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

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Mitozantrone

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◦ 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

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Vinca Alkaloids

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Taxanes: Paclitaxel, Docetaxel

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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

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Ironotecan

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Topotecan

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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

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Formestane

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Trilostane

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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

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Imatinib

Gefitinib

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