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Chemotherapy
- 2. 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
- 3. 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
- 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. 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
- 6. • 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
- 7. 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”
- 8. Oncogenesis = Process of Tumor Development • Probably multi-step process Decr’d ability to differentiate and control replication and growth
- 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 encourages tumor form’n Gen’ly need both initiation and promotion ◦ Initiators, promoters may be toxins OR radiation OR viruses)
- 11. 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”
- 13. Synth DNA precursors, proteins, etc. Premitotic synth of structures, mol’s
- 16. Brody 42.1 – G0
- 17. 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
- 19. 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
- 20. 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
- 21. 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
- 22. 50.2 Rang
- 23. 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
- 24. ◦ 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
- 25. 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
- 26. 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
- 27. 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
- 28. 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
- 29. 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)
- 30. Rand 50.3
- 31. 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
- 32. 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
- 33. Rang 50.4
- 34. 42-5 structures Nitrogen Mustards •Loss Cl intramolec cyclization of side chain Reactive ethylene immonium derivative
- 35. 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
- 36. 42.6 cyclophosph
- 37. 42.7 nitrosourea Nitrosoureas •Also activated in vivo •Alkylate DNA BUT alk’n prot’s toxicity
- 38. Temozolomide •Methylates G, A improper G-T base pairing
- 39. 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
- 40. 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
- 41. Folic acid essential for synth purines, and thymidylate Folate: pteridine ring + PABA + glutamate ◦ In cells, converted to polyglutamates then tetrahydrofolate (FH4)
- 42. 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
- 43. 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
- 45. 50.8 Rand
- 46. Pemetrexed
- 47. 45.2 Rand FYI…
- 48. 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
- 49. 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 (?)
- 51. Cytosine arabinoside ◦ Analog of 2’dC ◦ Phosph’d in vivo cytosine arabinoside triphosphate ◦ Inhibits DNA polymerase Gemcitabine – araC analog ◦ Fewer SE’s
- 53. 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
- 55. 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
- 56. ◦ 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
- 57. ◦ 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
- 59. 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
- 62. 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
- 64. 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
- 65. 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
- 66. 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
- 68. Rang 50.1 Antitumor Agents Working through Cell Signalling
- 69. 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
- 70. Cetuximab ◦ Monoclonal Ab directed against EGFR Erbitux – Famous anti-EGFR Ab Drugs Targeting Growth Factor Receptors
- 71. 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
- 72. 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