Topoisomerase II and leukemia.
Type II topoisomerases are essential enzymes that modulate DNA under- and overwinding, knotting, and tangling. Beyond their critical physiological functions, these enzymes are the targets for some of the most widely prescribed anticancer drugs (topoisomerase II poisons) in clinical use. Topoisomerase II poisons kill cells by increasing levels of covalent enzyme-cleaved DNA complexes that are normal reaction intermediates. Drugs such as etoposide, doxorubicin, and mitoxantrone are frontline therapies for a variety of solid tumors and hematological malignancies. Unfortunately, their use also is associated with the development of specific leukemias. Regimens that include etoposide or doxorubicin are linked to the occurrence of acute myeloid leukemias that feature rearrangements at chromosomal band 11q23. Similar rearrangements are seen in infant leukemias and are associated with gestational diets that are high in naturally occurring topoisomerase II-active compounds. Finally, regimens that include mitoxantrone and epirubicin are linked to acute promyelocytic leukemias that feature t(15;17) rearrangements. The first part of this article will focus on type II topoisomerases and describe the mechanism of enzyme and drug action. The second part will discuss how topoisomerase II poisons trigger chromosomal breaks that lead to leukemia and potential approaches for dissociating the actions of drugs from their leukemogenic potential.
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.
Maryjean
M
Pendleton
R Hunter
RH
Lindsey
Carolyn A
CA
Felix
David
D
Grimwade
Neil
N
Osheroff
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics*; D019457:Chromosome Breakage; D003474:Curcumin / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000502:physiology*; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000201:enzymology / Q000235:genetics*; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000235:genetics; D014178:Translocation, Genetic / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D002392:Catechin; C045651:epigallocatechin gallate; D019833:Genistein; D004250:DNA Topoisomerases, Type II; D003474:Curcumin
acute myeloid leukemia; acute promyelocytic leukemia; anticancer drug; chromosomal translocation; topoisomerase II poison