AT - Platinum Compounds Flashcards
Platinum based drugs are __________ complexes of platinum.
Coordination
What is the main dose-limiting side effect of cancer treatment with platinum compounds?
Neurotoxicity, whic causes peripheral neuropathies including polyneuropathy.
Platinum drugs act mostl on the adjacent N-_ position of ______, forming a 1,2 intrastrand crosslink. What does the resulting crosslinking cause?
N-7 of guanine.
Causes inhibition of DNA repair and/or DNA synthesis in cancer cells.
Platinum drugs cause crosslinking of DNA as:
Monoadducts
Interstrand crosslinks
Intrastand crosslinks
DNA protein crosslinks
What is the structure of a platinum based drug we need to know for exam?
Platinum has 4 attached atoms/moietys.
Two NH3 on the left.
One Cl top right.
One H2O+ on bottom right.
Binds to the guanine N7 position.
The loss of what receptor leads to less platinum entering cells, and consequently, drug resistance?
CTR1.
Once inside the cell, cisplatin is activated how?
The addition of water molecules to form a chemically reactive aqua species. This is facilitated by the relatively low chloride concentrations that are found within cells.
The conversion of cisplatin to its activated form, via addition of water molecules, is facilitated by what?
The relatively low chloride concentrations that are found within cells.
When in the cytoplasm, why does the activated aqua species of cisplatinum preferentially react with those cellular contents which have many cysteine or methionine amino acids?
They are high in sulphur.
Tripeptide glutathione and metallothioneins.
Levels of glutathione and metallothionein are relatively high in some platinum-resistant cancer cells, why does this cause resistance?
Mops up the platinum in the cytoplasm before the platinum can enter the nucleus and bind to the DNA.
Active export of platinum based chemotherapies from the cell can occur via
Copper exporters ATP7A and ATP7B.
Glutathione S-conjugate export GS-X pump.
What are the three ways that tumour resistance to cisplatin and carboplatin can occur?
(1) Loss of CTR1 - a mechanism by which they enter the cell = less platinum in cell.
(2) Elevated levels of glutathionine and metallothioneins - platinum based drugs react preferentially with these species as they have high sulphur levels.
(3) active export via copper exporters ATP7A and 7B and glutathione S-conjugate export GS-X pump.
Once the activated aqua platinum species has entered the nucleus, preferental covalent binding to the nitrogen on position _ of ______ occurs.
N7 guanine
The copper exporters ATP7A and 7B are involved with what?
Active export of platinum based drugs from the cytoplasm - resistance to treatment.
Also: Glutathionine S-conjugate export GS-X pump.
The major covalen bis-adduct that is formed by the activated aqua species of platinum involves what?
Adjacent guanines on the same strand of DNA (the intra-strand crosslink).
A minor adduct involves binding to guanines on opposite DNA strands (the inter-strand crosslink)
Once the activated aqua platinum species has entered the nucleus, preferential covalent binding to the nitrogen on position 7 of guanine occurs. The major covalent bis-adduct that is formed involves adjacent guanines on the same strand of DNA (the intra-strand crosslink).
What is a minor adduct that is also formed?
Binding to guanines on opposite DNA strands: the inter-strand crosslink.
What is the main removal pathway for DNA adducts caused by platinum species?
Nucleotide-excision repair (NER): increased NER, especially through increased activity of the endonuclease protein ERCC1 (excision repair cross-complimenting 1) can occur in tumours, and can lead to platinum drug resistance - as the adducts are removed before apoptotic signalling pathways are triggered.
