Feasibility and pharmacokinetic study of infusional dexrazoxane and dose-intensive doxorubicin administered concurrently over 96 h for the treatment of advanced malignancies

Chow, Warren; Synold, Timothy W.; Tetef, Merry; Longmate, Jeffrey; Frankel, Paul; Lawrence, Joyce; Al-Khadimi, Zaid; Leong, Lucille; Lim, Dean; Margolin, Kim; Morgan, Robert J.; Raschko, James; Shibata, Stephen; Twardowski, Przemyslaw; Yen, Yun; Doroshow, James H.

doi:10.1007/s00280-004-0803-4

Cited by 5 publications

(4 citation statements)

References 26 publications

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“…Non-cardiac toxicity and antitumor efficacy for the two treatment groups was nearly the same. Similar results were obtained by other studies and case series [ 25 – 29 ].…”

Section: Introductionsupporting

confidence: 92%

Efficacy and safety of Dexrazoxane (DRZ) in sarcoma patients receiving high cumulative doses of anthracycline therapy – a retrospective study including 32 patients

et al. 2016

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BackgroundAnthracyclines, as the most effective therapy, are the cornerstone of advanced stage sarcoma treatment. However, anthracyclines can also contribute to myocardial dysfunction and congestive heart failure, ultimately limiting the therapeutic potential of the drug. Coadministration of Dexrazoxane has been shown to effectively reduce cardiotoxicity, however primarily in patients suffering in diseases other than sarcoma.MethodsThe aim of this retrospective analysis was to evaluate safety and efficacy of chemotherapy with high cumulative doses of anthracyclines in combination with Dexrazoxane. The medical charts of 32 patients treated in four institutions were analyzed. Reasons for coadministration were rechallenge, reaching the cumulative anthracycline dose and preexisting heart failure.ResultsThe median age was 54 years [18–68 years]. The median cumulative anthracycline dose before adding DRZ was 450 mg/m2 and after administration of last anthracycline containing therapy 750 mg/m2. Either during treatment or follow up, 2/27 patients (7 %) without preexisting major cardiac findings developed anthracycline-induced cardiotoxicity. The median overall survival (OS) from start of the first anthracycline containing chemotherapy was 46 months and 17 months from the initial coadministration of DRZ. At rechallenge, the median progression free survival (PFS) with DRZ was 7 months. In continuous therapy, the median PFS was 13 months from beginning of chemotherapy and 9 months from the addition of DRZ.ConclusionChemotherapy with high cumulative doses of anthracyclines in addition with DRZ demonstrated a remarkable OS in these advanced disease patients. Cardiac side-effects due to high cumulative doses of anthracyclines requiring discontinuation of anthracycline treatment were rare. A PFS of 9 months from the beginning of the coadministration of DRZ indicates that continuing anthracycline therapy beyond established cumulative doses is a promising therapeutic option.

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“…Non-cardiac toxicity and antitumor efficacy for the two treatment groups was nearly the same. Similar results were obtained by other studies and case series [ 25 – 29 ].…”

Section: Introductionsupporting

confidence: 92%

Efficacy and safety of Dexrazoxane (DRZ) in sarcoma patients receiving high cumulative doses of anthracycline therapy – a retrospective study including 32 patients

et al. 2016

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“…One of the most common adverse effects of DOX is hypotension with a reported prevalence of 20% in high dose DOX-treated cancer patients (96). Hypotension is also a top perioperative cardiovascular complication in the patients with a history of anthracycline drug therapy, which was associated with or without depressed LV function (97).…”

Section: Concerns and Precautions On Potential Adverse Effectsmentioning

confidence: 99%

Dietary inorganic nitrate alleviates doxorubicin cardiotoxicity: Mechanisms and implications

Zhu

Das

et al. 2012

Nitric Oxide

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Doxorubicin (DOX) is one of the most powerful and widely prescribed chemotherapeutic agents to treat divergent human cancers. However, the clinical use of DOX is restricted due to its severe cardiotoxic side-effects. There has been ongoing search for cardioprotectants against DOX toxicity. Inorganic nitrate has emerged as a bioactive compound that can be reduced into nitrite and nitric oxide in vivo and in turn plays a therapeutic role in diseases associated with nitric oxide insufficiency or dysregulation. In this review, we describe a novel concept of using dietary supplementation of inorganic nitrate to reduce DOX-induced cardiac cellular damage and dysfunction, based on our recent promising studies in a mouse model of DOX cardiotoxicity. Our data show that chronic oral ingestion of sodium nitrate, at a dose equivalent to ~400% of the Acceptable Daily Intake of the World Health Organization, alleviated DOX-induced left ventricular dysfunction and mitochondrial respiratory chain damage. Such cardioprotective effects were associated with reduction of cardiomyocyte necrosis/apoptosis, tissue lipid peroxidation, and mitochondrial H2O2 generation following DOX treatment. Furthermore, proteomic studies revealed enhanced cardiac expression of mitochondrial antioxidant enzyme – peroxiredoxin 5 in the nitrate-treated animals. These studies suggest that inorganic nitrate could be an inexpensive therapeutic agent for long-term oral administration in preventing DOX-induced cardiac toxicity and myopathy during the prolonged pathological process. Future clinical trials in the cancer patients undergoing DOX chemotherapy are warranted to translate these experimental findings into an effective new therapy in preventing the DOX-induced cardiomyopathy.

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“…Interestingly, the maximal tolerated dose (MTD) of dexrazoxane determined by using short infusion schedules was approximately 10-15 times higher than the MTD determined with continuous infusion schedules [Tetef et al, 2001]. Myelosuppression appeared as the strongest toxic effect and was used to established the limiting dose of metal chelators [Tetef et al, 2001;Chow et al, 2004]. Thus, in planning a therapy with this class of agents, the infusion schedule must be carefully evaluated.…”

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confidence: 98%

Zinc depletion efficiently inhibits pancreatic cancer cell growth by increasing the ratio of antiproliferative/proliferative genes

Donadelli

Pozza

Costamagna

et al. 2007

J of Cellular Biochemistry

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We investigated the ability of the zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) to reduce pancreatic cancer cell viability. TPEN was much more efficient to inhibit pancreatic adenocarcinoma cell growth than a panel of anti-cancer drugs, including 5-fluorouracil, irinotecan, cisplatin, edelfosine, trichostatin A, mitomycin C, and gemcitabine, the gold standard chemotherapeutic agent for pancreatic cancer. Moreover, TPEN showed a dose- and time-dependent anti-proliferative effect significantly higher on pancreatic cancer cells than on normal primary fibroblasts. This effect may be explained by a significantly higher zinc depletion by TPEN in pancreatic cancer cells as compared to fibroblasts. Cell viability reduction by TPEN was associated to both G1-phase cell cycle arrest and apoptosis, and to the increased ratio of the expression level of cyclin-Cdk inhibitor versus cyclin genes and apoptotic versus anti-apoptotic genes. Finally, we show that apoptotic cell death induced by TPEN involved mitochondrial injury and caspase 3 and caspase 8 activation. In this study, we suggest that zinc depletion may be an efficient strategy in the treatment of pancreatic cancer because of its reduced antiproliferative effect on normal cells.

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Feasibility and pharmacokinetic study of infusional dexrazoxane and dose-intensive doxorubicin administered concurrently over 96 h for the treatment of advanced malignancies

Cited by 5 publications

References 26 publications

Efficacy and safety of Dexrazoxane (DRZ) in sarcoma patients receiving high cumulative doses of anthracycline therapy – a retrospective study including 32 patients

Efficacy and safety of Dexrazoxane (DRZ) in sarcoma patients receiving high cumulative doses of anthracycline therapy – a retrospective study including 32 patients

Dietary inorganic nitrate alleviates doxorubicin cardiotoxicity: Mechanisms and implications

Zinc depletion efficiently inhibits pancreatic cancer cell growth by increasing the ratio of antiproliferative/proliferative genes

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