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  1. 1. Mohammad akheelOmfs pg
  2. 2. Normal cells…•Differentiate, grow, mature, divide–Regulated, balanced; cell birth=cell death•Regulation: intracell signaling–Hyperplasia: new cells prod’d w/ growthstimulus via hormones, endogenous signals–Ex: hyperplasia of endometrial tissue duringmenstrual cycle is normal and necessary
  3. 3. BUT if intense, prolongeddemand …• 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 sevlayers cuboidal epithelium» Note: Replacement cells normal, justdifferent» Reversible
  4. 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. 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 connectivetissue
  6. 6. • Malignant – grow more rapidly; oftencalled “cancer”– Not cohesive; seldom have capsule– Irregular shape; disrupted architecture– Invade surrounding cells– Can break away to form second tumor•“Metastasis” from 1oto 2osite
  7. 7. Cancer (Neoplastic) Cells• May be:– Well-differentiated = retain normal cellfunction• Mimic normal tissue• Often benign– Poorly differentiated = disorganized• Can’t tell tissue of origin• “Anaplastic”
  8. 8. Oncogenesis = Process ofTumor Development• Probably multi-step process Decr’d ability to differentiate andcontrol replication and growth
  9. 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 encouragestumor form’n Gen’ly need both initiation and promotion◦ Initiators, promoters may be toxins OR radiationOR viruses)
  10. 10.  Most tumors arise “spontaneously” w/out knowncarcinogen exposure, AND Proto-oncogenes can be inherited (ex: “breast cancergene”) BUT environmental agents are known to cause DNAmutations, AND Risk factors known (Ex:◦ Cigarette smoking  lung cancer◦ UV light exposure  skin cancer) Theory: “Genetics loads the gun; the environmentpulls the trigger”
  11. 11. Synth DNA precursors,proteins, etc.Premitotic synth ofstructures, mol’s
  12. 12. Brody 42.1 – G0
  13. 13.  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
  14. 14.  In healthy cells, survival factors signal act’nanti-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 TumorNecrosis Factor Receptor
  15. 15.  Second pathway act’d by intracell signals, e.g.DNA damage◦ Players are p53 gene & prot; mitochondrialcytochrome c; Apaf-1 (prot); caspase 9 Effector caspases initiate pathway  cleavagecell constituents  cluster membr-bound“entities” (used to be cell) that arephagocytosed Anti-apoptotic genetic lesions nec for dev’tcancer◦ Apoptosis resistance characteristic of cancer cells
  16. 16.  Code for prot’s that regulate cell div/prolif’n whenturned on/off◦ Malfunctions, mutations may  oncogenesis◦ Changes w/ viruses, chem’s: point mutations, geneamplifications, 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 celldiv OFF Mutations  repression  cancer
  17. 17. 50.2 Rang
  18. 18.  Result of act’n proto-oncogenes or inact’n tumorsuppressor genes◦ Change in growth factors, receptors Incr’d growth factors prod’d◦ Change in growth factor pathways 2ndmessenger cascades (esp tyr-kinase receptor cascades)◦ Change in cell cycle transducers Cyclins, Cdk’s, Cdk inhibitors
  19. 19. ◦ Change in apoptotic mech’s◦ Change in telomerase expression◦ Change in local blood vessels  angiogenesis Note: Genes controlling any of theseprot’s/mech’s can be considered proto-oncogenes or tumor suppressor genes Note: Dev’t malignant cancer depends on sevtransform’ns
  20. 20.  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
  21. 21.  Side effects greatest in other rapidly-dividingcells◦ Bone marrow toxicity◦ Impaired wound healing◦ Hair follicle damage◦ Gi epith damage◦ Growth in children◦ Gametes◦ Fetus May themselves be carcinogenic
  22. 22.  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
  23. 23.  Suspended cancer cells (leukemias)◦ Killing 99.99% of 1011cancer cell burden, 107neoplasticcells remain◦ Can’t rely on host immunological defense to killremaining cancer cells Diagnosis, treatment difficult if rapidly growing◦ Ex: Burkitt’s lymphoma doubles ~24 h◦ Approx 30 doublings  tumor mass of 2 cm (109cells) May be detected, if not in deep organ◦ Approx 10 add’l doublings  20 cm mass (1012cells) –lethal◦ Therefore, “silent” for first ¾ existence
  24. 24.  Cytotoxic Agents◦ Alkylating Agents◦ Antimetabolites◦ Cytotoxic antibiotics◦ Plant derivatives Hormones◦ Suppress nat’l hormone secr’n or antagonizehormone action Misc (mostly target oncogene products)
  25. 25. Rand 50.3
  26. 26.  Contain chem grps that covalently bind cellnucleophiles 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
  27. 27.  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
  28. 28. Rang 50.4
  29. 29. 42-5 structuresNitrogen Mustards•Loss Cl  intramolec cyclization of side chain Reactive ethylene immonium derivative
  30. 30.  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
  31. 31. 42.6 cyclophosph
  32. 32. 42.7 nitrosoureaNitrosoureas•Also activated in vivo•Alkylate DNA BUT alk’n prot’s  toxicity
  33. 33. Temozolomide•Methylates G, A  improper G-T base pairing
  34. 34.  Cl- dissoc’s  reactive complex that reacts w/ H2Oand interacts w/ DNA  intrastrand cross-link (G N7w/ adjacent G O6)  denaturation DNA◦ Nephrotoxic◦ Severe n/v ameliorated w/ 5-HT3 antagonists (decr gastricmotility) Carboplatin – fewer above SE’s, but more myelotoxic
  35. 35.  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
  36. 36.  Folic acid essential for synth purines, andthymidylate Folate: pteridine ring + PABA + glutamate◦ In cells, converted to polyglutamates then tetrahydrofolate (FH4)
  37. 37.  Folate  FH4 cat’d bydihydrofolate reductasein 2 steps:◦ Folate  FH2◦ FH2  FH4 FH4 serves as methylgrp donor (1-C unit) todeoxyuridine (dUMP dTMP), alsoregenerating FH2
  38. 38.  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 forweeks, months
  39. 39. 50.8 Rand
  40. 40. Pemetrexed
  41. 41. 45.2 RandFYI…
  42. 42.  5-Fluorouracil – dUMP analog also worksthrough dTMP synthesis pathway◦ Converted  “fraudulent” nucleotide FdUMP ◦ Competitive inhibitor for thymidylate synthetaseactive site, but can’t be converted to dTMP◦ Covalently binds thymidylate synthetase◦ Mech action uses all 3routes  decr’d DNAsynthesis, also transcr’n/transl’n inhib’n
  43. 43.  Gemcitabine◦ Phosph’d  tri-PO4’s “Fraudulent nucleotide”◦ Also inhib’s ribonucleotide reductase  decr’dnucleotide synth Capecitabine is prodrug◦ Converted to 5FU in liver, tumor Enz impt to conversion overexpressed in cancer cells (?)
  44. 44.  Cytosine arabinoside◦ Analog of 2’dC◦ Phosph’d in vivo  cytosine arabinoside triphosphate◦ Inhibits DNA polymerase Gemcitabine – araC analog◦ Fewer SE’s
  45. 45.
  46. 46.  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
  47. 47. 42-10Fludarabine Pentostatin
  48. 48.  Substances of microbial origin that preventmammalian 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
  49. 49. ◦ Epirubicin, mitozantrone structurally related◦ SE’s: cardiotoxicity (due to free radical prod’n), bonemarrow suppression
  50. 50. ◦ 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
  51. 51. DactinomycinBleomycin
  52. 52.  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
  53. 53. Alkaloids
  54. 54. Paclitaxel, Docetaxel
  55. 55.  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
  56. 56.
  57. 57.  Tumors der’d from tissues responding tohormones may be hormone-dependent◦ Growth inhib’d by hormone antagonists OR otherhormones w/ opposing actions OR inhibitors of relevanthormone Glucocorticoids◦ Inhibitory on lymphocyte prolif’n◦ Used against leukemias, lymphomas
  58. 58.  Estrogens◦ Block androgen effects (ex: fosfestrol)◦ Used to recruit cells in G0  G1, so better targets forcytotoxic drugs Progestogens (ex: megestrol,medroxyprogesterone)◦ Used in endometrial, renal tumors GnRH analogs (ex: goserelin)◦ Inhibit gonadotropin release  decr’d circulatingestrogens
  59. 59.  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 hormonesynth at adrenal gland◦ Formestane inhibits aromatase at adrenal gland
  60. 60.
  61. 61. Rang 50.1Antitumor Agents Working through Cell Signalling
  62. 62.  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 tocytotoxins; poor clinical outcome predicted
  63. 63.  Cetuximab◦ Monoclonal Ab directed against EGFR Erbitux – Famous anti-EGFR AbDrugs Targeting Growth Factor Receptors
  64. 64.  Trastuzumab◦ “Humanized” mousemonoclonal Ab◦ Binds HER2 Membr prot structurallysimilar to EGFR Has integral tyr kinase activity Impt in breast cancer cells◦ May also induce p21 andp27 Cell cycle inhibitors
  65. 65.  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
  66. 66.
  67. 67.