2. 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
3. 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
4. – 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
5. 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
6. • 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
7. 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”
8. Oncogenesis = Process of
Tumor Development
• Probably multi-step process
Decr’d ability to differentiate and
control replication and growth
9. 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)
11. 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”
17. 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
19. 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
20. 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
21. 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
23. 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
24. ◦ 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 proto-
oncogenes or tumor suppressor genes
Note: Dev’t malignant cancer depends on sev
transform’ns
25. 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
26. 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
27. 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
28. 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
31. 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
32. Impt targets
◦ G N7 – strongly nucleophilic
A N1, A N3, C N3 also targets
DNA becomes cross-linked w/ agent
◦ 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
35. 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
39. 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
40. 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
41. Folic acid essential for synth purines, and
thymidylate
Folate: pteridine ring + PABA + glutamate
◦ In cells, converted to polyglutamates then
tetrahydrofolate (FH4)
42. 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
43. 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
48. 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
49. 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 (?)
51. Cytosine arabinoside
◦ Analog of 2’dC
◦ Phosph’d in vivo cytosine arabinoside triphosphate
◦ Inhibits DNA polymerase
Gemcitabine – araC analog
◦ Fewer SE’s
55. 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
56. ◦ Epirubicin, mitozantrone structurally related
◦ SE’s: cardiotoxicity (due to free radical prod’n), bone
marrow suppression
http://www.farmakoterapi.uio.no/cytostatika/images/16_1_t.gif
Mitozantrone
http://www.geocities.com/lubolahchev/Mitoxa4.gif
57. ◦ 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
59. 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
64. 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
65. 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
66. 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
70. Cetuximab
◦ Monoclonal Ab directed against EGFR
Erbitux – Famous anti-EGFR Ab
Drugs Targeting Growth Factor Receptors
71. 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
72. 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