Considerable plasma levels of a cytotoxic etoposide metabolite in patients undergoing high-dose chemotherapy

Stremetzne, S.; Jaehde, Ulrich; Kasper, Rachel; Beyer, Jörg; Siegert, W.; Schunack, Walter

doi:10.1016/s0959-8049(97)00087-7

Cited by 14 publications

(15 citation statements)

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“…Because the sensitivity of EPR spectroscopy is relatively low, we used higher concentrations of etoposide. Nevertheless these concentrations were clinically relevant because etoposide plasma levels of 100 g/ml (180 M) can be achieved in patients receiving high doses of this drug (Stremetzne et al, 1997). Under our experimental conditions, the concentration of etoposide phenoxyl radicals accumulated inside CD34…”

Section: Discussionmentioning

confidence: 82%

Myeloperoxidase-Dependent Oxidation of Etoposide in Human Myeloid Progenitor CD34+ Cells

Vlasova¹,

Wei²,

Goff³

et al. 2011

Molecular Pharmacology

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Etoposide is a widely used anticancer drug successfully used for the treatment of many types of cancer in children and adults. Its use, however, is associated with an increased risk of development of secondary acute myelogenous leukemia involving the mixed-lineage leukemia (MLL) gene (11q23) translocations. Previous studies demonstrated that the phenoxyl radical of etoposide can be produced by action of myeloperoxidase (MPO), an enzyme found in developing myeloid progenitor cells, the likely origin for myeloid leukemias. We hypothesized, therefore, that one-electron oxidation of etoposide by MPO to its phenoxyl radical is important for converting this anticancer drug to genotoxic and carcinogenic species in human CD34ϩ myeloid progenitor cells. In the present study, using electron paramagnetic resonance spectroscopy, we provide conclusive evidence for MPO-dependent formation of etoposide phenoxyl radicals in growth factor-mobilized CD34 ϩ cells isolated from human umbilical cord blood and demonstrate that MPO-induced oxidation of etoposide is amplified in the presence of phenol. Formation of etoposide radicals resulted in the oxidation of endogenous thiols, thus providing evidence for etoposide-mediated MPO-catalyzed redox cycling that may play a role in enhanced etoposide genotoxicity. In separate studies, etoposide-induced DNA damage and MLL gene rearrangements were demonstrated to be dependent in part on MPO activity in CD34 ϩ cells. Together, our results are consistent with the idea that MPO-dependent oxidation of etoposide in human hematopoietic CD34 ϩ cells makes these cells especially prone to the induction of etoposide-related acute myeloid leukemia.

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Section: Discussionmentioning

confidence: 82%

Myeloperoxidase-Dependent Oxidation of Etoposide in Human Myeloid Progenitor CD34+ Cells

Vlasova¹,

Wei²,

Goff³

et al. 2011

Molecular Pharmacology

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“…A relationship between several other MLL translocation breakpoints and DNA topoisomerase II in vitro cleavage sites induced by etoposide and these etoposide metabolites also was observed (17). The metabolites are of further interest because both adult and pediatric pharmacokinetic data suggest increasing plasma levels of the potentially genotoxic catechol from the first day to the last day of multipleday bolus etoposide infusions (35,36). In the MLL and AF-4 substrates shown in Fig.…”

Section: Discussionmentioning

confidence: 84%

Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation

Lovett

Nigro²,

Rappaport³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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We analyzed the der(11) and der(4) genomic breakpoint junctions of a t(4;11) in the leukemia of a patient previously administered etoposide and dactinomycin by molecular and biochemical approaches to gain insights about the translocation mechanism and the relevant drug exposure. The genomic breakpoint junctions were amplified by PCR. Cleavage of DNA substrates containing the normal homologues of the MLL and AF-4 translocation breakpoints was examined in vitro upon incubation with human DNA topoisomerase II␣ and etoposide, etoposide catechol, etoposide quinone, or dactinomycin. The der(11) and der(4) genomic breakpoint junctions both involved MLL intron 6 and AF-4 intron 3. Recombination was precise at the sequence level except for the overall gain of a single templated nucleotide. The translocation breakpoints in MLL and AF-4 were DNA topoisomerase II cleavage sites. Etoposide and its metabolites, but not dactinomycin, enhanced cleavage at these sites. Assuming that DNA topoisomerase II was the mediator of the breakage, processing of the staggered nicks induced by DNA topoisomerase II, including exonucleolytic deletion and templatedirected polymerization, would have been required before ligation of the ends to generate the observed genomic breakpoint junctions. These data are inconsistent with a translocation mechanism involving interchromosomal recombination by simple exchange of DNA topoisomerase II subunits and DNA-strand transfer; however, consistent with reciprocal DNA topoisomerase II cleavage events in MLL and AF-4 in which both breaks became stable, the DNA ends were processed and underwent ligation. Etoposide and͞or its metabolites, but not dactinomycin, likely were the relevant exposures in this patient. L eukemia has become an increasingly common complication of effective chemotherapy (reviewed in ref. 1). Two classes of chemotherapy are associated with leukemia-alkylating agents and DNA topoisomerase II inhibitors (reviewed in refs. 1-3). The hallmarks of leukemias associated with DNA topoisomerase II inhibitors are balanced chromosomal translocations, many of which involve the MLL gene at chromosome band 11q23 (reviewed in refs. 2, 4, and 5). It has been suggested that the MLL translocation mechanism may involve DNA topoisomerase IImediated chromosomal breakage and formation of the translocations when the breakage is repaired (2, 4, 5).DNA topoisomerase II catalyzes the relaxation of supercoiled DNA by transiently cleaving and religating both strands of the double helix (6). The DNA topoisomerase II homodimer introduces four-base staggered nicks in DNA as each subunit covalently binds and cleaves one strand (6). In the presence of ATP, the DNA open gate allows passage of a second DNA helix through the cleaved strands (6). Next, the cleaved DNA strands are religated, and after ATP hydrolysis, the enzyme homodimer attains its original conformational state to catalyze another cycle (6). DNA topoisomerase II has been implicated in MLL translocations, because several anticancer drugs interfere with its c...

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“…Studies now are underway to validate these ®ndings and to establish how they may be relevant to the translocation process. Etoposide catechol is detectable in the plasma of patients receiving chemotherapy with etoposide [86]. There are no data on the effects of the CYP3A4 polymorphism on etoposide or etoposide metabolite pharmacokinetics, but it is plausible that CYP3A4 genotype confers susceptibility in treatment-related leukemia because etoposide quinone increases DNA topoisomerase II cleavage and possibly may form N7 guanine adducts [57].…”

Section: Genetic Predisposition To Leukemias Related To Dna Topoisomementioning

confidence: 99%

Leukemias related to treatment with DNA topoisomerase II inhibitors*

Felix

2001

Med. Pediatr. Oncol.

186

169

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The epipodophyllotoxins etoposide and teniposide and other DNA topoisomerase II inhibitors including anthracyclines and dactinomycin are highly efficacious anticancer drugs. All are associated with a distinct form of leukemia characterized by chromosomal translocations as a treatment complication. Most of the translocations disrupt a breakpoint cluster region (bcr) of the MLL gene at chromosome band 11q23. Other characteristic translocations also may occur. The normal function of the nuclear enzyme DNA topoisomerase II is to catalyze changes in DNA topology between relaxed and supercoiled states by transiently cleaving and re-ligating both strands of the double helix. Anticancer drugs that are DNA topoisomerase II inhibitors are cytotoxic because they form complexes with DNA and DNA topoisomerase II. The complexes decrease the re-ligation rate, disrupt the cleavage-re-ligation equilibrium, and have a net effect of increasing cleavage. The increased cleavage damages the DNA and leads to chromosomal breakage. Cells with irreparable DNA damage die by apoptosis. The association of DNA topoisomerase II inhibitors with leukemia suggests that the drug-induced, DNA topoisomerase II-mediated chromosomal breakage may be relevant to translocations in addition to this anti-neoplastic, cytotoxic action. Epidemiological studies, genomic translocation breakpoint cloning and in vitro DNA topoisomerase II cleavage assays together lead to a model for treatment-related leukemia in which DNA topoisomerase II causes chromosomal breakage and translocations form when the breakage is repaired.

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Considerable plasma levels of a cytotoxic etoposide metabolite in patients undergoing high-dose chemotherapy

Cited by 14 publications

References 1 publication

Myeloperoxidase-Dependent Oxidation of Etoposide in Human Myeloid Progenitor CD34+ Cells

Myeloperoxidase-Dependent Oxidation of Etoposide in Human Myeloid Progenitor CD34+ Cells

Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation

Leukemias related to treatment with DNA topoisomerase II inhibitors*

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