Cancer Chemotherapeutics

nelso418's version from 2017-04-26 05:29


Question Answer
Alkylating agentsextant DNA polymers and inhibit DNA replication.
Antimetabolitestarget rate-limiting enzymes in de novo synthesis of DNA
Inhibition of rate-limiting enzymes is an efficient way to shut down a metabolic pathway
Some agents also promote incorporation of incorrect nucleotides into DNA

Nitrogen Mustards

Question Answer
Nitrogen Mustards MOAAlkylation of N7 of guanine leads to several major effects – The alkylated N7 guanine mispairs with thymine – Alkylation of N7 of guanine can cause lability, leading to ring-opening and base excision – The second bis-(2-chloroethyl) ring opening forms another DNA adduct. Nitrogen mustards alkylate in a non-specific fashion leading to DNA damage that is not easily repaired in cancer cells
SAR Nitrogen Mustardsactivated by hepatic enzymes – substituents on the key nitrogen impact lipophilicity, activity, and availability – Electron dense groups enhance the stability and cytotoxic killing – Aminos and substituted phenyl groups enhance the oral availability 
Resistance to Nitrogen Mustards (alkylating agents)Resistance occurs d/t modulation of cellular levels of drug (transport) and drug target – Increased intracellular conc. Of nucleophilic substances (glutathione) that attack the carbonium cation – defects in apoptosis d/t mutations in p53 – Cancer cell has proficient DNA repair (nucleotide excision repair, mismatch, O6-alkyl, methyl guanine methyltransferase (MGMT))
Metabolism – Mechlorethamine HCl (Mustargen ®)HCl salt stable in absence of water – Enters cell by active transport for choline - Sodium thiosulfate can be used to inactivate aziridine
SAR - Mechlorethamine HCl (Mustargen ®)contains 2 Cl atoms attached to ethyls
SAR Chlorambucil (Leukeran ®)electron withdrawing effect of aromatic ring decreases nucleophilic activity of nitrogen – more stable and selective for tumor cells
Metabolism Chlorambucil (Leukeran ®)parent compound and metabolite (phenylacetic acid mustard) are active – fatty acid metabolism B-oxidation – Excreted as monohydroxy and dihydroxy inactive derivatives (spontaneous reaction)
SAR Bendamustine (Treanda ®)benzimidazole ring
Metabolism Bendamustine (Treanda ®)CYP1A2 – inactivate by hydrolysis or adduct formation with macromolecules (sulfhydryl interactions) - activity due to parent compound – contcentration of metabolites low – Active metabolites – oxidation (gamma-hydroxy and N-desmethyl) –
MOA Bendamustine (Treanda ®)Cancer cell death due to DNA damage leading to apoptosis (minor outcome) and disruption of normal cell division (mitotic catastrophe – the major outcome) – DNA cross-links slowly repaired – activates base excision repair – impairs physiological arrest for cells at mitotic checkpoints – leads to mitotic catastrophe rather than apoptosis – lacks cross resistance with other classical alkylators
SAR Cyclophosphamid (Cytoxan ®)oxazaphosphorine ring – phosphoramide linakge decreases the nucleophilicity of the nitrogen mustard
Metabolism Cyclophosphamid (Cytoxan ®)Prodrug – oxidation by CYP2B to 4-hydroxycyclophosphamide (90%)(oxidized to 4-ketocyclophosphamide) – Tautomerization (nonenzymatic) to aldophosphamide (oxidized ot carboxyphosphamide) – Nonenzymatic cleavage to Acrolein (uro and nephron toxicity can cause hemorrhagic cystitis) – Phosphoramide mustard cyclizes to aziridinium ion – cyclophosphamide can be converted to chloroacetaldehyde by 3A4 (highly nephrotoxic and neurotoxic, causes glutathione depletion)
SAR Ifosfamide (Ifex ®)differs from cyclophosphamide in spacing of 2-chloroethyl groups (further apart on different atoms) – spacing gives increased water sol., changes spectrum of activity and tox.
Metabolism Ifosfamide (Ifex ®)3A4, slower than cyclophosphamide, more oxidation of chloroethyl side chains into --chloroacetaldehyde to chloroacetic acid
SAR Mesna (Mesnex ®)Mercaptoethanesulfonic acid
Metabolism Mesna (Mesnex ®)Oxidized to dimesna (intert), Dimesna is filtered, reabsorbed and secreted in the tubules (about 1/3 is reduced back to mesna by glutathione reductase) – mesna and dimesna are too hydrophilic to passively cross biological membranes so do not inactivate ifosfamide at the cellulare level – mesna binds to urotoxic metabolites and inactivates


Question Answer
SAR Nitrosoureasare unstable and their mechanism depends on decomposition into reactive electrophiles – the 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 – highly carcinogenic and mutagenic – profound and delayed myelosuppression to 6 weeks
MOA Nitrosoureasextremely unstable and decompose in the aqueous environment of the cell – first, a proton is abstracted from the urea (depicted in red), which undergoes an SN2 reaction to form an oxazolidinone ring – this involves a chloride leaving group – the unstable oxazolidinone ring rearranges into vinyl diazotic acid and isocyanate (carbamoylates lysine), which spontaneously decompose into gaseous intermediates (CO2 and N2) – Acetaldehyde and vinyl carbocation alkylate DNA (active). Pathway A results in production of reactive electrophiles that alkylate DNA. Pathway B results in a carbamoylating species (lysine) and a carbocation that alkylates DNA
SAR Carmustine (BiCNU, Gliadel ®)contains 2 chloroethyl groups - 1,3-bis(chloroethyl)-1-nitrosourea – lipid soluble, crosses BBB, unionized
SAR Lomustine (CCNU ®)1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea – lipid soluble, crosses BBB effectively, stable enough for oral
SAR Streptozocin (Zanosar ®)methylnitrosourea of 2-deoxyglucose – D-glucopyranose (water soluble carbohydrate and confers islet cell specificity) – lacks the highly reactive 2-chloroethyl moiety – decreases carbamoylation activity (less active DNA alkylation agent
Metabolism Streptozocin (Zanosar ®)methylnitrosourea portion – forms a methyl carbonium ion (monofunctional alkylating agent) and alkylates DNA and inhibits new DNA synthesis

Cisplatin and Platinum agents

Question Answer
MOA Platinum agentsfeature a square planar Pt(II) complex – it is electron deficient, but draws electrons from chloride ions – the neutral platin agent enters the tumor cell – It is a good electrophile and is attacked by cellular water and chloride leaves – antitumor activity correlates with cross-linking of DNA – the metal is a good electrophile to form adducts with two DNA base pairs – intrastrand cross-links occur mostly with guanine-guanine dinucleotides (60-65%) – Intrastrand cross links also occur with guanine-adenine nucleotides (25-30%) – less frequently form interstrand cross-links between guanine and adenine (1-3%)
MOA Cisplatin (Platinol ®)inhibits DNA replication and transcription – leads to DNA breaks and mutations – Recognition by p53 can lead to cell cycle arrest and apoptosis by many mechanisms – adducts form major distortion to the DNA double helix – disrupts hydrogen bonding of base pairs
SAR Amifostine (Ethyol ®)Thiophosphate cytoprotective agent
Metabolism Amifostine (Ethyol ®)Prodrug – alkaline phosphatase dephosphorylates in tissue to active free thiol metabolite – rapidly metabolized to active free thiol - free thiol detoxifies cisplatin (sulfhydryl antioxidant) – reactive metabolites of cisplatin (hydroxylated) – reactive oxygen species generated by exposure to radiation therapy
Selectivity Amifostine (Ethyol ®)Ability to differentially protect normal tissues versus tumor – higher capillary alkaline phosphatase activity – higher pH – better vascularity of normal tissues relative to tumor tissue (preferential takeup by normal tissues)
SAR Oxaliplatin (Eloxatin ®)forms 1,2-diaminocyclohexane – oxalate is a leaving group
Metabolism Oxaliplatin (Eloxatin ®)Less dependent on CRT1 copper (II) transporter for intracellular access – Nonenzymatic conversion to active derivatives via displacemnt of labile oxalate – form monoaquo and diaquo DACH platinum – form monochloro and dichloro DACH platinum – Inter and intra strand Pt-DNA cross-links
MOA Oxaliplatin (Eloxatin ®)inhibit DNA replication and transcription – conformation changes differ and are less likely to be recognized by MMR proteins – DACH extends into the major groove of DNA-hydrophobic DNA intrusion contributes to cytotoxicity

Thymidylate Cycle

Question Answer
1Dihydrofolate (DHF) is reduced by DHFR to tetrahydrofolate (THF)
2tetrahydrofolate (THF) is converted to N5, N10 – THF by serine hydroxy methyltransferase (SHMT)
3tetrahydrofolate (THF) and deoxyuridylate (dUMP) bind to the active site of thymidylate synthase
4a proton is abstraced by cofactor N10 and a one carbon transfer to deoxyuridylate (dUMP) takes place
5deoxythymidylate = thymidylate (dTMP) is formed and DHF is reduced to THF

Folate Antimetabolites

Question Answer
Folate Antimetabolitesprevent biosynthesis or utilization of cellular metabolites – are “false metabolites” or look like normal substrates for nucleotide biosynthesis – almost all clinically useful agents are releated to metabolites and cofactors for nucleic acid syntheis – Cell-phase specific agents (S-phase)
Folate Antimetabolites MOAinhibit key enzymes – competitive inhibitor (active, site resembles substrate or cofactor) – allosteric inhibitor (end product of biosynthetic pathway, pathway under feedback control) – Incoroporated in place of a normal cellular substituent in place of DNA or RNA and inhibit normal function – many arrest chain elongation – may inhibit a number of different enzymes
MOA Methotrexatepotent folic acid antag. That is structurally similar to 7,8-dihydrofolate (DHF) – successfully competes with DHF for the DHFR active site – 7,8-DHF concentration builds up in the cell – high 7,8-DHF concentrations cause feedback inhibition of thymidylate synthase – also effective at inhibiting glycine amide ribonucleotide formyltransferase (GAR) – inhibit de novo purine synthesis – GARFT and AICAR
SAR Methotrexate7,8 double bond – N-10 methyl group (an antag of DHFR but does not have antitumor activity) – 4-amino group (increases basicity of pteridine ring at N1, increased affinity for DHFR and increases influx into cell 100x) – the result of these difference is that methotrexate is positioned 180 degrees inverted relative to the orientation of 7,8-DHF – also not a substrate for DHFR – it inhibits the active site
Metabolism MethotrexateFolyl polyglutamage synthase (FPGS) condenses glutamates to folic acid species – facilitates intracellular accumulation of folates – monoglutamates are freely transportable into and out of cells – up to 6 glutamyl residues are added to MTX – allows selective intracellular retention of these large anionic molecules – more efficient in tumor cells, which promotes selective toxicity – Hydrolase converts polyglutamate forms of MTX – MTX-polyglutamte is converted to MTX before extracellular transport. 90% of the drug is excreted renally as parent metabolite
Leucovorina chemoprotectant drug taken with methotrexate to ameliorate toxicity to normal cells
Leucovorin SARTHF analogue, the C5,6 and C7,8 positions are reduced
MOA Leucovorinenters cell by carrier mediated transport – converted to other THF coenzymes – does not require DHFR for activation, bypasses DHFR Step – may inhibit the transport of methotrexate into the cells and stimulate its efflux
MOA PermetrexedBetter substrate for FPGS than MTX; greater intracellular accumulation of poly-Glu metabolites – multi-targeted antifolate – inhibits TS (primary site), DHFR, GARFT – multi-targeting allows for activity in tumors that develop mutations in or overexpress thimydylate synthase
SAR PermetrexedPyrrole derivatives of THF; N5 or N8 of pteridine ring is replaced and N10 bridge between pteridine and benzoate Pteridine ring replaced with smaller 5-membered nitrogen heterocycle (pyrrole), N10 replaced with methylene bridge – better transport into tumor – different spectrum of enzyme inhibition – binds strongly to thymidylate synthase and GAR transformylase
SAR Pralatrexate10-deaza analog of MTX, propargyl group substitution (10 position propyl with a triple bond)
MOA Pralatrexateprimarily targets DHFR
Metabolism Pralatrexate10-fold higher FPGS polyglutamation efficacy