Cancer Chemotherapy

1. Cancer Chemotherapy Chapter 42

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. 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)

11. 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”

12. Cell Cycle = Growth, Division

13. Cell Cycle Phases Premitotic synth of structures, mol’s Synth DNA precursors, proteins, etc.

14. Cycle Checkpoints

15. Cdk’s, Cyclins Implement Cycle Decisions

16. Brody 42.1 – G0

17. 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

19. 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

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. 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

22. 50.2 Rang

23. 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

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. 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

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. 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

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. 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)

30. Rand 50.3

31. 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

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. Nitrogen Mustards 42-5 structures • Loss Cl  intramolec cyclization of side chain •  Reactive ethylene immonium derivative

35. 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

36. 42.6 cyclophosph

37. Nitrosoureas • Also activated in vivo • Alkylate DNA BUT alk’n prot’s  toxicity 42.7 nitrosourea

38. Temozolomide • Methylates G, A  improper G-T base pairing

39. 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

40. 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

41. Folic Acid Analogs • 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. 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

45. 50.8 Rand

46. Pemetrexed

47. FYI… 45.2 Rand

48. 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

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 (?)