Anticancer drugs Flashcards
Which anticancer drugs bind covalently to DNA?
- Nitrogen mustards
- Nitrosureas
- Aziridines
- Platinum compounds
How do nitrogen mustards produce their effect?
Covalently link an alkyl group to chemical moieties in nucleic acids and proteins
What side chains does nitrogen mustard have?
Two chloroethyl side chains
How does nitrogen mustard attack guanine?
One of the side chains undergoes cyclisation and forms an immonium ion intermediate, which is highly reactive and attacks the N7 group of guanine
What is the result of nitrogen mustard covalently binding to guanine?
- Cross-link between DNA strands
- Cross-link between bases in same strand
- Inhibition of DNA replication and gene transcription
What happens if the second nitrogen mustard side chain reacts with H2O instead of another guanine?
Monoalkylated guanine is produced
What does monoalkylated guanine do?
Forms an anomalous base pair with thymine
How do nitrogen mustards cause strand scission?
- Monoalkylated guanine is recognised by DNA repair systems
2. Strand scission occurs when cell attempts to repair alkylated DNA
Which side reactions of nitrogen mustards contribute to the general toxicity of these drugs?
Reactions with other nucleophilic groups in DNA, RNA and protein
What is phenylalanine a precursor of?
Melanin
Where does melphalan accumulate?
Melanomas
What side chain do nitrosureas have?
Chloroethyl side chain (at least one)
What groups do nitrosureas covalently add?
Alkyl or carbamoyl moieties
What are the preferred sites of attack of nitrosureas?
N7 and O6 positions of guanine
How is mitomycin C activated?
Chemical or enzymatic reduction of the quinone group
What is the principal coordinate of cisplatin action?
Intra-strand cross-link formed by the binding of the drug to two neighbouring guanines
What is cisplatin-induced intrastrand cross-linking thought to induce?
Major bending of DNA duplex towards major groove
How does cisplatin inhibit DNA replication?
- Major bending of DNA duplex towards major groove
- Physical block provided by platinum adduct on template strand
- Inhibits DNA polymerases
How do anthracyclines kill tumour cells?
- Intercalate in DNA
2. Generation of free radicals due to presence of hydroxyquinone moiety
What is the effect of anthracycline free radical damage?
- Attack DNA causing DNA cleavage
2. Lipid peroxidation
Where is lipid peroxidation most dangerous?
In cardiac tissue
Basis of severe side effects of anthracycline therapy
How do antimetabolites interfere with production of DNA and RNA?
- Inhibition of normal precursor production
2. Substitution of purines and pyrimidines in normal nucleic acid synthesis
What is administered with methotrexate to salvage normal tissues?
Leucovorin
Why is leucovorin unaffected by methotrexate?
Does not require dihydrofolate reductase for its conversion to tetrahydrofolate
Why does leucovorin reduce methotrexate toxicity only in normal cells
Allows for a small amount of pyrimidine synthesis, which is enough for normal cells but not for tumour cells, which have a much higher tetrahydrofolate requirement
What is the role of topoisomerases?
Permit selected regions of DNA to become sufficiently untangled to allow replication and transcription
What is the major component of microtubules?
Tubulin dimer
Protein complex containing two non-identical α and β subunits
Arranged head-to-tail in linear protofilaments
How many tubulin protofilaments form a microtubule?
13
Which end of the microtubule is usually anchored in an organising centre?
The minus end
What occurs at the plus end of the microtubule?
Growth or shrinkage of microtubule
How can the response of breast cancer to hormonal therapy be predicted?
Amounts of oestrogen and progesterone receptors in tumour tissue
Where does tamoxifen exert oestrogen agonist effects?
Bone and uterus
Which enzyme converts androgen precursors to estradiol?
Aromatase
What is the purpose of aromatase inhibitors in post-menopausal women?
Prevent formation of oestrogen in peripheral tissues such as muscle or fat
What is chemical castration?
Biochemical inhibition of testosterone production
What increases the risk of cardiac dysfunction from trastuzumab use?
Coadministration with anthracyclines
What is bevacizumab administered with to treat metastatic colorectal cancer?
5-fluoro-uracil
Describe the structure of the EGFR
- Transmembrane glycoprotein
- Extra-cellular ligand-binding domain
- Intracellular RTK domain
How is the EGFR activated?
Ligand-binding causes autophosphorylation and increased biological activity
What type of activity does the BCR-ABL protein have?
Tyrosine kinase activity
