Classical Chemotherapy Flashcards
How might resistance arise to DNA alkylator (Cyclophosphamide) therapy?
Increased expression of glutathione-S-transferase, increased levels of glutathione, increased expression of excision repair enzymes (e.g. DNA glycosylases), changes in drug uptake
How might resistance arise to DNA-platinating agent (Cis-platin) therapy?
Increased repair mechanism for intrastrand crosslinks, increased expression of thiol containing proteins (glutathione, metallothionein)
How might resistance arise to DNA intercalator (Doxorubicin) therapy?
Increased expression of P-glycoprotein which increases drug efflux from cell
How might resistance arise to anti-mitotic (Vincristine, Paclitaxel) therapy?
Increased expression of P-glycoprotein, mutations in tubulin gene
What are the disruptors of microtubule formation?
Vinca alkaloids - Vincristine/Vinblastine
What are the disruptors of microtubule disassembly?
Paclitaxel and Docetaxel
How do Nitrogen mustards cause DNA alkylation?
Interstrand crosslinking via alkylation, of the N7 of Guanine in DNA, from Aziridinium ion. This stops enzymes like DNA polymerase from being able to separate the strands, and thus stopping replication.
How does Cis-platin work?
Chlorine ligands are displaced by water in vivo, water then reacts with biological nucleophiles like N7 of Guanine. The intrastrand crosslinks inhibit DNA polymerase.
How do DNA intercalators/Topoisomerase inhibitors work?
The large planar structure (aromatic scaffolding) in Anthracyclines intercalates into DNA via pi-pi stacking. Hydrogen bonds are also formed to different DNA bases. In turn, they inhibit DNA Topoisomerase II from repairing the double strand break.
How does disruption of microtubule assembly work?
The drug will bind to free alpha-beta tubulin dimers which disrupts the balance between polymerisation and depolymerisation, this leads to dissolution of microtubules, destruction of the mitotic spindle and in cancer cells, death by catastrophic mitosis.
How does disruption of microtubule disassembly work?
The drug stabilises microtubules and prevents their disassembly and cell replication. This disruption leads to the formation of abnormal bundles of microtubuli.
How does 5-FU perform its function in the body?
5-FU is converted into 5-FdUMP in vivo. This then binds with N5–10-methylenetetrahydrofolate and then covalently binds to Thymidylate synthase creating a frozen transition state complex. This prevents the formation of Thymidylate from Uracil, leading to an inhibition of DNA and RNA synthesis and cell death.
What is P-glycoprotein?
A efflux pump in cells that controls the removal of waste. Its overexpression is a method of chemotherapy drug resistance.
