AT L2 Platinums

Question 1

How are platinums activated

Answer 1

addition of water molecules inside the cell to form a chemically reactive aqua species

Question 2

3 mechanisms of drug resistance that stop platinums reaching the DNA

Answer 2

1. Loss of CTR1 Cu transporters - platinums might enter using this transporter
2. High levels of glutathione or methalothioneins mops up activated platinum
3. Active export through ATP7A/7B Cu exporters and GS-X pump

Question 3

2 mechanisms of drug resistance once plat is DNA bnound

Answer 3

1. Increased nucleotide excision repair
2. increase tolerance of platinum DNA adducts by

a) ingnoring the damage - loss of DNA mismatch repair
b) bypassing adducts of polymerase beta and mew
c) down-regulate apoptotic pathway

Question 4

mode of action of platinums

Answer 4

preferential covalent binding at N7 of G. Forms major intrastrand and minor interstrand crosslinks.

Must generate significant distortion as small molecule manages to bridge across two strands

Question 5

Strategies to circumvent resistance: increasing delivery of platinum to the tumour 3

Answer 5

liposomes
copolymers
intreaperritoneal administration for ovarian cancer

Question 6

Strategies to circumvent resistance: e.g. of combiing plat with molecularly targeted agents

Answer 6

combine with trastuzumab (her2) or bevacizumab (vegf)