AT - Platinum Compounds

Question 1

Platinum based drugs are __________ complexes of platinum.

Answer 1

Coordination

Question 2

What is the main dose-limiting side effect of cancer treatment with platinum compounds?

Answer 2

Neurotoxicity, whic causes peripheral neuropathies including polyneuropathy.

Question 3

Platinum drugs act mostl on the adjacent N-_ position of ______, forming a 1,2 intrastrand crosslink. What does the resulting crosslinking cause?

Answer 3

N-7 of guanine.

Causes inhibition of DNA repair and/or DNA synthesis in cancer cells.

Question 4

Platinum drugs cause crosslinking of DNA as:

Answer 4

Monoadducts
Interstrand crosslinks
Intrastand crosslinks
DNA protein crosslinks

Question 5

What is the structure of a platinum based drug we need to know for exam?

Answer 5

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.

Question 6

The loss of what receptor leads to less platinum entering cells, and consequently, drug resistance?

Answer 6

CTR1.

Question 7

Once inside the cell, cisplatin is activated how?

Answer 7

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.

Question 8

The conversion of cisplatin to its activated form, via addition of water molecules, is facilitated by what?

Answer 8

The relatively low chloride concentrations that are found within cells.

Question 9

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?

Answer 9

They are high in sulphur.

Tripeptide glutathione and metallothioneins.

Question 10

Levels of glutathione and metallothionein are relatively high in some platinum-resistant cancer cells, why does this cause resistance?

Answer 10

Mops up the platinum in the cytoplasm before the platinum can enter the nucleus and bind to the DNA.

Question 11

Active export of platinum based chemotherapies from the cell can occur via

Answer 11

Copper exporters ATP7A and ATP7B.

Glutathione S-conjugate export GS-X pump.

Question 12

What are the three ways that tumour resistance to cisplatin and carboplatin can occur?

Answer 12

(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.

Question 13

Once the activated aqua platinum species has entered the nucleus, preferental covalent binding to the nitrogen on position _ of ______ occurs.

Answer 13

N7 guanine

Question 14

The copper exporters ATP7A and 7B are involved with what?

Answer 14

Active export of platinum based drugs from the cytoplasm - resistance to treatment.

Also: Glutathionine S-conjugate export GS-X pump.

Question 15

The major covalen bis-adduct that is formed by the activated aqua species of platinum involves what?

Answer 15

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)

Question 16

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?

Answer 16

Binding to guanines on opposite DNA strands: the inter-strand crosslink.

Question 17

What is the main removal pathway for DNA adducts caused by platinum species?

Answer 17

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.

Question 18

The GS-X pump is involved with what?

Answer 18

Active export of platinum based drugs: glutathionine S-conjugate export GS-X pump.

See also:
Copper exporters ATP7A and ATP7B.

Question 19

ERCC1

Answer 19

Endonuclease protein involved in removal of the DNA adducts caused by platinum based drugs via the process of nucleotide-excision repair (NER).

Can be overexpressed in tumour cells, causing platinum drug resistance by removing adducts before the triggering of apoptotic pathways.

Question 20

NER

Answer 20

Nucleotide excision repair, ERCC1 etc.

Question 21

How can resistance to platinum drugs via increased tolerance to platinum-DNA adducts happen?

Answer 21

1) Loss of DNA mismatch repair
2) Bypassing of adducts by POLB and POLN
3) Though downregulation of apoptotic pathways.

Question 22

What are the major ongoing strategies to circumvent cisplatin and carboplatin resistance? (4)

Answer 22

1. Increased delivery of platinum to tumours.
2. Combination of platinum drugs with molecularly targeted agents.
3. Using novel platinum drugs to target existing resistance mechanisms
4. Platinum resistance modulators.

Question 23

What are examples of the ways that we can increase the delivery of platinum to tumours? (3)

Answer 23

1. Liposomes
2. Co-polymers
3. Intraperitoneal administration for ovarian cancer.

Question 24

We can combine platinum drugs with molecularly targeted agents such as:

Answer 24

Bevac izu mab

Trast uzu mab

Question 25

Novel platinum drugs targeting resistance mechanisms include:

Answer 25

Oxalplatin, picoplatin.

Satraplatin

Question 26

Platinum resistance modulators such as ______ and ________ work on GSH and GST.

Answer 26

TLK286

Decitabine.

Question 27

What is avastin?

Answer 27

Monoclonal antibody (Beva izu mab) that binds with vascular endothelial growth factor (VEGF) (2), which tumour cells release to stimulate blood-vessel growth. IT prevents VEGF from interacting with VEGFR on the endothelial cells that line BVs.