DA 4 Exam 3

thompk31's version from 2017-04-26 11:23

Section 1

Question Answer
6-MercaptopurineInhibits purine ring biosynthesis - Inhibits DNA synthesis
6-ThioguanineInhibits purine ring biosynthesis - Inhibits DNA synthesis
AlimtaInhibits dihydrofolate reduction - Blocks thymidylate and purine synthesis
MethotrexateInhibits dihydrofolate reduction - Blocks thymidylate and purine synthesis
CamptothecinsBlocks topoisomerase function
EtoposideBlocks topoisomerase function
TeniposideBlocks topoisomerase function
DaunorubicinBlocks topoisomerase function
DoxorubicinBlocks topoisomerase function
Protein Tyrosine Kinase InhibitorsBlocks activities of the signaling pathways
AntibodiesBlocks activities of the signaling pathways
HydroxyureaInhibits ribonucleotide reductase
5-FluorouracilInhibits thymidylate synthesis
GemcitabineInhibits DNA synthesis
CytarabineInhibits DNA synthesis
FludarabineInhibits DNA synthesis
2-ChorodeoxyadenosineInhibits DNA synthesis
ClofarabineInhibits DNA synthesis
Platinum AnalogsForms adducts with DNA
Alkylating AgentsForms adducts with DNA
MitomycinForms adducts with DNA
TemozolomideForms adducts with DNA
L-AsparaginaseDeaminates asparagine - Inhibits protein synthesis
EpothilonesInhibits function of microtubules
TaxanesInhibits function of microtubules
Vinca AlkaloidsInhibits function of microtubules
EstramustineInhibits function of microtubules
AtraInducers of differentiation
Arsenic TrioxideInducers of differentiation
Histone Deacelyase Inhibitors Inducers of differentiation

Section 2

Question Answer
Cytosine ArabinosideS phase specific
HydroxyureaS phase specific
6-MercaptopurineS phase specific - Self limiting
MethotrexateS phase specific - Self limiting
VincristineM phase specific
VinblastineM phase specific
PaclitaxelM phase specific
Alkylating AgentsNon-Cell specific
NitrosoureasNon-Cell specific
Antitumor antibioticsNon-Cell specific
ProcarbazineNon-Cell specific
CisplatinNon-Cell specific
DecarbazineNon-Cell specific

Section 3

Question Answer
MechlorethamineNitrogen mustard
ChlorambucilNitrogen mustard
BendamustineNitrogen mustard
CyclophosphamideNitrogen mustard
IfosfamideNitrogen mustard
MesnaNitrogen mustard

Alkylating Agents MOA

Question Answer
MechlorethamineEnters cells by active transport system for chlorine.
ChlorambucilMore stable and selective for tumor cells.
BendamustineDNA cross-links slowly repaired - Activates base excision pair - Impairs physiological arrest of adduct-containing cells at mitotic checkpoints - Leads to mitotic catastrophe rather than apoptosis - Does not require intact p53 to cause cytotoxicity.
StreptozocinLooks like D-glucopyranose which is why it is used for pancreatic cancer.
NitrosoureasA proton is abstracted from the urea, which undergoes an SN2 reaction to form an oxazolidinone ring (involves a Cl- leaving group). The unstable oxazolidinone ring rearranges into vinyl diazotic acid and isocyanate, which spontaneously decompose s into gaseous intermediates. Acetaldehyde and vinyl carbocation alkylate DNA.
Nitrogen MustardsAlkylate in a non-specific fashion leading to DNA damage that is not easily repaired in cancer cells.
MesnaUroprotective - Used to counteract the effects of acrolein in Ifosfamide and cyclophosphamide.
CarmustineLipid soluble, crosses BBB, and unionized. Administered in wafers (extends half life).
LomustineLipophillic, unionized, crosses BBB (oral administration). Get non-enzymatic cision, giving you two halves. Right half - spontaneously leads to alkylation of DNA by chloroethyldiazohydroxide. Left half - leads to carbomoylation of lysine.

Alkylating Agents SAR

Question Answer
ChlorambucilElectron withdrawing effect of aromatic ring decreases nucleophilic activity of nitrogen. More stable and selective for tumor cells
BendamustineBenzimidazole ring (purine-like structure)
CyclophosphamideOxazaphosphorine ring. Phosphoramide linkage decreases the nucleophilicity of the nitrogen mustard.
IfosfamideSpacing of 2-chloroethyl groups
Mesna Mercaptoethanesulfonic acid.
Carmustine 1,3-bis(chloroethyl)-1-nitrosourea
StreptozocinMethylnitrosourea of 2-deoxyglucose. D-glucopyranose – (water soluble carbohydrate)
Nitrogen MustardsSubstituents on the key nitrogen impact lipophilicity, activity, and availability. Electron dense groups enhance the stability of these drugs and cytotoxic killing. Amino acids and substituted phenyl groups enhance the oral availability of these drugs.
NitrosoureasThe carrier molecule (R) affects tissue specificity and distribution. N-substituent (R’) affects mechanism of spontaneous, nonenzymatic decomposition. Cytotoxicity is due to alkylating and carbamoylating moieties generated.

Alkylating Agents Metabolism

Question Answer
MechlorethamineSodium thiosulfate can be used to inactivate aziridine to inactive thiosulfate ester.
ChlorambucilGets activated by fatty acid and beta oxidation enzymes to phenyl acetic acid mustard.
BendamustineActivity due solely to parent compound, not a lot of metabolism. Active metabolites by oxidation (CYP 1A2). Inactivate by hydrolysis or adduct formation with macromolecules (sulfhydryl interactions).
Cyclophosphamide(very common) Prodrug activated by oxidation of CYP2B to 4-Hydroxycyclophosphamide. Can undergo tautomerization. Undergoes ring cleavage to aldophosphamide. Aldophosphamide gives rise to Acrolein and Phosphoramide Mustard nonenzymatically. Acrolein is a toxic active metabolite that can cause cystitis. 4-hydroxycyclophosphamide is converted to the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide by aldehyde dehydrogenase.
IfosfamideMetabolism is slower than cyclophosphamide. Prodrug activated by oxidation of CYP3A4 to a hydroxyl group. Ring cleavage, release of acrolein, and formation of aziridine (the active species for nitrogen mustards).
StreptozocinMetabolizes like the right half of Lomustine (alkylates DNA)

Platinum Agents MOA

Question Answer
Platinum agentsFeature a Pt(II), square planar complex that is electron deficient, but draws electrons from chloride ions. The neutral platen enters the tumor cells. Chloride leaves when the pt agent is attacked by cellular water. Antitumor activity correlates with cross-linking of DNA (primarily intrastrand). Results in apoptosis and cell cycle suppression.
CisplatinLose a chloride which is replace by a hydroxyl group. This hydroxyl group cross-links with DNA. The same thing happens with the other chloride and you get formation of two DNA cross-linked adducts which form major distortions in the DNA double helix. It also inhibits DNA replication and transcription. Looking for recognition by p53 to cause apoptosis.
AmifostineProdrug. Alkaline phosphatase dephosphorylates it to active free thiol metabolite. The free thiol detoxifies Cisplatin. ROS generated when exposed to radiation.
OxaliplatinLess dependent on CRT1 copper(II) transporter for intracellular access. Inter- and intra-strand Pt-DNA cross-links. Conformational changes are less likely to be recognized by MMR proteins.

Platinum Agents SAR

Question Answer
OxaliplatinOxalate is leaving group.

Platinum Agents Metabolism

Question Answer
OxaliplatinNon-enzymatic conversion to active derivatives via displacement of oxalate. Forms monoaquo and diaquo DACH platinum. Form monochloro and dichloro DACH platinum.

Folic Acid Antimetabolites MOA

Question Answer
Methotrexate1) Folic acid antagonist that competes with DHF for the DHFR active site. 2) Causes 7,8-DHF to build up in the cell which causes feedback inhibition of thymidylate synthase and GAR. Psudo irreversible inhibitor. Greater affinity than DHF. Indirect MOA due to polyglutamyl metabolite and DHF polyglutamates (inhibits DHFR, thymidylate synthase, and de novo purine synthesis).
LeucovorinTHF analogue; the C5,6 and C7,8 positions are reduced. It is converted to other THF coenzymes and does not require DHFR for activation and is therefore used as a chemoprotectant for high dose methotrexate.
PermetrexedBetter substrate for FPGS than MTX which gives it greater intracellular accumulation of poly-Glu metabolites. Better transport into tumor and different spectrum of enzyme inhibition (binds strongly to thymidylate synthase and GAR transformylase). Multi-targeting allows for it to have activity against tumors that have mutations.
PralatrexateTargets DHFR. 12-14 x greater uptake into cancer cell via RFC1.10-fold higher FPGS polyglutamation efficacy.More drug is resident in cancer cell for longer time.

Folic Acid Antimetabolites SAR

Question Answer
Methotrexatestructurally similar to 7,8-DHF. Methotrexate is positioned 180 degrees inverted relative to the orientation of 7,8-DHF. It is not a substrate for DHFR, it inhibits the activation site.
PermetrexedPyrrole derivative of THF. Replaced N with methylene bridge. Has benzimidazole ring now as well.
Pralatrexate10-deaza analog of MTX, propargyl group substitution

Folic Acid Antimetabolites Metabolism

Question Answer
MethotrexateMetabolized by FPGS and Hydrolase which converts polyglutamate forms to MTX. MTX-polyglutamate is converted to MTX before extracellular transport. 90% of the drug is excreted renally as parent metabolite.

Purine Antimetabolites MOA

Question Answer
AzithioprineProdrug of mercaptopurine. Nonenzymatic release of 6-mercaptopurine by interaction with sulfhydryl compounds. This slow release of 6-MP provides a sustained effect as an immunosuppressant.
6-Mercaptopurine(major) Inhibits de novo purine synthesis by Methyl-TIMP. (minor) 6-TGN'sIncorporated into DNA/RNA = apoptosis. Must be converted to nucleotides to exhibit cytotoxicity.
FludarabineDephosphorylated to fludarabine (serum phosphatases). Enters cells via nucleoside transporter protein.Phosphorylated intracellularly to triphosphate (2-fluoro-ara-ATP). Inhibits DNA synthesis and terminate the chain due to arabinose sugar.
Cladribine1) incorporates as a chain terminator 2) inhibits ribonucleotide reductase which converts RNA to DNA. 3) High levels of intracellular 2-chloro-dAMP leads to inhibition of DNA repair enzymes.
ClofarabineInhibits DNA synthesis and repair of DNA damage by inhibiting ribonucleotide reductase and DNA polymerases.
Pentostatinadenosine deaminase inhibitor which prevents metabolism of some of the other purine antimetabolite drugs. Much greater affinity than the natural substrate.
HydroxyureaS-phase specific drug that inhibits ribonucleotide reductase

Purine Antimetabolite SAR

Question Answer
6-MercaptopurineSulfur analog of hypoxanthine
FludarabineArabinose sugar with 3-OH in wrong position which allows it to be a chain terminator. 2-Fluoro group makes it resistant to adenosine deaminase.
Cladribine2-chlorodeoxyadenosine analog. Chlorine makes it resistant to deaminases.
Clofarabine2-fluoro group increases acid stability and resists cleavage by phosphorylases. 2-chloro group makes it resistant to adenosine deaminase. (These SARs make it more efficacious).

Purine Antimetabolite Metabolism

Question Answer
6-MercaptopurineHGPRT activates 6-MP to thiopurine nucleotide. Kinases convert to triphosphate.TPMT and XO inactivates 6-MP to inactive methylated nucleobases (important to avoid toxicity). DI with XOI's (allopurinol). Poor metabolizers will have almost no turnover of this metabolite.
CladribinePhosphorylated by deoxycytidine kinase to 2-chloro-deoxyadenosine monophosphate (chlorinated dAMP). Inactivated by 5'-nucleotidase. Cells that have high kinase activity and low 5'-nucleotidase activity will be selectively killed.

Pyrimidine Antimetabolite MOA

Question Answer
5-FUDecreases dTTP induces perturbation of other deoxynucleotides. Inhibition of TS increases dUTP incorporation into DNA. Imbalances are thought to severely disrupt DNA synthesis and repair resulting in lethal damage. Excision repair breaks DNA but no TTP available for repair. High intracellular levels of MTHF are required for optimal binding with 5-FU for binding to TS. LV enters the cell via reduced folate carrier, anabolized to MTHF and polyglutamated.
CapecitabineConsidered to have equivalent efficacy and lack of increased toxicity compared to 5-FU
TrifluridineMOA depends on metabolite. Monophosphate - Inhibits thymidylate synthase (irreversibly). Triphosphate - Competitive inhibition of thymidine triphosphate by incorporating into DNA by DNA polymerase (MAJOR).
TipiracilPrevents trifluridine from being metabolized. Thymidine phosphorylase inhibitor.
CytarabineSteric hinderance causing DNA inhibition
GemcitabineDiphosphate inhibits ribonucleotide reductase. Triphosphate competes with dCTP for incorporation into DNA. When incorporated into DNA, only one additional nucleotide is incorporated to growing DNA strand. Inhibition of further DNA synthesis.

Pyrimidine Antimetabolite SAR

Question Answer
5-FUThe electronegative 5-fluorine of 5-FdUMP makes the C-6 position more electrophilic. This results in a fast nucleophilic attack by Cys195 of thymidylate synthase to form a fluorinated ternary complex. C-F bond less susceptible to enzymatic cleavage. Fluorine is a relatively small atom, so it does not sterically inhibit formation of the complex.
CapecitabineFluoropyrimidine carbamate
CytarabineD-arabinoside that has2’-difluoro analogue of deoxycytidine
Gemcitabine2’-OH is beta configured instead of alpha-configured causing steric hinderance.

Pyrimidine Antimetabolite Metabolism

Question Answer
5-FUPhosphoribosyltransferase converts 5-FU to (5-FUMP). UMP kinase converts to 5-FUDP. 5-FUDP is converted to a 2’-deoxyribose via ribonucleotide reductase. A phosphatase removes a phosphate of 5-FUDP to give the active metabolite, 5-fluoro-deoxyuridine monophosphate (5-FdUMP). 5-FU is converted to 5-Fluoro-5,6-dihydrouracil by dihydropyrimidine dehydrogenase. 5-Fluoro-5,6-dihydrouracil is converted to alpha-Fluorouridopropionic acid by dihydropyrimidinase. This is then converted to alpha-fluoro-beta-alanine by beta-ureidopropionase and is theis the final catabolic metabolite excreted in the urine.
CapecitabineMetabolized in liver to 5’-DFCR. Converted to 5’-DFUR by cytidine deaminase(primarily in liver and tumor but found in most tissues). Converted to 5-FU by thymidine phosphorylase at tumor site.Many tissues express the enzyme and have a higher concentration than normal tissues.Increases tumor selectivity up to 3.5-fold. Cleaves the 5’-deoxy sugar. Inactivation by dihydropyrimidine dehydrogenase, but avoids first pass metabolism.
TrifluridineMetabolized to 5-(trifluoromethyl) uracil by thymidine phosphorylase (inactive).
Tipiracilnot metabolized
Cytarabineara-cytidine-triphosphate is active by cellular kinases. Cytidine deaminase inactivates it.
Gemcitabineactivated by kinases, deactivated by deaminases.Elimination is gender-dependent. Women have lower renal clearance overall.