L8 - Anticancer drug design Flashcards
How is the structure of carboplatin different to cisplatin?
More stable leaving groups
What does the different structure of carboplatin mean compared to cisplatin?
Reduced toxicity
- Less neurotoxicity, nephrotoxicity, ototoxicity
How is the structure of oxaliplatin different to cisplatin?
Additional benzene ring
What does the different structure of oxaliplatin mean compared to cisplatin?
Broader activity
Less resistance
What are some barriers that affect activity of platinum-based compounds?
Hydrolysis before DNA crosslinking can occur
Glutathione in cell can react with drug & impact efficacy
What are FOUR methods of resistance against platinum-based compounds?
Loss of DNA mismatch repair [cell does not address any mutations] –> increased drug tolerance
Bypass of DNA adducts [‘merged molecules’] –> increaseed drug tolerance
Decreased apoptosis –> increased drug tolerance
Increased nucleotide-excision repair [fixes problem & allows cancer cell to continue surviving] –> increased removal of drug from DNA
What is the function of topoisomerase I?
Make single-strand DNA breaks
Change linking of topologically constrained DNA by 1
What is the function of topoisomerase II?
Make double-strand DNA breaks
Change linking of topologically constrained DNA by 2
If double-strands cannot join back together/process stalled by drug –> permanent double-strand break which is considered cytotoxic
How do vinca alkaloids act on microtubules?
Bind to polymerising end –> prevent elongation of microtubule
–> Prevents anaphase –> no cell division
How do taxanes act on microtubules?
Stabilise microtubule –> prevent shortening & depolymerisation
–> Prevents anaphase –> no cell division
Why does combination chemotherapy exist?
Different mechanisms offset acquired drug resistance
Different range of adverse effects that are ‘less’ & more manageable
What are THREE limitations regarding effectiveness of chemotherapy?
Poor intrinsic selectivity for cancer cells [all cells that are dividing are affected]
Limited drug distribution –> poor blood flow in tumours; low drug diffusion
Resistance mechanisms [intrinsic &acquired]
What is the main difference between methotrexate & pemetrexed?
Methotrexate acts on one enzyme (dihydrofolate reductase) in folate synthesis
Pemetrexed acts on multiple enzymes in the folate synthesis pathway –> more efficacious
How is fluorouracil’s tumour selectivity improved?
Using prodrug capecitabine
Final step of conversion from capecitabine to fluorouracil occurs in tumour cells themselves –> selective treatment
Where does significant normal tissue toxicity occur in?
Cycling cells
Hair –> alopecia
GI tract –> diarrhoea
Bone marrow –> myelosuppression, bone pain
