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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

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slide2

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
slide3

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
slide4

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
slide5

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
slide6

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
slide7

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”
slide8

Oncogenesis = Process of Tumor Development

  • Probably multi-step process
  • Decr’d ability to differentiate and control replication and growth
steps to cancer
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
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 phases
Cell Cycle Phases

Premitotic synth of

structures, mol’s

Synth DNA precursors,

proteins, etc.

slide17
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
apoptosis review
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
slide20
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
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
uncontrolled proliferation
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
slide24
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
anticancer drugs are antiproliferative
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
slide26
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
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
slide28
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
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)
alkylating agents
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
slide32
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
slide34

Nitrogen Mustards

42-5 structures

  • Loss Cl  intramolec cyclization of side chain
    •  Reactive ethylene immonium derivative
cyclophosphamide
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
slide37

Nitrosoureas

  • Also activated in vivo
  • Alkylate DNA BUT alk’n prot’s  toxicity

42.7 nitrosourea

slide38

Temozolomide

  • Methylates G, A  improper G-T base pairing
cisplatin
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
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 Analogs
  • Folic acid essential for synth purines, and thymidylate
  • Folate: pteridine ring + PABA + glutamate
    • In cells, converted to polyglutamates then  tetrahydrofolate (FH4)
slide42
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
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
slide47

FYI…

45.2 Rand

pyrimidine analogs
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
slide49
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 (?)
slide51
Cytosine arabinoside
    • Analog of 2’dC
    • Phosph’d in vivo  cytosine arabinoside triphosphate
    • Inhibits DNA polymerase
  • Gemcitabine – araC analog
    • Fewer SE’s
slide52

42-11

Gemcitabine

http://www.pfeist.net/ALL/arac/images/spongo2.gif

purine analogs
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
slide54

42-10

Pentostatin

Fludarabine

cytotoxic antibiotics
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
slide56
Epirubicin, mitozantrone structurally related
  • SE’s: cardiotoxicity (due to free radical prod’n), bone marrow suppression

Mitozantrone

http://www.geocities.com/lubolahchev/Mitoxa4.gif

http://www.farmakoterapi.uio.no/cytostatika/images/16_1_t.gif

slide57
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
slide58

Dactinomycin

Bleomycin

plant alkaloids
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
slide60

Vinca Alkaloids

http://biotech.icmb.utexas.edu/botany/gifs/vdes.gif

slide61

Taxanes: Paclitaxel, Docetaxel

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

http://biotech.icmb.utexas.edu/botany/gifs/tax.gif

slide62
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
slide63

Ironotecan

Topotecan

http://www.axxora.com/files/formula/lkt-i6933.gif

http://www.cancerquest.org/images/topotecan.gif

http://www.chemheritage.org/EducationalServices/pharm/chemo/readings/ages/ages04.gif

hormones
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
slide65
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
slide66
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
slide67

Trilostane

Formestane

http://img.alibaba.com/photo/50310947/Trilostane.jpg

http://www.axxora.com/files/formula/LKT-F5769.gif

http://www.neurosci.pharm.utoledo.edu/MBC3320/images/Flutamide.gif

http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/tamoxifen.gif

binding epidermal growth factor receptors cell prolif n
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
slide70

Drugs Targeting Growth Factor Receptors

  • Cetuximab
    • Monoclonal Ab directed against EGFR
  • Erbitux – Famous anti-EGFR Ab
slide71
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

slide72
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
slide73

Gefitinib

Imatinib

http://www.chemistrydaily.com/chemistry/upload/thumb/9/9a/200px-Imatinib_mesylate.png

http://dric.sookmyung.ac.kr/NEWS/jul01/gleevecmech.jpg

slide74

http://www.wwu.edu/depts/healthyliving/PE511info/cancer/My%20Cancer%20Webs/Symptoms%20and%20Therapy_files/image001.jpghttp://www.wwu.edu/depts/healthyliving/PE511info/cancer/My%20Cancer%20Webs/Symptoms%20and%20Therapy_files/image001.jpg

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