Loading presentation...

Present Remotely

Send the link below via email or IM


Present to your audience

Start remote presentation

  • Invited audience members will follow you as you navigate and present
  • People invited to a presentation do not need a Prezi account
  • This link expires 10 minutes after you close the presentation
  • A maximum of 30 users can follow your presentation
  • Learn more about this feature in our knowledge base article

Do you really want to delete this prezi?

Neither you, nor the coeditors you shared it with will be able to recover it again.


Cancer Chemotherapy

No description


on 11 November 2015

Comments (0)

Please log in to add your comment.

Report abuse

Transcript of Cancer Chemotherapy

Nitrogen Mustards
-S is more nucleophilic
-Fewer SE
MOA: Primary target of DNA cross-linking agents is the actively dividing DNA. Cross-linked DNA is stable and cannot be replicated or degraded. Alkylation of DNA results in inhibition of DNA synthesis and function, DNA mispair, broken strand --> leading to cell death.
-Beta-Carbon is easily attacked by a nucleophile because it is adjacent to the EWG Cl

-The ring has (+) charge
-Guanosine attacks the 3-membered ring
-DNA undergoes alkyl modification after DNA attacks
Steps of MOA:
1) Intramolecular nucleophlic attack
2) Intermolecular attack
3) Intramolecular nucleophilic attack
4) Intermolecular attack
*Forms crosslinked DNA
-Not cell-cycle specific
-More toxic to G1 and S phases
DNA Cross-Linking Agents
Will nitrogen mustard decompose in aqueous media?
Yes - water acts as a nucleophile.

Will acidic or basic solution enhance stability?
Decomposition reactions can be inhibited with a slightly acidic pH buffer solution to enhance solubility.
Want N to still be nucleophilic -
R group can modulate that by making it e- donating
R = e- donating
This compound is more active and more toxic
This compound has decreased e- density and less toxicity. It has resonance b/c of benzene ring is conjugated.
-It can easily pass membrane.
-Has better water solubility.
-Phosphate group is EWG
-More stable than melphalan
ED group: Too reactive for oral administration

pKa = 6.1 - ratio of unionized to ionized drug = 20:1
Predominant form is free base
Salt form provides water solubility to stabilize
Aromatic - stabilizes the long pair of electrons through resonance with the conjugated phenyl ring
-Less reactive; decreased SE
-Phe helps transport into cells
-Orally active
Cyclophosphamide (Cytoxan)
-Prodrug: must be activated by P450
-High F (po = IV)
-Higher cell permeability because decreased e- density on N and decreased basicity
-Unlikely to undergo cyclization to form ring in this form
No activity
Ion form = active
-Hard to get out of the membrane (trapped in cells)
-Compromises EWG of the phosphate - decreased nucleophilicity
-Has higher bioavailability and relative selecitivity
Active form
4. DNA alkylator - Mitomycin
Organoplatinum Complexes
4. Mitomycin
Topoisomerase Inhibitors
Enzymes that control the degree of DNA supercoiling and maintain proper DNA structure by catalyzing the breaking and rejoining of the DNA strands during cell cycle.

TopoI cuts a single stranded DNA
TopoII cuts both strands of DNA
*Specific to tumor cells
Mitomycin must be reduced to hydroquinone - releases methyl.
It can undergo reduction because tumor cells have "reducing environment" - they are fast growing.

Blood vessel growth is not fast enough to supply blood flow to the tumor cells.

Tumor cells receive less blood and thus less oxygen - oxygen would have provided oxidative process.
MOA: bifunctional at both the electrophilic aziridine ring and the methylenegroup ajdacent to the carbamate ester. Results in cross-linked DNA and cell death.
DNA-alkylator and DNA methylator
Transfers methyl group to guanosine.

Normally, G-C - but now, C cannot recognize G with the methyl. G pairs with T instead and causes mismatch to stop DNA replication.
DNA alkylating agent and DNA methylator
Cell permeability so good that it can penetrate BBB (Not ionized)

-PO abs is rapid
-High F (given po)

*Penetrates BBB

Drug Resistance
(AGT) removes the methyl group to repair the mutation
-Prevents cell death
-Certain patients who do not respond to these agents in the treatment of brain CA may have this enzyme
-Two amine
-No alkyl group
-Forms bond between Carbon and Platinum
-Causes mismatch and cell death
*Needs water to be activated to remove the chloride

-There is more Cl present in extracellular fluid which keeps it from becoming active
-Intracellularly, there is lower concentration and this reaction is favored
*Less active extracellularly
*More active intracellularly
Two Cl
-Forms active species 10x slower than cisplatin
-Less toxicity
Oxanic acid
-Less active compared to cisplatin
-Less resistance due to unique structure

-Less water soluble
-Chiral, conjugated, 5-membered ring
-Lactone must be intact to be active
-Mimicks DNA base pair to prevent DNA synthesis
-Stables ternary complex (Topo)
-Prevents religation and causes cell death
-S-Phase specific - so want to consider the dosing schedule
*5-member ring
*Basic side chain
*Water soluble salt formed
*Carbamate ester
*Improved water solubility
*Cell cycle specific - S phase or early G2 phase
-Both are highly water insoluble - both have sugars but still need enhancers for IV formulation
-Risk for hypersensitivity reactions
-Both undergo lactone hydrolysis to generate INactive hydroxyl acid
-Planar structures
**S-phase specific
-Etoposide is stable orally
Teniposide has higher lipophilicity - facilitating cellular uptake and results in 10x potency
-Microbial origin
-Flat ring system slides between the two DNA strands
-Inhibits DNA replication via action at TopoII by stabilizing the ternary drug-enzyme-DNA cleavable complex
-Does not allow the DNA to reseal
-3' amino plays a role in arranging the DNA sequence specificity of the intercalation process
-Removal of 4-OCH3 increases antitumor activity by facilitating the intercalation process
Valrubicin, Idarubicin
-Intercalation into DNA double helix to stabilize the cleavable complex, leading to inhibiton of synthesis or poisoning of TopoII
-Generation of free radicals, leading to DNA and cell membrane damage
-Lipophilic increased (substitution on amino)
-More rapid and extensive penetration into tumor cells
Antimetabolites: Pyrimidine Analogs
-Serve as false substrates for critical nucleotide biosynthesis
-Inhibits the formation of nucleotides
-Interferes with DNA and RNA synthesis by preventing nucleoside production
-Cell-cycle specific: Kills cells in S phase
-Fluorouracil and Floxuridine are prodrugs
-Floxuridine has faster onset of action (only requires one modification)
-Must be phosphorylated to become active
-Active form is 5-F-dUMP
-5-F-dUMP interferes with dTMP synthesis pathway
-Metabolized to 5-FU and converted to the active 5-F-dUMP
-Tumor selective because thymidine phosphorylase (enzyme to convert prodrug) is more active in tumors than in normal tissue
Thymidine Synthesis
Antimetabolites: Purine Antagonist
-Active form is monophosphate
-Inhibit first step of purine ring biosynthesis and blocks formation of ATP

AntiMetabolites: Polymerase and Chain elongation inhibitors
All nucleosides must be converted to triphosphate nucleotides and act as fraudulent nucleotide
*Stereo-chemistry of hydroxy
**Longer half-life than cytarabine
-MOA: It also inhibits deaminase which prevents its degradation
-Longer half-life because of two F because of inhibitory action
-If a patient has a high level of deaminase, can use this agent to prevent resistance treatment
Antimetabolites: Folic Acid Analogs
Paclitaxel (Taxol)
-Binds to beta-tubulin
-Stabilize the microtubule polymer and protect it from disassembling

*15-Membered tricyclic ring fused to an oxetane ring and esterified side chain at C13
*C10 - acetate ester
-Benzyl amide in side chain
Doxetaxel (Taxotere)
*C10 hydroxy
*Carbamate ester on side chain
-More water soluble than Taxol
Vinca Alkaloids
-polymerization inhibitors
*Acetylation on the hydroxy groups destroys activity
*Stereochemistry and methyoxycarbonyl at C18
Small Molecule: Kinase Inhibitors
*Active orally

Lapatinib (Tykerb)
-Dual (irreversible) inhibitor of intracellular tyrosine kinase domains EFGR and HER2 receptors
-Binds to ATP-binding pocket
-Directly and efficiently inhibit phosphorylation and activation of downstream signaling pathways
-Active po
-SELECTIVELY inhibit the kinase domain of EGFR
-Bind to ATP-binding pocket - directly and efficiently inhibit phosphorylation and activation of downstream signaling pathways
-Orally active
Imatinib (Gleevec)
-Selectively inhibits BCR/ABL kinase

*Selective for CML
*Highest selectivity
-Binds to EGFR with higher affinity than its natural ligands
-Competitively inhibit binding of natural ligand
-Induces apoptosis, CDC, ADCC
-Binds to receptor (extracellular)
Monoclonal Antibody
-Humanized mouse mAb
-Blocks ligand binding of HER2
-For it to be effective, patient must have overexpression of HER2
Targeting Tyrosine Kinase
Goal of these drugs is to inhibit phosphorylation to stop cell proliferation
Hormone Antagonist:

-Competitively binds to the ER site and blocks recruitment of coactivator proteins
-ER must be overexpressed for this drug to work
Epigenetics Inhibitor
Azacitadine, Decitabine
-Inhibition of DNA methyltransferase(DNMT)
Vorinostat (SAHA, Zolinza)
-Targets histone deacetylase (HDAC)
-HDAC removes the acetyl groups from the lysine residue leading to the formation of a condensed and transcriptionally silenced chromatin
-Inhibit HDAC results in hyperacetylation of histones
**"HDAC removes the positive charge"
-Diethyl amine to increase water solubility
-At pH7.4, active lactone exists in equilibrium with the hydroxy acid hydrolysis product
-Basic side chain is metabolized by CYP3A4
-Intercalates with DNA and disrupts the DNA replication
-Prodrug and is activated by 3A4 through hydrolysis of the carbamate ester
-Highly protein bound
-5 membered ring
-Enhanced half-life
-natural product

-4 rings are needed to slide into DNA complex
-Loss of C4 ether facilitates its interaction between DNA base pairs
-More lipophilic and better penetration into tumor cells
-Penetrates BBB
-both have 4 rings
Pyrimidine Analogs
-dTMP is produced via methylation of dUMP
-Needs to be monophosphate to be utilized
-Mimic natural ligands so enzymes cannot differentiate between natural ligand and the drug
-Needs to undergo phosphorylation to be active
-3 mechanisms: decreased DNA synthesis, transcription/translation inhibition
-Substrates: dUMP and methyleneTHF
-Product: dTMP
-Any product that looks like uracil, thymine, dUMP or folate will interfere with thymidine synthesis
-This explains the mechanism for antimetabolites: pyrimidine analogs and folate analogs
-This works because tumor cells are growing - this will prevent the production of dTMP
-Nucleotides pairing
-DNA methylator acts here to cause mismatch
-Stopping any step along this pathway will cause interference with protein synthesis, leading to cell death
-Triphospate is the starting material for the polymerase to extend the chain
Background: FYI
**The reason why antimetabolites are prodrugs are because they need to be phosphorylated
Enzyme to transfer the CH3 group
Inactive form
-Normally there is proton
-Cannot undergo normal elimination by the cofactor
-Enzyme becomes inactivated
Production of dTMP is prevented
-5-F-dUMP results in a very fast formation of a fluorinated ternary complex
Monophosphates are active and inhibit the first step of purine ring biosynthesis and block the formation of AMP
If patient does not show response to this drug, just the level of this enzyme
Folic Acid
-Essential for synthesis of purines and thymidylate
-In cells, converted to polyglutamates then FH4
-FH4 serves a methyl donor to deoxyuridine
-Binds tightly to enzyme due to amino group
-Inhibits dehydrofolate reductase (DHFR) competitively 1000x fold higher than folic acid
-Actively transported into cells
-Resistance confers from decreased uptake
-Inhibit DHFR to deplete FH4 in cell to prevent production of dTMP
-Indirectly inhibit thymidylate synthase
Leucovorin Rescue Tx: "antidote"
-This is needed when severe toxicity occurs from methotrexate
-Leucovorin is converted in vivo without needing dihydrofolate reductase
-Causes production of DNA cellular protein inspite of presence of MTX
-Started 24-36 hours after MTX diminishing toxicity without abolishing antitumor effect
Other Folate Analogs
-Phase specific: M phase - where one cell divides into 2 daughter cells
-Microtubule dynamics are important - serve as a spring
-Need to polymerize and depolymerize to stabilize microtubule
-PKC is serine kinase
-Apoptosis = induced cell death
-Complement-Dependent Cytotoxicity - recruit complement protein and attacks membrane
-Antibody-Depdendent Cellular Cytotoxicity - Recognize and kill Ab-labeled target cells
Full transcript