Cardiotoxicity of a new anthracycline derivative (SM-5887) following intravenous administration to rabbits: Comparative study with doxorubicin

Suzuki, Tadashi; Minamide, Seiki; Iwasaki, Tsutomu; Yamamoto, Hirohisa; Kanda, Hiroshi

doi:10.1023/a:1005862730941

Cited by 48 publications

(9 citation statements)

References 5 publications

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“…The anthracycline Amr thus mimicked Etop, which only induces DSBs. Amr and Etop both have limited cardiotoxicity ( 26 , 44 , 50 ), again suggesting that DNA damage alone is insufficient to induce cardiotoxicity.…”

Section: Resultsmentioning

confidence: 99%

Uncoupling DNA damage from chromatin damage to detoxify doxorubicin

Qiao

Zanden

Wander

et al. 2020

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

112

201

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The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanism of anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.

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Section: Resultsmentioning

confidence: 99%

Uncoupling DNA damage from chromatin damage to detoxify doxorubicin

Qiao

Zanden

Wander

et al. 2020

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

112

201

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“…2 Chest computed tomography in case 6. a Before amrubicin plus cisplatin chemotherapy. b After 4 cycles of amrubicin plus cisplatin chemotherapy deleterious effects on doxorubicin-induced cardiotoxicity in animal models [20,21]. However, the accumulative or synergic cardiac toxicities of amrubicin following doxorubicin are still unclear in clinical use.…”

Section: Discussionmentioning

confidence: 99%

Salvage chemotherapy with amrubicin and platinum for relapsed thymic carcinoma: experience in six cases

et al. 2009

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It has been reported that cisplatin-based chemotherapy shows beneficial effects in certain patients with advanced thymic carcinoma. However, the usefulness of salvage therapy has not been reported. We focused on a new anthracycline agent, amrubicin, combined with platinum compounds as salvage chemotherapy in patients with thymic carcinoma. Six cases of unresectable and locally advanced thymic carcinoma relapsed from prior cisplatin-containing chemotherapy were treated with amrubicin (30-40 mg/m(2) day 1-3) plus platinum compounds (cisplatin 60 mg/m(2) day 1 or nedaplatin 70 mg/m(2) day 1) chemotherapy as salvage chemotherapy. Two patients showed a partial response. However, Grade 3/4 neutropenia and thrombocytopenia occurred in all and two of the patients, respectively. We conclude that thymic carcinoma is sensitive to platinum-based chemotherapy and that amrubicin appears to have significant activity against thymic carcinoma. The major toxicity is hematological toxicities.

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“…Its antitumor activity was found to be superior to that of doxorubicin in experimental therapeutic models using human tumor xenografts 33. In addition, AMR showed much less cardiotoxicity than doxorubicin in chronic experimental models using rabbits and dogs 34,35…”

Section: Anthracyclines: Doxorubicin Epirubicin and Amrubicinmentioning

confidence: 99%

Review of the Management of Relapsed Small-Cell Lung Cancer with Amrubicin Hydrochloride

Kimura

Kudoh

Hirata

2011

Clin Med Insights Oncol

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Lung cancer is the leading cause of cancer death, and approximately 15% of all lung cancer patients have small-cell lung cancer (SCLC). Although second-line chemotherapy can produce tumor regression, the prognosis is poor. Amrubicin hydrochloride (AMR) is a synthetic anthracycline anticancer agent and a potent topoisomerase II inhibitor. Here, we discuss the features of SCLC, the chemistry, pharmacokinetics, and pharmacodynamics of AMR, the results of in vitro and in vivo studies, and the efficacy and safety of AMR monotherapy and combination therapy in clinical trials. With its predictable and manageable toxicities, AMR is one of the most attractive agents for the treatment of chemotherapy-sensitive and -refractory relapsed SCLC. Numerous studies are ongoing to define the applicability of AMR therapy for patients with SCLC. These clinical trials, including phase III studies, will clarify the status of AMR in the treatment of SCLC.

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Cardiotoxicity of a new anthracycline derivative (SM-5887) following intravenous administration to rabbits: Comparative study with doxorubicin

Cited by 48 publications

References 5 publications

Uncoupling DNA damage from chromatin damage to detoxify doxorubicin

Uncoupling DNA damage from chromatin damage to detoxify doxorubicin

Salvage chemotherapy with amrubicin and platinum for relapsed thymic carcinoma: experience in six cases

Review of the Management of Relapsed Small-Cell Lung Cancer with Amrubicin Hydrochloride

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