Cancer Chemotherapy

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Cancer Chemotherapy

• Chapter 42

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• Normal cells
• Differentiate, grow, mature, divide
• Regulated, balanced cell birthcell 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

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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
• Incrd 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
• Doesnt 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
• Cant tell tissue of origin
• Anaplastic

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Oncogenesis Process of Tumor Development

• Probably multi-step process
• ? Decrd 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
• gt1 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)

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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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Cell Cycle Phases
Premitotic synth of structures, mols
Synth DNA precursors, proteins, etc.
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Cycle Checkpoints
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Cdks, 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 hypophosphd
• Inhibs expression prots impt to cycle
  progression
• Binds E2F transcrn factors
• Controls genes impt to DNA repln
• Growth factor binding ? actn to G1

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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

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• 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

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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

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50.2 Rang
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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

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• 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

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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 ? initn 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 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

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• 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 ¾ existence

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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)

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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
• ? 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

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Rang 50.4
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Nitrogen Mustards
42-5 structures

• Loss Cl ? intramolec cyclization of side chain
• ? Reactive ethylene immonium derivative

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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

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42.6 cyclophosph
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Nitrosoureas

• Also activated in vivo
• Alkylate DNA BUT alkn prots ? toxicity

42.7 nitrosourea
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Temozolomide

• Methylates G, A ? improper G-T base pairing

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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

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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

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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 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

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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

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50.8 Rand
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Pemetrexed
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FYI
45.2 Rand
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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 cant be converted to dTMP
• Covalently binds thymidylate synthetase
• Mech action uses all 3routes ? decrd DNA
  synthesis, also transcrn/transln inhibn

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• 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 (?)

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• Cytosine arabinoside
• Analog of 2dC
• Phosphd in vivo ? cytosine arabinoside
  triphosphate
• Inhibits DNA polymerase
• Gemcitabine araC analog
• Fewer SEs

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42-11
Gemcitabine
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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

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42-10
Pentostatin
Fludarabine
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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

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• Epirubicin, mitozantrone structurally related
• SEs cardiotoxicity (due to free radical
  prodn), bone marrow suppression

Mitozantrone
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• 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

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Dactinomycin
Bleomycin
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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

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Vinca Alkaloids
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Taxanes Paclitaxel, Docetaxel
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ions/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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Ironotecan
Topotecan
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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

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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 ? decrd circulating
  estrogens

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• 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

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Trilostane
Formestane
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Antitumor Agents Working through Cell Signalling
Rang 50.1
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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

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Drugs Targeting Growth Factor Receptors

• Cetuximab
• Monoclonal Ab directed against EGFR
• Erbitux Famous anti-EGFR Ab

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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

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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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Gefitinib
Imatinib
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