Absence of generation of oxygen-containing free radicals with 4′-deoxydoxorubicin, a non-cardiotoxic anthracycline drug

Dickinson, Alan C.; Dejordy, John O.; Boutin, Michael G.; Teres, Daniel

doi:10.1016/0006-291x(84)90579-5

Cited by 22 publications

(4 citation statements)

References 12 publications

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“…In the chronic study, 4'-deoxy-DXR was less cardiotoxic than DXR; however, its cardio-toxicity was more severe than that caused by 4'-amino-3'hydroxy-DXR, as the fon~aer analogue induced a significant widening of the SaT-segment duration and impaired the adrenaline-induced relaxation (-dF/dtmax) of isolated heart preparations, whereas the latter did not. The present data suggest that the rat model is useful for the study of anthracycline cardiotoxicity, since other experimental models have failed to reveal any cardiotoxic effect for 4"-deoxy-DXR [11].…”

Section: Discussionmentioning

confidence: 72%

Reduced cardiotoxicity and increased cytotoxicity in a novel anthracycline analogue, 4′-amino-3′-hydroxy-doxorubicin

Danesi

Bernardini

Agen

et al. 1992

Cancer Chemother. Pharmacol.

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The acute and chronic cardiotoxicity and cytotoxicity of the novel doxorubicin (DXR) derivative 4'-amino-3'-hydroxy-DXR were compared with those of 4'-deoxy-DXR and DXR. In the acute cardiotoxicity study, the ECG and hemodynamic changes recorded in anesthetized rats that had been treated i.v. with 10 mg/kg 4'-amino-3'-hydroxy-DXR or 8.6 mg/kg 4'-deoxy-DXR were significantly less severe than those caused by 13 mg/kg DXR. In the chronic cardiotoxicity study, rats received 3 weekly i.v. injections of 3 mg/kg DXR, 3 mg/kg 4'-amino-3'-hydroxy-DXR, or 2 mg/kg 4'-deoxy-DXR during the first 14 days of the study and were observed for an additional 35-day period. DXR induced severe cardiomyopathy that was characterized by ECG changes in vivo (S alpha T-segment widening and T-wave flattening) and by impairment of the contractile responses (Fmax, +/- dF/dtmax) to adrenaline of hearts isolated from treated animals. 4'-Deoxy-DXR caused a progressive enlargement of the S alpha T segment in vivo and a significant impairment of the -dF/dtmax value in vitro, which were less severe than those produced by DXR. The least cardiotoxic drug was 4'-amino-3'-hydroxy-DXR, which induced minor ECG changes without causing significant alterations in the contractile responses of isolated hearts to adrenaline. On the basis of the drug concentration required to inhibit 50% of the colony formation (IC50) of cell lines in vitro, 4'-amino-3'-hydroxy-DXR was less active than 4'-deoxy-DXR but at least twice as active as DXR against human cancer and murine transformed cell lines. These data indicate that 4'-amino-3'-hydroxy-DXR is significantly less cardiotoxic and more cytotoxic than DXR.

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Section: Discussionmentioning

confidence: 72%

Reduced cardiotoxicity and increased cytotoxicity in a novel anthracycline analogue, 4′-amino-3′-hydroxy-doxorubicin

Danesi

Bernardini

Agen

et al. 1992

Cancer Chemother. Pharmacol.

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“…The participation of anthracyclines in the slow spontaneous production of oxygen radicals can be detected by spin trapping [42], The superoxide radical formed by redox cycling of anthracyclines results in hydroxyl radical formation through the iron-driven Haber-Weiss reaction [34], In addition, the iron-doxorubicin complex may bind to vital cellular structures [43] and may induce direct toxicity without involving hydroxyl radical formation [44], It has been shown recently that anthracyclines promote lipid peroxidation by reductive mobilization of membrane-bound nonheme nonferritin iron [45], Many previous studies indicate that it is possi ble to prevent the formation of free radicals in vitro and in vivo by preventing the participation of iron in the HaberWeiss reaction through iron chelation with deferoxamine (desferrioxamine, DFO) [46,47], In view of existing evi dence supporting the role of iron in anthracycline toxicity, it was reasonable to assume that iron chelation may inhib it anthracycline toxicity by interfering with free radical formation.…”

Section: Role Of Iron In Antracycline Cardiotoxicitymentioning

confidence: 99%

Prevention of Anthracycline Cardiotoxicity by Iron Chelation

Hershko

Pinson²,

Link³

1996

Acta Haematol

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The use of anthracycline antineoplastic drugs is limited by a cumulative, dose-dependent toxicity to the heart. Of the cellular organelles proposed as possible primary sites of anthracycline toxicity, the mitochondrial membrane appears to be the most likely target. Cardiolipin, a major phospholipid component of the inner mitochondrial membrane is rich in polyunsaturated fatty acids and is particularly susceptible to peroxidative injury by harmful radicals produced by redox cycling of anthracyclines. This, in turn, leads to the inactivation of key enzymes in the mitochondrial respiratory chain. Since the formation of free radicals is catalyzed by iron through the Haber-Weiss reaction, it was hypothesized that iron depletion by deferoxamine (DFO) may limit anthracycline cardiotoxicity. Recent studies indicate that iron-loading aggravates doxorubicin cardiotoxicity by enhancing mitochondrial damage, and this can be prevented by prior DFO treatment. Although these observations are intriguing, further studies are required to show that the cardioprotective effects of DFO do not interfere with the therapeutic, antitumoral action of anthracyclines.

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“…The participation of anthracycline in the slow spontaneous production of oxygen radicals can be detected by spin trapping. 36 The superoxide radical formed by redox cycling of anthracyclines results in hydroxyl radical formation through the irondriven Haber-Weiss reaction.' In addition, the irondoxorubicin complex may bind to vital cellular structures3' and may induce direct toxicity without involving hydroxyl radical formation.38 It has been shown recently that anthracyclines promote lipid peroxidation by the reductive mobilization of membrane-bound nonheme nonferritin iron.39 Many previous studies indicate that it is possible to prevent the formation of free radicals in vitro and in vivo by preventing the participation of iron in the Haber-Weiss reaction through iron chelation with d e f e r~x a m i n e .~.~' In view of existing evidence supporting the role of iron in anthracycline toxicity, it was reasonable to assume, that iron chelation may inhibit anthracycline toxicity by interfering with free radical formation.…”

Section: Role Of Iron In Anthracycline C Ardiotoxicitymentioning

confidence: 99%

The Role of Iron and Iron Chelators in Anthracycline Cardiotoxicity

Hershko

Link

Tzahor

et al. 1993

Leukemia & Lymphoma

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The redox cycling of anthracyclines promotes the formation of free radicals which are believed to play a central role in their cardiotoxicity. A number of observations indicate that the mechanism of the antineoplastic effect of anthracyclines is independent of their cardiotoxic effect and that it may be possible to prevent toxicity without interfering with therapeutic effect. Iron plays an important role in anthracycline toxicity by promoting the conversion of superoxide into highly toxic hydroxyl radicals through the Haber-Weiss reaction. Conversely, iron deprivation by its high-affinity binding to iron chelating compounds may inhibit anthracycline toxicity by interfering with free radical formation. ICRF-187, a bispiperazonedione which is hydrolyzed intracellularly into a bidentate chelator resembling EDTA, is able to decrease adriamycin-induced free hydroxyl radical formation and to prevent the development of clinical cardiac toxicity in patients receiving long-term anthracycline therapy. Our studies in rat heart cell cultures have shown that iron overload aggravates anthracycline toxicity and that this interaction can be prevented by prior iron chelating treatment. Since iron overload caused by multiple blood transfusions and bone marrow failure is a common condition in patients requiring anthracycline therapy, these observations may have significant clinical implications to the prevention of anthracycline cardiotoxicity.

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Absence of generation of oxygen-containing free radicals with 4′-deoxydoxorubicin, a non-cardiotoxic anthracycline drug

Cited by 22 publications

References 12 publications

Reduced cardiotoxicity and increased cytotoxicity in a novel anthracycline analogue, 4′-amino-3′-hydroxy-doxorubicin

Reduced cardiotoxicity and increased cytotoxicity in a novel anthracycline analogue, 4′-amino-3′-hydroxy-doxorubicin

Prevention of Anthracycline Cardiotoxicity by Iron Chelation

The Role of Iron and Iron Chelators in Anthracycline Cardiotoxicity

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