Professional Documents
Culture Documents
Normal cells
Differentiate, grow, mature, divide
Regulated, balanced; cell birth=cell
death
Regulation: intracell signaling
42-5 structures
42.7 nitrosourea
Temozolomide
Methylates G, A improper G-T base pairing
Cisplatin
Cl- dissocs 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 SEs, but
more myelotoxic
Antimetabolites
Mimic structures of normal
metabolic mols
Inhibit enzs competitively OR
Incd into macromols inappropriate
structures
Kill cells in S phase
Three main groups
Folate antagonists
Pyr analogs
Pur analogs
Folic Acid Analogs
Folic acid essential for synth purines,
and thymidylate
Folate: pteridine ring + PABA +
glutamate
In cells, converted to polyglutamates then
tetrahydrofolate (FH4)
Folate FH4 catd
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
Methotrexate
Higher affinity for enz than does FH2
Addl H or ionic bond forms
Depletion FH4 in cell depln dTMP
thymine-less death
Inhibn DNA synth
Uptake through folate transport system
Resistance through decrd uptake
Metabolites (polyglutamate derivs)
retained for weeks, months
50.8 Rand
Pemetrexed
FYI
45.2 Rand
Pyrimidine Analogs
5-Fluorouracil dUMP analog also
works through dTMP synthesis
pathway
Converted fraudulent nucleotide
FdUMP
Competitive inhibitor for thymidylate
synthetase active site, but cant be
converted to dTMP
Covalently binds thymidylate synthetase
Mech action uses all 3routes decrd DNA
synthesis, also transcrn/transln inhibn
Gemcitabine
Phosphd tri-PO4s
Fraudulent nucleotide
Also inhibs ribonucleotide reductase
decrd nucleotide synth
Capecitabine is prodrug
Converted to 5FU in liver, tumor
Enz impt to conversion overexpressed in
cancer cells (?)
Cytosine arabinoside
Analog of 2dC
Phosphd in vivo cytosine
arabinoside triphosphate
Inhibits DNA polymerase
Gemcitabine araC analog
Fewer SEs
42-11
Gemcitabine
http://www.pfeist.net/ALL/arac/images/spongo2.gif
Purine Analogs
6-Mercaptopurine, 6-Thioguanine
Converted to fraudulent nucleotides
Inhibit enzs 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 prolifn
42-10
Fludarabine Pentostatin
Cytotoxic Antibiotics
Mitozantrone
http://www.geocities.com/lubolahchev/Mitoxa4.gif
http://www.farmakoterapi.uio.no/cytostatika/images/16_1_t.gif
Dactinomycin
Intercalates in DNA minor groove between
adjacent GC pairs
Interferes w/ RNA polymerase movement
decrd transcrn
Also may work through topoisomerase II
Bleomycin
Glycopeptide
Chelates Fe, which interacts w/ O2
Genn 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
Plant Alkaloids
Work at mitosis
Effect tubulin, therefore microtubule
activity
Prevention spindle formn OR
Stabilize (freeze) polymerized
microtubules
Arrest of mitosis
Other effects due to tubulin defects
Phagocytosis/chemotaxis
Axonal transport in neurons
Vinca Alkaloids
http://biotech.icmb.utexas.edu/botany/gifs/vdes.gif
Taxanes: Paclitaxel, Docetaxel
http://home.caregroup.org/clinical/altmed/interactions/Images/Drugs/docetaxe.gif
http://biotech.icmb.utexas.edu/botany/gifs/tax.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
Ironotecan
Topotecan
http://www.axxora.com/files/formula/lkt-i6933.gif
http://www.cancerquest.org/images/topotecan.gif
http://www.chemheritage.org/EducationalServices/pharm/chemo/readings/ages/ages04.gif
Hormones
Tumors derd from tissues responding
to hormones may be hormone-
dependent
Growth inhibd by hormone antagonists OR
other hormones w/ opposing actions OR
inhibitors of relevant hormone
Glucocorticoids
Inhibitory on lymphocyte prolifn
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 decrd
circulating estrogens
Hormone antagonists
Tamoxifen impt in breast cancer
treatment
Competes w/ endogenous estrogens for
receptor
Inhibits transcrn 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
Trilostane
Formestane
http://img.alibaba.com/photo/50310947/Trilostane.jpg
http://www.axxora.com/files/formula/LKT-F5769.gif
http://www.neurosci.pharm.utoledo.edu/MBC3320/images/Flutamide.gif
http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/tamoxifen.gif
Antitumor Agents Working through Cell Signalling
Rang 50.1
Binding Epidermal Growth
Factor Receptors Cell
Prolifn
EGFR present on many solid tumors
Tyr-kinase type receptors
Ligand binding kinase cascade
transcription factor synth
incrd cell prolifn
metastasis
decrd apoptosis
Cells expressing EGFR resistant to
cytotoxins; poor clinical outcome
predicted
Drugs Targeting Growth Factor
Receptors
Cetuximab
Monoclonal Ab directed against EGFR
Erbitux Famous anti-EGFR Ab
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
Gefitinib
Imatinib
http://www.chemistrydaily.com/chemistry/upload/thumb/9/9a/200px-Imatinib_mesylate.png
http://dric.sookmyung.ac.kr/NEWS/jul01/gleevecmech.jpg
http://www.wwu.edu/depts/healthyliving/PE511info/cancer/My%20Cancer
%20Webs/Symptoms%20and%20Therapy_files/image001.jpg