How does Topoisomerase II inhibition affect cancer cells?

Question

Topoisomerase II poisons represent some of the most important and widely prescribed anticancer drugs currently in clinical use. These drugs encompass a diverse group of natural and synthetic compounds that are commonly used to treat a variety of human malignancies. At the present time, six topoisomerase II-targeted anticancer agents are approved for use in the United States, and additional drugs are prescribed elsewhere in the world. These agents all act as traditional topoisomerase II poisons and function primarily by inhibiting enzyme-mediated DNA ligation.

Briefly describe what TopoII does and how it works. Explain what "inhibiting enzyme-mediated DNA ligation" means.

My thoughts for the first question are Type II topoisomerases cut both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils. They use the hydrolysis of ATP. It changes the linking number of circular DNA by ±2. After the ends are cut, the ends of the DNA are separated and a second DNA duplex is passed through the break. The cut DNA is re- ligated. This allows the enzyme to increase or decrease the linking number of a DNA loop by 2 units. It also promotes chromosome disentanglement. Inhibiting enzyme-mediated DNA ligation means that it prevents the enzymes are not allowed to ligate. This is prevented by not allowing the formation of a phosphodiester bond.

Cancer cells grow much more rapidly than most cells in the body. What would be the consequence of "inhibiting enzyme-mediated DNA ligation" and why might this be particularly deleterious in cancer cells?

I am really unsure on this one.

I have looked at the Wikipedia answers to this question and they are wrong.

Answer 1

First question:

In general, topoisomerases are enzymes that relieve supercoiling in DNA strands and tangling in chromosomes. Type II topoisomerases is special among eukaryotic topoisomerases, considering they use divalent metal ions and ATP hydrolysis in their active site. The enzyme cuts both strands of the DNA helix simultaneously (double strand break) in order to manage DNA tangles and supercoils. It changes the linking number of circular DNA by ±2. After the ends are cut, the ends of the DNA are separated and a second DNA duplex is passed through the break. The cut DNA is re- ligated. This allows the enzyme to increase or decrease the linking number of a DNA loop by 2 units. Inhibiting enzyme-mediated DNA ligation means that it prevents the enzyme to re-ligate the DNA strand after it is cut. In other words, the prevention of a phosphodeister bond between nucleotides.

Second question:

In normal cells, DNA topoisomerase II plays several vital roles, mainly to relieve DNA tangles and coiling. This is done by generating "transient double strand breaks" in the DNA strand, which can sometimes cause harmful translocations and damage. Damage of this type is linked to certain specific types of leukemia. This intrinsically "harmful" quality of DNA topoisomerase II can be exploited in cancer cells due to their high replication rate . Certain cancer drugs, such as etoposide, act by altering the active site of topoisomerase II, preventing (inhibiting) the enzyme from ligating cleaved DNA molecules, causing permanent DNA breaks (and inhibiting replication). The fast replication rate of cancer cells ensures that there are large amounts of the enzyme present in the cell, increasing the effectiveness of any Topoisomerase II poisons. However, this drug can also act against some other types of tissues with large amounts of Topoisomerase II, such as cardiac tissue. Also, cancer cells are constantly in a growing/replication cycle, so they exhibit large amounts of the isoform Topoisomerase IIa, the type that is most likely to produce permanent and detrimental DNA breaks.

Source:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2647315/