Cancer Chemotherapy Chapter 42. Normal cells… Differentiate, grow, mature, divide –Regulated,...
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Transcript of Cancer Chemotherapy Chapter 42. Normal cells… Differentiate, grow, mature, divide –Regulated,...
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Cancer Chemotherapy
Chapter 42
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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
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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
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– 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
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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
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• 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
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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”
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Oncogenesis = Process of Tumor Development
• Probably multi-step process Decr’d ability to differentiate
and control replication and growth
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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)
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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”
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Cell Cycle = Growth, Division
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Synth DNA precursors,proteins, etc.
Premitotic synth ofstructures, mol’s
Cell Cycle Phases
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Cycle Checkpoints
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Cdk’s, Cyclins Implement Cycle Decisions
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Brody 42.1 – G0
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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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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
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• 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
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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
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50.2 Rang
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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
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– 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
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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
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• 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
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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
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• 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
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Drugs Used in Cancer Chemotherapy
• Cytotoxic Agents– Alkylating Agents– Antimetabolites– Cytotoxic antibiotics– Plant derivatives
• Hormones– Suppress nat’l hormone secr’n or
antagonize hormone action
• Misc (mostly target oncogene products)
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Rand 50.3
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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
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• 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
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Rang 50.4
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42-5 structures
Nitrogen Mustards
•Loss Cl intramolec cyclization of side chain
Reactive ethylene immonium derivative
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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
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42.6 cyclophosph
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42.7 nitrosourea
Nitrosoureas
•Also activated in vivo
•Alkylate DNA BUT alk’n prot’s toxicity
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Temozolomide•Methylates G, A improper G-T base pairing
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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
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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
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Folic Acid Analogs• Folic acid essential for synth purines,
and thymidylate• Folate: pteridine ring + PABA +
glutamate– In cells, converted to polyglutamates then
tetrahydrofolate (FH4)
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• 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
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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
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50.8 Rand
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Pemetrexed
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45.2 Rand
FYI…
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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
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• 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 (?)
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• Cytosine arabinoside– Analog of 2’dC– Phosph’d in vivo cytosine
arabinoside triphosphate– Inhibits DNA polymerase
• Gemcitabine – araC analog– Fewer SE’s
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http://www.pfeist.net/ALL/arac/images/spongo2.gif
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
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42-10
Fludarabine Pentostatin
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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
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– 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
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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
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Dactinomycin
Bleomycin
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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
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http://biotech.icmb.utexas.edu/botany/gifs/vdes.gif
Vinca Alkaloids
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http://biotech.icmb.utexas.edu/botany/gifs/tax.gif
Taxanes: Paclitaxel, Docetaxel
http://home.caregroup.org/clinical/altmed/interactions/Images/Drugs/docetaxe.gif
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• 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
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http://www.chemheritage.org/EducationalServices/pharm/chemo/readings/ages/ages04.gif
Ironotecan
http://www.cancerquest.org/images/topotecan.gif
Topotecan
http://www.axxora.com/files/formula/lkt-i6933.gif
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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
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• 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
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• 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
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http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/tamoxifen.gifhttp://www.neurosci.pharm.utoledo.edu/MBC3320/images/Flutamide.gif
Formestane
http://www.axxora.com/files/formula/LKT-F5769.gif
Trilostane
http://img.alibaba.com/photo/50310947/Trilostane.jpg
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Rang 50.1
Antitumor Agents Working through Cell Signalling
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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
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• Cetuximab– Monoclonal Ab directed against EGFR
• Erbitux – Famous anti-EGFR Ab
Drugs Targeting Growth Factor Receptors
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• 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
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• 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
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http://www.chemistrydaily.com/chemistry/upload/thumb/9/9a/200px-Imatinib_mesylate.png
http://dric.sookmyung.ac.kr/NEWS/jul01/gleevecmech.jpg
Imatinib
Gefitinib
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http://www.wwu.edu/depts/healthyliving/PE511info/cancer/My%20Cancer%20Webs/Symptoms%20and%20Therapy_files/image001.jpg