Chemo (cont.)

nelso418's version from 2017-04-26 09:49

Purine Antimetabolites

Question Answer
SAR MercaptopurineSulfur analogue of hypoxanthine
Metabolism MercaptopurineHGPRT = hypoxanthine guanine phosphoribosyltransferase – enzyme that activates 6-MP as a nucleotide to 6-TIMP – Deficiency in HPGRT results in decreased affinity, lack of enzyme causes resistance - Must be converted to nucleotides to exhibit cytotoxicity – TPMT is the major inactivating enzyme to 6-methyl-MP and is a potent inhibitor of amidophosphoribosyl transferase– XO metabolizes to thioxanthine then to thiouric acid – dose lowering occurs with XO inhibitors
MOA Mercaptopurineinhibits de novo purine synthesis (major) also incorporated into DNA/RNA = apoptosis (minor) – inhibit T-IMP, T-GMP, T-dGTP – inhibits Methyl-TIMP the first and rate limiting step of de novo purine synthesis
Metabolism AzathioprineProdrug of mercaptopurine – nonenzymatic release of 6-MP by interaction with sulfhydryl compounds – Key point – this slow release of 6-MP provides a sustained effect as an immunosuppressant
SAR Fludarabine (Fludara ®)antimetabolite of adenosine – arabinose sugar (wrong stereochemistry) – 2-fluoro group – C-F bond is resistant to deaminase activity
Metabolism Fludarabine (Fludara ®)rapidly dephosphorylated to fludarabine (serum phosphatases) – phosphorylated intracellularly to triphosphate (2-fluoro-ara-ATP)
MOA Fludarabine (Fludara ®)Inhibits DNA synthesis (ribonucleotide reductase, DNA primase, and DNA polymerase) – incorporated into DNA and RNA – terminates chain when incorporated into DNA, activates apoptosis – inhibits RNA function, processing, and mRNA translation
SAR Cladribine (Leustatin ®)2-chlorodeoxyadenosine, CdA - Cl is resistant to deamination by adenosine deaminase
Metabolism Cladribine (Leustatin ®)Phosphorylated by deoxycytidine kinase to 2-chloro-deoxyadenosine monophosphate (chlorinated dAMP), which accumulates – inactivated by a 5’-nucleotidase – Key point – cells that have high kinase activity and low 5’-nucleotidase activity will be selectiviely killed
MOA Cladribine (Leustatin ®)kinases convert to corresponding nucleotide triphosphate – incorporates into DNA (chain terminator) – inhibits ribonucleotide reductase, decreasing cellular dNTP pools – accumulates as 2-chloro-dAMP in cells – high levels of dNTPs leads to inhibition of DNA repair enzymes – the cell cannot repair single stranded breaks – broken ends of DNA activate the ADP-ribose polymerase resulting in depletion of NAD and ATP cofactors – key result – inhibition of DNA synthesis and repair through depletion of cofactors and allosteric inhibition of key enzymes – can kill cells that are stationary or not dividing
SAR Clofarabine (Clolar ®)2-chlorine resistant to deamination by adenosine deaminase also a better substrate for deoxycytidine kinase and inhibitors of ribonucleotide reductase – 2’-fluorine substitution on arabinose ring better at inhibiting elongation– 2’-fluoro derivative of fludarabine – increases acid stability (fluorine is a good hydrogen bond acceptor) – resists cleavage of glycosidic bond by bacterial nucleoside phosphorylases (remove sugar from base) – incorporates multiple structural enhancements (2’-fluoro and 2-chloro) making it more potent
MOA Clofarabine (Clolar ®)inhibits DNA synthesis and repair of DNA damage – inhibits ribonucleotide reductase – inhibits DNA polymerases – more effacious than Cladribine and Fludarabine
Metabolism Clofarabine (Clolar ®)converted to corresponding nucleoside triphosphate
SAR Pentostatinantimetabolite (methylene) – ring expanded purine nucleoside – 2’-deoxycoformycin
Metabolism Pentostatineliminated by renal secretion
MOA Pentostatinadenosine deaminase inhibitor – transition state analogue – inhibits adenosine to inosine – and deoxyadenosine to deoxyinosine – inhibits the rate of catabolism and excretion below the rate of synthesis of dATP – inhibit DNA synthesis due to inhibition of ribonucleotide reductase (due to elevated dATP) – interefere with RNA synthesis – increased 5-adenosyl homocysteine (impact on SAM cycle) – triphosphate derivative incorporated into DNA causes strand breaks
MOA Hydroxyurea (Hydrea ®)chelates Fe2+ cofactor of ribonucleotidee reductase – cells arrest at G1-S interface (S-phase specific drug) – inhibits ribonucleotide reductase – rate limiting step in synthesis of DNA – does not affect RNA or protein synthesis

Pyrimidine Antimetabolites

Question Answer
Pyrimidine antimetabolite MOAInhibit the synthesis of essential precurosors of DNA – primarily inhibit synthesis of deoxythymidine monophosphate – inhibit DNA and RNA function – become incorporated into DNA and terminate elongation
SAR Capecitabine (Xeloda ®)N-4-pentoxycarbanoyl-5’-deoxy-5-fluorocytidine – fluoropyrimidine carbamate
Metabolism Capecitabine (Xeloda ®)Metabolized in liver to 5’DFCR (carbosyesterase) - Converted to 5’-DFUR by cytidine deaminase - Converted to 5-FU by thymidine phosphorylase at tumor site – cleaves the 5’-deoxy sugar – inactivated by dihydropyrimidine dehydrogenase (catabolizes 5-FU)
SAR Gemcitabine (Gemzar ®)2’-difluoro analogue of deoxycytidine
MOA Gemcitabine (Gemzar ®)enters cell via nucleoside transporter - Diphosphate (dFdCDP) 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 (DNA strand termination ~ cytarabine).
Metabolism Gemcitabine (Gemzar ®)activated via kinases, deactivated via deaminase
SAR CytarabineD-arabinoside – 2’OH is beta configured instead of alpha as in ribose - resembles deoxyribose and if incorporated into DNA, causes steric hindrance to rotation around the N-1 nucleoside bond and interferes with base pairing
Metabolism Cytarabineactivated by cellular kinases (deoxycytidine kinase) – Ara-CMP to AraCTP competes with dCTP for incorporation into DNA – first kinase step is rate-limiting – deactivated by pyrimidine nucleoside deaminase (cytidine deaminase/uracil route) – Ara-U = uracil arabinoside = arauridine – inactive
Metabolism 5-FUmust be converted intracellularly activated to its deoxynucleotide form – Phosphoribosyltransferase converts 5-FU to 5-fluorouridine monophosphate (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) – Dihydropyrimidine dehydrogenase reduces C-5,6 double bond to inactivate to FBAL
MOA 5-FUconverts to 5-FdUMP that directly inhibits thymidylate synthase from creating dTMP – decreases dTTP induces perturbation of other deoxynucleotides (dATP, dGTP, and dCTP) – inhibition of TS might decrease 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
SAR 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 small so it does not sterically inhibit
5-FU with Leucovorinprovides synergism – 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
MOA Trifluridine/Tipiracil (Lonsurf ®)depends on metabolite – monophosphate (5-trifluoromethyl uridylate) inhibits thymidylate synthase – forms a covalent bond with thymidylate synthase – irreversible thymidylate synthase inhibitor - triphosphate is competitive inhibition of thymidine triphosphate – incorporated into DNA by DNA polymerase – Tipiracil – prevents trifluridine from being metabolized and enhances AUC – thymidine phosphorylase inhibitor
Metabolism Trifluridine/Tipiracil (Lonsurf ®)Metabolized to 5-(trifluoromethyl) uracil by thymidine phosphorylase (inactive)

Microtubule Damaging Agents (M-phase specific)

Question Answer
Vinca alkaloids MOAbind at the dimer of the alpha and beta tubulin subunits near the GTP-binding site – binding of vinca alkaloids blocks GTP binding and prevents tubulin polymerization – at high conc. more binding sites are exposed, and the tubulin polymer disintegrates - leads to unusual cellular pathologies featuring “clumps” or “stars” of tubulin spindle fibers
Vinca alkaloids MetabolismAll vinca alkaloids undergo O4 deacetylation and CYP3A4 modifications before biliary excretion.
Vinca alkaloids SARhave a vindoline and a catarhanthine portion that both bind to tubulin subunitslength of alkyl bridge at C-6’ and C-9’ of cartarhanthine moiety differ – substituents at C-4’ (olefin or tertiary alcohol) – N1 indole nitrogen of vindoline moiety – Acetylation of either hydroxyl group or removal of the C18-methoxycarbonyl group increases activity
Taxanes MOAtaxanes bind to a different β-tubulin site and promote tubulin formation, rather than inhibit it as with the vinca alkaloids and colchicine. - taxane-tubulin binding promotes elongation of microtubules and inhibits disassembly into the mitotic spindle – mitotic phase of cell is disrupted - extensive polymerization causes formation of large structures called asters -
Taxanes SARditerpenoid molecules derived form taxadiene (C20 diterpene) with a C15-taxane core fused to an oxetane ring - divided into “northern” (critical functional groups) and “southern” (taxane) portions – Northern portion gives proper orientation of functional groups – southern gives receptor binding
Metabolism Vincristineis highly metabolized via CYP3A4/5 and patients with liver damage are at risk for liver toxicity.
SAR Paclitaxelbinds at the β-tubulin subunit in a folded-T or “butterfly” shape - paclitaxel is not very water-soluble, therefore, it is administered with a Cremophor-80 vehicle This vehicle can cause hypersensitivity – pretreat with H1-blocker like diphenhydramine and a glucocorticoid
MOA Paclitaxelcatalyze microtubule formation at low temperature without GTP. - binds to beta-tubulin subunit and inhibits disassembly
Metabolism PaclitaxelCYP2C8 6-alpha-hydroxy paclitaxel (inactive), CYP3A4 para hydroxylated benzyl substituents (inactive)
SAR Docetaxelmore water soluble than paclitaxel (less than nab-paclitaxel) and is co-administered with polysorbate 80 - require pretreatment with dexamethasone for 3 days started 1 day before therapy – prevents fluid retention and hypersensitivity
SAR Ixabepilone (Ixempra ®)semisynthetic analogue of epothilone B with a lactam substitution instead of the lactone – decreases metabolism by carbosyesterases
Metabolism Ixabepilone (Ixempra ®)metabolized by liver CYP3A4 to >30 inactive metabolites. – give with a H1 and H2 blocker to prevent hypersensitivity – Vehicle is Cremophor EL


Some patients have a mutant variant of p53 that causes overexpression of MAP4 (microtubule assembly protein) that increases sensitivity to paclitaxel.

Topoisomerase Inhibitors

Question Answer
MOA Epipodophyllotoxinbind to topoisomerase II and have NO effect on microtubular structure or function at usual concentrations – inhibit repair of DNA break – does not bind directly to DNA – enzyme remains bound to free end of broken DNA strand – Cell cycle specific S or early G2 – 4’-OH associated with ability to induce DNA breaks
SAR Epipodophyllotoxinhighly water insoluble need Polysorbate 80 or caster oil – hypersensitivity reaction possible
MOA Podophyllotoxininhibits microtubule assembly and binds to tubulin at site distinct from vinca alkaloid binding.
SAR Podophyllotoxin versus EpipodophyllotoxinsOH compared to glucoside – glucoside associated with inability to inhibit microtubules – B-D-glucopyranosyl substituent – Epimer of C-4 on the C ring – E ring C-4’ = OCH3 compared to OH
SAR TopotecanSubstitutions on ring A enhance water solubility and potency – dimethylamine increases water solubility
Metabolism Topotecanlactone = UDP glucuronyl transferase (O-10-Beta-glucuronide) – Dihydroxyacid = CYP3A4
SAR IrinotecanBasic group on ring A increases water solubility
Metabolism Irinotecana prodrug – SN-38 active metaboliteCarboxylesterase of liver removes the basic prodrug moiety – SN-38 inactivated by glucuronidation-UGT1A1 to SN-38G – undergoes cleavage by bacterial glucuronidases and reenters the circulation through intestinal absorption – Enterohepatic recycling
MOA Camptothecininhibits topoisomerase I by binding to the topoisomerase I-DNA covalent complex – prevent religation of single-stranded breaks – Intercalates with DNA (inserts into bases) and exhibits hydrogen bonding to base pairs and topoisomerase I – binding occurs after single-stranded nick and disrupts geometry for re-ligation – when DNA polymerase collides with topotecan-bound TOP1-DNA complex, a second DNA strand break can occur - S-phase specific – ongoing DNA synthesis is necessary to exhibit activity – does not inhibit restin/metabolically inactive cells – needs active DNA replication and cell division – time-dependent – enhanced when tumor cells are deficient in mutiple forms of DNA repair
SAR Camptothecinalkaloid with a fused 5-ring backbone and pentacyclic lactone – flat ring allows intercalation with DNA – insoluble in water

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