Mechanistic Basis of Chemotherapy 2 Flashcards
What is groove binding?
Spaces between entwined backbones form 2 grooves of different width
Drugs can bind in major or minor groove
Describe Bleomycin
Drugs directly bind on nucleic acids
Major groove
Describe Dactinomycin
Drugs directly bind on nucleic acids
Minor groove binder
Describe the MoA of Bleomycin
Drugs directly bind on nucleic acids
5 N atoms arranged in squared-pyramidal conformation
Binds divalent metals
Molecular O bound by Fe = can produce highly reactive free radicals + Fe(III) = Fe2+ oxidised
Free radicals produce DNA single-strand breaks at 3’-4’ bonds in deoxyribose
Yields free base = cytotoxicity in G2 phase
This is all dependent on oxygen + metal ions
What are 3 drugs known to methylate O6-position of guanine?
Drugs acting directly on nucleic acids
Procarbazine, dacarbazine + temozolomide
Why is O6-methylation of guanine cytotoxic?
Drugs acting directly on nucleic acids
O6-methylguanine preferentially pairs with thymine
= mispair = G-C
= mutation = cell destruction
Describe Procarbazine
Drugs acting directly on nucleic acids
DNA alkylation via radical based mechanism
Methylation takes places via methyl radical
Describe Dacarbazine (IV single dose)/Temozolomide (oral)
Drugs acting directly on nucleic acids
Methylate guanine via diazomethane/ methyl carbocation generated in situ
Describe Temozolomide resistance
Drugs acting directly on nucleic acids
Binds to DNA + flips methylated DNA base out of helix + into catalytic site
Catalyses transfer of methyl group to cysteine residue in active site
Regeneration of guanine + methylation of protein
Efficiently repair chemo-induced DNA damage
Describe Busulfan
Drugs acting directly on nucleic acids
Alkyl sulfonate
Describe Organoplatinum complexes
Drugs acting directly on nucleic acids
Contain electron-deficient metal atom = attracts electron rich DNA nucleophiles (bases of DNA)
Electron-donating ligand (chloride) displaced by H2O
Bifunctional = accept 2 DNA nitrogen
Intrastrand cross-links
= DNA distortion = DNA mechanism unable to correct permanent damage = cell cycle arrest = apoptosis
Describe the chemical MoA of Cisplatin
Drugs acting directly on nucleic acids
Chloride leaves = H2O added
= cisplatin monoaquo form (active)
Chloride leaves = H2O added
= cisplatin diaquo form (active)
2H2O leave = cross-linked DNA
What are examples of organoplatinum complexes?
Drugs acting directly on nucleic acids
Cisplatin, Carboplatin + Oxaliplatin
Protect against kidney toxicity = patients aggressively hydrated + use diuretics
Describe Oxaliplatin/Carboplatin MoA
Drugs acting directly on nucleic acids
Contain electron-deficient metal atom attracts electron rich DNA nucleophiles
Undergoes nonenzymatic conversation via H2O to active derivatives via displacement of labile oxalate ligand
Reactive species formed = covalently bind with macromolecules
Inter + intrastrand crosslinks between 2 adjacent guanines
Inhibit DNA replication + transcription
How antimetabolites work?
Drugs acting on enzymes
Are false substrates for critical nucleotide biosynthesis enzymes
= block the synthesis of DNA nucleotides + reduce tumour growth
What are examples of antimetabolites?
Drugs acting on enzymes
Pyrimidine antagonists = fluorouracil, capecitabine
Purine antagonists = mercaptopurine, thioguanine
Folate antagonists = methotrexate (pemetrexed (methotrexate analogue))
Describe Pyrimidine antagonists MoA
Drugs acting on enzymes
Inhibit thymidylate synthase (TS)
TS converts dUMP to deoxythymidine monophosphate (dTMP)
Inhibition of TS prevents synthesis of thymine (major building block of DNA)
= apoptosis
Mimic dUMP = NO product formed = TS not regenerated = TS irreversibly inhibited
Describe Pyrimidine antagonists in MoA
Drugs acting on enzymes
Fluorouracil = prodrug = converted to active metabolite, 5-FdUMP
= binds + inhibits thymidylate synthase preventing thymine synthesis
Capecitabine = prodrug = converted to active metabolite, 5-FdUMP
Describe Purine antagonist MoA
Drugs acting on enzymes
Inhibit production of purine nucleotides = insufficient amount of purines for DNA synthesis
OR
Directly incorporated into DNA during its synthesis = blocking cell division
Prodrugs
