Doxorubicin-DNA adducts induce a non-topoisomerase II-mediated form of cell death.

@article{Swift2006DoxorubicinDNAAI,
  title={Doxorubicin-DNA adducts induce a non-topoisomerase II-mediated form of cell death.},
  author={L. Swift and A. Rephaeli and A. Nudelman and D. Phillips and S. Cutts},
  journal={Cancer research},
  year={2006},
  volume={66 9},
  pages={
          4863-71
        }
}
Doxorubicin (Adriamycin) is one of the most commonly used chemotherapeutic drugs and exhibits a wide spectrum of activity against solid tumors, lymphomas, and leukemias. [...] Key Result Here, we show that doxorubicin-DNA adducts (formed by the coadministration of doxorubicin with non-toxic doses of formaldehyde-releasing prodrugs) induce a more cytotoxic response in HL-60 cells than doxorubicin as a single agent.Expand
The cardio-protecting agent and topoisomerase II catalytic inhibitor sobuzoxane enhances doxorubicin-DNA adduct mediated cytotoxicity
TLDR
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The data indicate that doxorubicin and doxazolidine induce apoptosis via different mechanisms andDoxzolidine cytotoxicity is topoisomerase II independent. Expand
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Analysis of covalent ellipticine- and doxorubicin-derived adducts in DNA of neuroblastoma cells by the ³²P-postlabeling technique.
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The results suggest that covalent binding of ellipticine to DNA of UKF-NB-3 and UKF -NB-4 neuroblastoma cell lines is the predominant mechanism responsible for the cytotoxicity of this drug. Expand
DNA methyltransferase I is a mediator of doxorubicin-induced genotoxicity in human cancer cells.
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It is shown that sub-lethal exposure to doxorubicin-induced micronuclei formation in human cancer cells but not in non-tumorigenic cells, and it is proposed that DNMT1 levels in tumor cells may determine the effectiveness of doxorbicin in chemotherapy. Expand
Molecular basis for the DNA damage induction and anticancer activity of asymmetrically substituted anthrapyridazone PDZ-7
TLDR
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TLDR
The therapeutic potential of TM is highlighted to sensitize tumor cells to doxorubicin for endometrial cancer treatment, and the combination of doxorbicin with a sub-cytotoxic level of TM was significantly more effective at inducing apoptosis inDoxorUBicin resistant cell lines. Expand
Activation of clinically used anthracyclines by the formaldehyde-releasing prodrug pivaloyloxymethyl butyrate
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Although apoptosis assays indicated a greater than additive effect for epirubicin/AN-9 combinations, this effect was much more pronounced for doxorubic in/AN -9 combinations. Expand
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References

SHOWING 1-10 OF 57 REFERENCES
The Power and Potential of Doxorubicin‐DNA Adducts
TLDR
The adducts appear to be more cytotoxic than doxorubicin alone, and also less susceptible to drug‐efflux forms of resistance, they offer new approaches to improving the anticancer activity of the anthracyclines. Expand
Sequence specificity of adriamycin-DNA adducts in human tumor cells.
TLDR
It is shown that when Adriamycin is used in conjunction with the formaldehyde-releasing prodrug AN-9 in IMR-32 tumor cells, this allows the formation of sufficiently high levels of adducts in genomic DNA to enable detection of their DNA sequence specificity for the first time. Expand
Apoptosis induced by topoisomerase inhibitors.
TLDR
A role for topoisomerases in chromatin fragmentation during the execution phase of apoptosis is reviewed, and recent observations that support this role are reviewed. Expand
Comparison of dna cleavage induced by etoposide and doxorubicin in two human small‐cell lung cancer lines with different sensitivities to topoisomerase ii inhibitors
TLDR
The findings suggest that reversal of these lesions plays a major role in cell survival rather than the occurrence of DNA breaks immediately following drug exposure, consistent with the view that inhibition of DNA re‐ligation rather than stimulation of DNA cleavage is the critical step for drug action. Expand
Differential single- versus double-strand DNA breakage produced by doxorubicin and its morpholinyl analogues
TLDR
Doxorubicin and MX2 were equipotent at causing SSB in the human ovarian carcinoma cell line, ES-2, however, neutral elution under deproteinated conditions revealed marked differences in the degree of DNA DSB. Expand
Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II.
TLDR
In studies in vitro, mammalian DNA topoisomerase II mediates DNA damage by adriamycin and other related antitumor drugs, and has been shown to induce single- and double-strand breaks in DNA. Expand
Recent advances in understanding and exploiting the activation of anthracyclines by formaldehyde.
TLDR
Some of the cellular consequences of these adducts have now been studied, and it appears that their formation can overcome anthracycline-resistance mechanisms, and that they are more efficient at inducing apoptosis than when functioning primarily through impairment of topoisomerase II. Expand
From DNA damage to G2 arrest: the many roles of topoisomerase II.
TLDR
regulation of the topoisomerase II/Cdc2 interaction could represent a novel mechanism to delay mitotic onset of DNA strand breaks and G2 arrest. Expand
Nuclear targeting and nuclear retention of anthracycline-formaldehyde conjugates implicates DNA covalent bonding in the cytotoxic mechanism of anthracyclines.
TLDR
The results implicate drug-DNA covalent bonding in the tumor cell toxicity mechanism of these anthracyclines. Expand
Characterization of covalent adriamycin-DNA adducts.
TLDR
It is shown by homo- and heteronuclear NMR spectroscopy that the covalent Adriamycin-DNA adduct is structurally equivalent to that resulting from direct reaction with formaldehyde. Expand
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