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Mohammad akheel
Omfs pg
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
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
– 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
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
• 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 (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”
Oncogenesis = Process of
Tumor Development
• Probably multi-step process
 Decr’d ability to differentiate and
control replication and growth
 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)
Chemotherapy
 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”
Chemotherapy
Synth DNA precursors,
proteins, etc.
Premitotic synth of
structures, mol’s
Chemotherapy
Chemotherapy
Brody 42.1 – 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
Chemotherapy
 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
 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
 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
50.2 Rang
 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
◦ 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
 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
 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
 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
 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
 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)
Rand 50.3
 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
 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
Rang 50.4
42-5 structures
Nitrogen Mustards
•Loss Cl  intramolec cyclization of side chain
 Reactive ethylene immonium derivative
 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
42.6 cyclophosph
42.7 nitrosourea
Nitrosoureas
•Also activated in vivo
•Alkylate DNA BUT alk’n prot’s  toxicity
Temozolomide
•Methylates G, A  improper G-T base pairing
 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
 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 essential for synth purines, and
thymidylate
 Folate: pteridine ring + PABA + glutamate
◦ In cells, converted to polyglutamates then 
tetrahydrofolate (FH4)
 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
 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
Chemotherapy
50.8 Rand
Pemetrexed
45.2 Rand
FYI…
 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
 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 (?)
Chemotherapy
 Cytosine arabinoside
◦ Analog of 2’dC
◦ Phosph’d in vivo  cytosine arabinoside triphosphate
◦ Inhibits DNA polymerase
 Gemcitabine – araC analog
◦ Fewer SE’s
http://www.pfeist.net/ALL/arac/images/spongo2.gif
42-11
Gemcitabine
 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
42-10
Fludarabine Pentostatin
 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
◦ 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
◦ 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
Dactinomycin
Bleomycin
 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
http://biotech.icmb.utexas.edu/botany/gifs/vdes.gif
Vinca Alkaloids
http://biotech.icmb.utexas.edu/botany/gifs/tax.gif
Taxanes: Paclitaxel, Docetaxel
http://home.caregroup.org/clinical/altmed/interactions/Images/Drugs/docetaxe.gif
 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
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
 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
 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
 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
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
Rang 50.1
Antitumor Agents Working through Cell Signalling
 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
 Cetuximab
◦ Monoclonal Ab directed against EGFR
 Erbitux – Famous anti-EGFR Ab
Drugs Targeting Growth Factor Receptors
 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
 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
http://www.chemistrydaily.com/chemistry/upload/thumb/9/9a/200px-Imatinib_mesylate.png
http://dric.sookmyung.ac.kr/NEWS/jul01/gleevecmech.jpg
Imatinib
Gefitinib
http://www.wwu.edu/depts/healthyliving/PE511info/cancer/My%20Cancer
%20Webs/Symptoms%20and%20Therapy_files/image001.jpg

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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
  • 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
  • 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)
  • 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
  • 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
  • 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
  • 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