Mechanistic Basis of Chemotherapy 3 Flashcards
Describe MoA of Methotrexate
Drugs acting on enzymes
Compete with 7,8-dihydrofolate for dihydrofolate reductase (DHFR) enzyme
What may happen if use methotrexate + trimethoprim together?
Severe systemic toxicity
Both agents inhibit dihydrofolate reductase
= reduces folate metabolism + increase potential for myelosuppression
Both have potential to cause nephrotoxicity = elevated levels of drugs
Competitive protein binding + reduced tubular secretion + addition of drugs = increases free serum levels of MTX + decreases its excretion
What are microtubules?
Help determine cell shape
Involved in intracellular movement of organelles
During cell division = microtubules form mitotic spindle to facilitate chromosome replication
Instability = continual assembly + disassembly
Tubulin protein
Describe tubulin
Dimer consisting of 2 monomers
What are examples of microtubule targeting drugs?
Drugs acting on structural proteins
Vinca alkaloids
Taxanes
Describe the MoA of vinca alkaloids
Drugs acting on structural proteins
Microtubule destabilising agents
Block tubulin polymerisation by binding at the interface of 2 tubulin heterodimers + inhibit uptake of GPT, which is essential for microtubule elongation
= mitotic spindle cannot be formed
= prevent cells from undergoing mitosis
= unable to replicate
Work in metaphase
Describe the MoA of Docetaxel (taxanes)
Drugs acting on structural proteins
Binds to B-subunit of tubulin
This locks tubulin in place
The microtubule/docetaxel complex does not have ability to disassemble
= adversely effects cell function = microtubules cannot function
Chromosomes rely on microtubules for mitosis
= cancer cell death
Describe MoA of Paclitaxel (taxanes)
Drugs acting on structural proteins
Microtubule stabilising agents
Promote microtubule polymerisation
= mitotic spindle doesn’t breakdown + cells arrested in mitosis
= unable to replicate
Work in metaphase
Describe MoA of Colchicine
Drugs acting on structural proteins
Microtubule targeting drug
Binds at interface to 2 heterodimers at single high affinity site on B-tubulin
Inhibits its target = by binding to colchicine binding site of microtubules
= inhibit polymerisation
= apoptosis
Similar to vinca alkaloids
ALSO destroy tumour vasculature = leave tumour without blood + oxygen
Describe the MoA of Estramustine
Drugs acting on structural proteins
Microtubule targeting drugs
Binds to microtubule-associated protein 4 = dissociation of protein from microtubule = depolymerisation + disassembly, apoptosis + cell death
Describe the cell cycle
G0 = phase where the cell has left the cycle + has stopped dividing
G1 = cell metabolically active + continuously grows
S = DNA replication takes place
G2 = cell growth continues + cell synthesises proteins for division
M = duplicated chromosome separate into 2 daughter nuclei + cell divides into 2 daughter cells, each with full copy of DNA
Describe the cell cycle checkpoints
G1 = start/restriction checkpoint or major checkpoint = ensures everything ready for DNA synthesis
G2/M = DNA damage checkpoint = everything ready to enter M phase + divide
Metaphase-to-anaphase transition = spindle checkpoint = ensure cell is ready to complete cell division
Describe histone deacetylase inhibitors (HDACi)
Miscellaneous
Silence tumour suppressor genes = HDAC
Inhibitors act by modifying gene expression to restore normal differentiation or death programmes of transformed cells
Describe matrix metalloproteinase inhibitors (MMPis)
Miscellaneous
Play important role in metastasis
Play role in breakdown, normal turnover + remodelling of extracellular matrix
Promote tumour growth by degrading matrix barriers + enhancing angiogenesis
Describe how MMPs work
Miscellaneous
Zinc ion interacts with susceptible carbonyl oxygen
Activates peptide bond for hydrolysis
NH of peptide forms hydrogen bond to alanine
Bridging H2O between zinc cofactor + glutamate residue
Bridging H2O acts as nucleophile for hydrolysis
Describe the MoA of Marimastat (MMPi)
Miscellaneous
Mimics the peptide structure of natural MMP substrates + binds to MMPs
= prevent degradation of basement membrane
Inhibitor binds to zinc = blocks activity
