
“thymine-less death”
•  Inhib’n DNA synth
• Uptake through folate transport system
– Resistance through decr’d uptake
• Metabolites (polyglutamate deriv’s) 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 can’t be
converted to dTMP
– Covalently binds thymidylate synthetase
– Mech action uses all 3routes  decr’d DNA
synthesis, also transcr’n/transl’n inhib’n
• Gemcitabine
– Phosph’d  tri-PO4’s
• “Fraudulent nucleotide”
– Also inhib’s ribonucleotide reductase 
decr’d nucleotide synth
• Capecitabine is prodrug
– Converted to 5FU in liver, tumor
• Enz impt to conversion overexpressed in cancer
cells (?)
• Cytosine arabinoside
– Analog of 2’dC
– Phosph’d in vivo  cytosine arabinoside
triphosphate
– Inhibits DNA polymerase
• Gemcitabine – araC analog
– Fewer SE’s
42-11
Gemcitabine
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Purine Analogs
• 6-Mercaptopurine, 6-Thioguanine
– Converted to “fraudulent nucleotides”
– Inhibit enz’s 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 prolif’n
42-10
Fludarabine
Pentostatin
Cytotoxic Antibiotics
• Substances of microbial origin that prevent
mammalian cell division
• Anthracyclines
– Doxorubicin
• Intercalates in DNA
• Inhibits repl’n via action at topoisomerase II
– Topoisomerase II catalyzes nick in DNA strands
– Intercalated strand/topoisomerase complex stabilized 
permanently cleaved helix
– Epirubicin, mitozantrone structurally related
– SE’s: cardiotoxicity (due to free radical
prod’n), bone marrow suppression
Mitozantrone
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– Dactinomycin
• Intercalates in DNA minor groove between adjacent
GC pairs
• Interferes w/ RNA polymerase movement  decr’d
transcr’n
• Also may work through topoisomerase II
– Bleomycin
• Glycopeptide
• Chelates Fe, which interacts w/ O2
•  Gen’n 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 form’n 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
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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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Hormones
• Tumors der’d from tissues responding to
hormones may be hormone-dependent
– Growth inhib’d by hormone antagonists
OR other hormones w/ opposing actions
OR inhibitors of relevant hormone
• Glucocorticoids
– Inhibitory on lymphocyte prolif’n
– 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  decr’d
circulating estrogens
• Hormone antagonists
– Tamoxifen impt in breast cancer treatment
• Competes w/ endogenous estrogens for
receptor
• Inhibits transcr’n 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
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Antitumor Agents Working through Cell Signalling
Rang 50.1
Binding Epidermal Growth Factor
Receptors  Cell Prolif’n
• EGFR present on many solid tumors
• Tyr-kinase type receptors
• Ligand binding  kinase cascade 
transcription factor synth
–  incr’d cell prolif’n
–  metastasis
–  decr’d 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
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