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I am thinking the role of doxorubicin's pathways in cancers such as leukemia and lymphoma:

  • topoisomerase inhibitor and inhibit DNA activity
  • intercalant - intercalant DNA bases and inhibit DNA activity

I am interested in which of these mechanisms are most relevant in leukemia and lymphoma.

How does doxorubicin work in leukemia and lymphoma?

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    $\begingroup$ isnt it just case of chemotherapy, that is treatment directed to block cell proliferation thus stopping progression of cancer? $\endgroup$ – aaaaa says reinstate Monica Jun 7 '15 at 8:53
  • $\begingroup$ I think you are right! It seems that it is not used without chemotherapy? At least this is right: Used in Combination Cancer Chemotherapy: Leukemia, lymphoma, solid tumors, soft tissue carcinomas. Please, make your comment an answer. $\endgroup$ – Léo Léopold Hertz 준영 Jun 7 '15 at 9:17
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    $\begingroup$ I need to search literatures to answer this. What I know is the first explanation about the mechanism is that it works as an intercalator perhaps because there was not much knowledge about topoisomerases at that time. However, DNA fragmentation was described at the same time. I think interacalators themselves do not have abilities to fragment DNA. It is easier to come up idea that topoisomerase inhibition would be responsible for DNA fragmentation. Having said that, I do not have any knowledge to deny contribution of intercalating effect for anti-cancer effects. $\endgroup$ – 243 Jun 7 '15 at 18:33
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    $\begingroup$ @Masi that is chemotherapy. Chemo is a cocktail of drugs $\endgroup$ – aaaaa says reinstate Monica Jun 7 '15 at 20:28
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Doxorubicin is part of chemotherapy drugs. Most of them are targeting proliferation of cells, e.g. by blocking cell division or DNA replication.

Intercalants and topoisomerase inhibitors are powerful in interfering with DNA replication (not DNA activity). Other chemo drugs might inhibit proper operation of cell division machinery, such as through interfering with cytoskeleton functions.

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  • $\begingroup$ What do you think role between intercalation and topoisomerase inhibition? $\endgroup$ – Léo Léopold Hertz 준영 Jun 7 '15 at 20:51
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I do not have the complete answer, but the links below could be useful.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748742/

The article above says etoposide, which is top II inhibitor and effective against cancer, is not a intercalator.

http://www.ingentaconnect.com/content/ben/cpd/2001/00000007/00000017/art00004?crawler=true

You would find the description below in the article. I just quote their description here.

"As with many other DNA intercalating drugs, topoisomerase II-dependent DNA cleavage is thought to be the critical event responsible for the anticancer activity, [101] whereas free radicalmediated DNA cleavage is probably more closely related to the cardiotoxic side effects [118]."

http://www.degruyter.com/view/j/aiht.2013.64.issue-4/10004-1254-64-2013-2371/10004-1254-64-2013-2371.xml

The chemical, MLN944 (XR5944) described in the link above was designed as Topo inhibitor, but the topo inhibitory effects were less regardless of anti-tumor activity.

There is another type of anti-cancer drugs intercalating into DNA: cisplatin. Interaction of DNA with cisplatin result in formation of DNA adducts. Therefore, it may be difficult to explain anti-cancer effects by only intercalation. For the reference of cisplatin: http://en.wikipedia.org/wiki/Cisplatin

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Doxorubicin and etoposide are both inhibitors of DNA topoisomerase II.

When chromosomes replicate as a cell divides, the helical nature of DNA results in the daughter molecules being tangled up (catenated). Topo II is an amazing enzyme; it binds to DNA, cuts a gap in both strands, and then passes another DNA molecule through the gap. Thus it untangles DNA.

If you inhibit Topo II, two things happen. Firstly, the inhibition usually takes place after the first DNA molecule has been cut. Thus inhibiting Topo II causes severe double stranded DNA damage, which is hard for the cancer cell to repair, and it dies. Secondly, the physical entanglement which remains stops the clean separation of the chromosomes during mitosis. Depending on the Topo II inhibitor in use, this can trigger a cell cycle checkpoint which stops the cell dividing Downes et al, 1994, or can cause the cell to rip the chromosomes to pieces as it tries to separate them anyway. I worked in the same lab as Downes et al, above, and have done this experiment with several Topo II inhibitors, including etoposide and doxorubicin. It's quite spectacular.

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