Chemotherapy

1. Mohammad akheel
Omfs pg

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 1
o
to 2
o
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
2
nd
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 10
11
cancer cell burden, 10
7
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 (10
9
cells)
May be detected, if not in deep organ
◦Approx 10 add’l doublings  20 cm mass (10
12
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/ -NH
2
, -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/ H
2O
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 (FH
4)

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

52. http://www.pfeist.net/ALL/arac/images/spongo2.gif
42-11
Gemcitabine

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

54. 42-10
Fludarabine
Pentostatin

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

58. Dactinomycin
Bleomycin

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

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

61. http://biotech.icmb.utexas.edu/botany/gifs/tax.gif
Taxanes: Paclitaxel, Docetaxel
http://home.caregroup.org/clinical/altmed/interactions/Images/Drugs/docetaxe.gif

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

63. http://www.chemheritage.org/EducationalServices/pharm/chemo/readings/ages/ages04.gif
Ironotecan
http://www.cancerquest.org/images/topotecan.gif
Topotecan
http://www.axxora.com/files/formula/lkt-i6933.gif

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

67. http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/tamoxifen.gif
http://www.neurosci.pharm.utoledo.edu/MBC3320/images/Flutamide.gif
Formestane
http://www.axxora.com/files/formula/LKT-F5769.gif
Trilostane
http://img.alibaba.com/photo/50310947/Trilostane.jpg

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

73. http://www.chemistrydaily.com/chemistry/upload/thumb/9/9a/200px-Imatinib_mesylate.png
http://dric.sookmyung.ac.kr/NEWS/jul01/gleevecmech.jpg
Imatinib
Gefitinib

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