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Topoisomerase II and leukemia

Maryjean Pendleton1, R Hunter Lindsey, Carolyn A Felix

  • 1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.

Annals of the New York Academy of Sciences
|February 6, 2014
PubMed

Insights

Type II topoisomerases are crucial enzymes targeted by anticancer drugs. These drugs can cause DNA breaks, leading to specific leukemias, but new strategies may separate therapeutic effects from leukemogenic potential.

Area of Science:

  • Molecular Biology
  • Genetics
  • Pharmacology

Background:

  • Type II topoisomerases regulate DNA topology, essential for cellular processes.
  • These enzymes are targeted by widely used anticancer drugs (topoisomerase II poisons).
  • Topoisomerase II poisons induce DNA breaks by stabilizing enzyme-cleaved DNA complexes.

Purpose of the Study:

  • To elucidate the mechanism of type II topoisomerase and topoisomerase II poison action.
  • To investigate how topoisomerase II poisons induce chromosomal breaks and lead to leukemia.
  • To explore strategies for dissociating the anti-cancer effects of these drugs from their leukemogenic potential.

Main Methods:

  • Review of existing literature on type II topoisomerases, their inhibitors, and associated leukemogenesis.
  • Analysis of drug mechanisms and their interaction with DNA and topoisomerase II.
  • Examination of chromosomal rearrangements linked to specific topoisomerase II poisons and leukemia types.

Main Results:

  • Topoisomerase II poisons, including etoposide, doxorubicin, and mitoxantrone, are effective anticancer agents but carry risks.
  • Drug-induced DNA breaks are implicated in specific leukemias, such as acute myeloid leukemia with 11q23 rearrangements (etoposide, doxorubicin) and acute promyelocytic leukemia with t(15;17) (mitoxantrone, epirubicin).
  • Naturally occurring topoisomerase II-active compounds in diet may also contribute to infant leukemias.

Conclusions:

  • Understanding the dual action of topoisomerase II poisons is critical for cancer therapy.
  • Further research is needed to develop safer topoisomerase II-targeting anticancer drugs.
  • Strategies to mitigate the leukemogenic potential of these essential drugs are a key area for future investigation.
Keywords:
acute myeloid leukemiaacute promyelocytic leukemiaanticancer drugchromosomal translocationtopoisomerase II poison

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