Cancer chemotherapy
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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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Cancer Chemotherapy

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Cancer chemotherapy

Cancer Chemotherapy

Chapter 42


Cancer chemotherapy

  • 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


Cancer chemotherapy

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


Cancer chemotherapy

  • 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


Cancer chemotherapy

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


Cancer chemotherapy

  • 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 chemotherapy

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”


Cancer chemotherapy

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 growth division

Cell Cycle = Growth, Division


Cell cycle phases

Cell Cycle Phases

Premitotic synth of

structures, mol’s

Synth DNA precursors,

proteins, etc.


Cycle checkpoints

Cycle Checkpoints


Cdk s cyclins implement cycle decisions

Cdk’s, Cyclins Implement Cycle Decisions


Cancer chemotherapy

Brody 42.1 – G0


Cancer chemotherapy

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


Cancer chemotherapy

  • 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


Cancer chemotherapy

50.2 Rang


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


Cancer chemotherapy

  • 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


    Cancer chemotherapy

    • 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


    Cancer chemotherapy

    • 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)


    Cancer chemotherapy

    Rand 50.3


    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


    Cancer chemotherapy

    • 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


    Cancer chemotherapy

    Rang 50.4


    Cancer chemotherapy

    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


    Cancer chemotherapy

    42.6 cyclophosph


    Cancer chemotherapy

    Nitrosoureas

    • Also activated in vivo

    • Alkylate DNA BUT alk’n prot’s  toxicity

    42.7 nitrosourea


    Cancer chemotherapy

    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)


    Cancer chemotherapy

    • 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


    Cancer chemotherapy

    50.8 Rand


    Cancer chemotherapy

    Pemetrexed


    Cancer chemotherapy

    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


    Cancer chemotherapy

    • 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 (?)


    Cancer chemotherapy

    • Cytosine arabinoside

      • Analog of 2’dC

      • Phosph’d in vivo  cytosine arabinoside triphosphate

      • Inhibits DNA polymerase

    • Gemcitabine – araC analog

      • Fewer SE’s


    Cancer chemotherapy

    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


    Cancer chemotherapy

    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


    Cancer chemotherapy

    • 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


    Cancer chemotherapy

    • 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


    Cancer chemotherapy

    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


    Cancer chemotherapy

    Vinca Alkaloids

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


    Cancer chemotherapy

    Taxanes: Paclitaxel, Docetaxel

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

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


    Cancer chemotherapy

    • 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


    Cancer chemotherapy

    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


    Cancer chemotherapy

    • 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


    Cancer chemotherapy

    • 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


    Cancer chemotherapy

    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


    Cancer chemotherapy

    Antitumor Agents Working through Cell Signalling

    Rang 50.1


    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


    Cancer chemotherapy

    Drugs Targeting Growth Factor Receptors

    • Cetuximab

      • Monoclonal Ab directed against EGFR

    • Erbitux – Famous anti-EGFR Ab


    Cancer chemotherapy

    • 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


    Cancer chemotherapy

    • 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


    Cancer chemotherapy

    Gefitinib

    Imatinib

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

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


    Cancer chemotherapy

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


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