chemotherapy
TRANSCRIPT
![Page 1: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/1.jpg)
Mohammad akheel Omfs pg
![Page 2: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/2.jpg)
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
![Page 3: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/3.jpg)
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
![Page 4: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/4.jpg)
– 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
![Page 5: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/5.jpg)
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
![Page 6: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/6.jpg)
• 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
![Page 7: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/7.jpg)
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”
![Page 8: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/8.jpg)
Oncogenesis = Process of Tumor Development
• Probably multi-step process Decr’d ability to differentiate
and control replication and growth
![Page 9: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/9.jpg)
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)
![Page 10: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/10.jpg)
![Page 11: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/11.jpg)
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”
![Page 12: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/12.jpg)
![Page 13: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/13.jpg)
Synth DNA precursors,proteins, etc.
Premitotic synth ofstructures, mol’s
![Page 14: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/14.jpg)
![Page 15: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/15.jpg)
![Page 16: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/16.jpg)
Brody 42.1 – G0
![Page 17: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/17.jpg)
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
![Page 18: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/18.jpg)
![Page 19: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/19.jpg)
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
![Page 20: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/20.jpg)
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
![Page 21: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/21.jpg)
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
![Page 22: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/22.jpg)
50.2 Rang
![Page 23: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/23.jpg)
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
![Page 24: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/24.jpg)
◦ 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
![Page 25: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/25.jpg)
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
![Page 26: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/26.jpg)
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
![Page 27: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/27.jpg)
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
![Page 28: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/28.jpg)
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
![Page 29: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/29.jpg)
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)
![Page 30: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/30.jpg)
Rand 50.3
![Page 31: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/31.jpg)
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
![Page 32: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/32.jpg)
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
![Page 33: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/33.jpg)
Rang 50.4
![Page 34: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/34.jpg)
42-5 structures
Nitrogen Mustards
•Loss Cl intramolec cyclization of side chain
Reactive ethylene immonium derivative
![Page 35: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/35.jpg)
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
![Page 36: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/36.jpg)
42.6 cyclophosph
![Page 37: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/37.jpg)
42.7 nitrosourea
Nitrosoureas
•Also activated in vivo
•Alkylate DNA BUT alk’n prot’s toxicity
![Page 38: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/38.jpg)
Temozolomide•Methylates G, A improper G-T base pairing
![Page 39: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/39.jpg)
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
![Page 40: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/40.jpg)
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
![Page 41: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/41.jpg)
Folic acid essential for synth purines, and thymidylate
Folate: pteridine ring + PABA + glutamate◦ In cells, converted to polyglutamates then
tetrahydrofolate (FH4)
![Page 42: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/42.jpg)
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
![Page 43: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/43.jpg)
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
![Page 44: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/44.jpg)
![Page 45: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/45.jpg)
50.8 Rand
![Page 46: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/46.jpg)
Pemetrexed
![Page 47: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/47.jpg)
45.2 Rand
FYI…
![Page 48: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/48.jpg)
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
![Page 49: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/49.jpg)
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 (?)
![Page 50: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/50.jpg)
![Page 51: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/51.jpg)
Cytosine arabinoside◦ Analog of 2’dC◦ Phosph’d in vivo cytosine arabinoside
triphosphate◦ Inhibits DNA polymerase
Gemcitabine – araC analog◦ Fewer SE’s
![Page 52: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/52.jpg)
http://www.pfeist.net/ALL/arac/images/spongo2.gif
42-11
Gemcitabine
![Page 53: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/53.jpg)
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
![Page 54: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/54.jpg)
42-10
Fludarabine Pentostatin
![Page 55: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/55.jpg)
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
![Page 56: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/56.jpg)
◦ 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
![Page 57: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/57.jpg)
◦ 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
![Page 58: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/58.jpg)
Dactinomycin
Bleomycin
![Page 59: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/59.jpg)
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
![Page 60: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/60.jpg)
http://biotech.icmb.utexas.edu/botany/gifs/vdes.gif
Vinca Alkaloids
![Page 61: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/61.jpg)
http://biotech.icmb.utexas.edu/botany/gifs/tax.gif
Taxanes: Paclitaxel, Docetaxel
http://home.caregroup.org/clinical/altmed/interactions/Images/Drugs/docetaxe.gif
![Page 62: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/62.jpg)
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
![Page 63: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/63.jpg)
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
![Page 64: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/64.jpg)
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
![Page 65: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/65.jpg)
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
![Page 66: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/66.jpg)
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
![Page 67: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/67.jpg)
http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/tamoxifen.gifhttp://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
![Page 68: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/68.jpg)
Rang 50.1
Antitumor Agents Working through Cell Signalling
![Page 69: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/69.jpg)
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
![Page 70: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/70.jpg)
Cetuximab◦ Monoclonal Ab directed against EGFR
Erbitux – Famous anti-EGFR Ab
Drugs Targeting Growth Factor Receptors
![Page 71: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/71.jpg)
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
![Page 72: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/72.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
![Page 73: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/73.jpg)
http://www.chemistrydaily.com/chemistry/upload/thumb/9/9a/200px-Imatinib_mesylate.png
http://dric.sookmyung.ac.kr/NEWS/jul01/gleevecmech.jpg
Imatinib
Gefitinib
![Page 74: Chemotherapy](https://reader036.vdocuments.us/reader036/viewer/2022081512/555dabcdd8b42a68328b46ae/html5/thumbnails/74.jpg)
http://www.wwu.edu/depts/healthyliving/PE511info/cancer/My%20Cancer%20Webs/Symptoms%20and%20Therapy_files/image001.jpg