Targeting DNA topoisomerase II in cancer chemotherapy

Question 1

Drugs which target TOP2 are divided into how many classes?

Answer 1

Two.
Those that lead to increases in levels of TOP2-DNA covalent complexes - TOP poisons.

Those that inhibit TOP2 catalytic activity but do not generate increases in the levels of TOP2. Thought to kill cells via the elimination of the essential enzymatic activity of TOP2 and thus are termed - TOP catalytic inhibitors.

Question 2

How do TOP poisons work?

Answer 2

Lead to increases in levels of TOP2-DNA covalent complexes.

Question 3

How do TOP catalytic inhibitors work?

Answer 3

Thought to kill cells via the elimination of the essential enzymatic activity of TOP2.

Question 4

What are the cell physiology effects of TOP poisons?

Answer 4

1. Blocked transcription and replication.
2. DNA strand breaks are linked to proteins, as expected.
3. Cells subsequently commit apoptosis, and etoposide is an agent commonly used to study apoptotic processes.

Question 5

Most clinically active drugs that target TOP2 work via

Answer 5

Trapping an enzyme intermediate termed the covalent complex. The principal action of the TOP2-targeting drugs is to generate enzyme-mediated DNA damage.

Question 6

Anthracycline use is limited by

Answer 6

Cardiotoxicity, thought that TOP2 poisons that target TOP2B might contribute more to cardiotoxicity than TOP2a isoform targeters.

Question 7

Camptothecins target

Answer 7

TOP1

Question 8

How do Camptothecins work?

Answer 8

They intercalate between the -1 and +1 bases of the DNA in the tertiary complex, in which the -1 base is the nucleotide that is covalently bound to TOP1.

Contacts via H-bonds etc.

Question 9

TOP2 poisons can be further divided into what?

Answer 9

Intercalating: Doxorubicin and other anthracyclines, motoxantrone, mAMSA.

Non-intercalating: Epipodophyllotoxins, etoposide and teniposide, and fluoroquinolones.