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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)
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”
Synth DNA precursors,proteins, etc.
Premitotic synth ofstructures, mol’s
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
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
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 (?)
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.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
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