Tumor‐selective Distribution of an Active Metabolite of the 9‐Aminoanthracycline Amrubicin

Noguchi, Toshihiro; Ichii, Shinji; Morisada, Shinya; Yamaoka, Takashi; Yanagi, Yoshikazu

doi:10.1111/j.1349-7006.1998.tb00497.x

Cited by 46 publications

(41 citation statements)

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“…Amrubicin is a fully synthetic 9 aminoanthracycline, converted in the body to amrubicinol by reduction of the 13-position ketone, possessing higher antitumor activity than the parent molecule. Although classified as anthracycline agents, amrubicin and amrubicinol exert cytotoxic effects as DNA topoisomerase inhibitors, not mainly as DNA intercalators [Onoda et al 2006;Ohe et al 1989;Hanada et al 1998;Noda et al 1998;Noguchi et al 1998aNoguchi et al , 1998bYana et al 2007;Kato et al 2006]. Amrubicin showed more potent antitumor activity than doxorubicin in several human tumor xenografts implanted in nude mice.…”

Section: Cytotoxic Agentsmentioning

confidence: 99%

Relapsed small cell lung cancer: treatment options and latest developments

et al. 2014

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According to recent analyses, there was a modest yet significant improvement in median survival time and 5-year survival rate of limited stage small cell lung cancer (SCLC) in North America, Europe, Japan and other countries over the last 30 years. The median survival time of limited stage SCLC is 15-20 months and 5-year survival rate is 15% or less. In terms of extensive stage SCLC, a median survival time of 9.4-12.8 months and 2-year survival of 5.2-19.5% are still disappointing. Despite being highly sensitive to first-line chemotherapy and radiotherapy treatments, most patients with SCLC experience relapse within 2 years and die from systemic metastasis. While several clinical trials of cytotoxic chemotherapies and molecular targeting agents have been investigated in the treatment of relapsed SCLC, none showed a significant clinical activity to be able to exceed topotecan as second-line chemotherapy. There are problematic issues to address for relapsed SCLC, such as standardizing the treatment for third-line chemotherapy. Topotecan alone was the first approved therapy for second-line treatment for relapsed SCLC. Amrubicin is a promising drug and a variety of trials evaluating its efficacy have been carried out. Amrubicin has shown superiority to topotecan in a Japanese population, but was not superior in a study of western patients. There are some controversial issues for relapsed SCLC, such as treatment for older patients, third-line chemotherapy and efficacy of molecular targeting therapy. This article reviews current standard treatment, recent clinical trials and other topics on relapsed SCLC.

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Section: Cytotoxic Agentsmentioning

confidence: 99%

Relapsed small cell lung cancer: treatment options and latest developments

et al. 2014

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“…Amrubicin is converted to its active metabolite, amrubicinol, which has been shown to exert a 10-to 100-fold more active antitumor effect than the parent compound (9,10). Among clinical studies, a Phase I/II trial in patients with untreated non-small-cell lung cancer patients with doses of 40, 45 or 50 mg/m 2 on Days 1-3 showed a maximum tolerated dose (MTD) of 50 mg/m 2 and dose-limiting toxicities (DLTs) of leukopenia, neutropenia, thrombocytopenia and gastrointestinal complications (11 …”

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Phase II study of amrubicin at a dose of 45 mg/m²in patients with previously treated small-cell lung cancer

Asao

Nokihara

Yoh

et al. 2015

Jpn. J. Clin. Oncol.

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Objective: Most of the previous studies of amrubicin in patients with previously treated small-cell lung cancer were conducted at a dose of 40 mg/m 2 . The aim of this study was to assess the efficacy and safety of amrubicin at a dose of 45 mg/m 2 in patients with relapsed or refractory small-cell lung cancer.Methods: Previously treated small-cell lung cancer patients were eligible. Amrubicin at a dose of 45 mg/m 2 was administered on Days 1-3 every 3 weeks. The primary endpoint was the response rate.Results: From June 2003 to January 2005, 35 patients were enrolled, of whom 34 received this study treatment. Four cycles or more could be administered in 21 patients (62%). Dose reduction was required in 15 (52%) of the 29 patients who had received two cycles or more. Three complete responses and 15 partial responses were observed among the 34 treated patients, yielding a response rate of 53% (95% confidence interval, 35-71%). Median progression-free survival of the patients was 4.4 months (95% confidence interval, 2.4-5.1 months). Median survival time was 8.2 months (95% confidence interval, 6.6-10.0 months) and 1-year survival rate was 24% (95% confidence interval, 9-39%). Grade 3/4 leukopenia, neutropenia and thrombocytopenia were observed in 76, 97 and 38% of the patients, respectively. Febrile neutropenia occurred in 12 patients (35%), and one patient died from pneumonia. Conclusions: While amrubicin at a dose of 45 mg/m 2 showed high response rate for both sensitive and refractory relapse, the incidence of febrile neutropenia was also high. The utility of amrubicin at 45 mg/m 2 might accordingly be limited.

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“…Amrubicinol was distributed more in tumor tissues than in normal tissues compared to doxorubicin, and the level of amrubicinol in the tumor correlated to the in vivo efficacy of amrubicin. 6,7) We thus suppose that amrubicinol plays an important role in the in vivo antitumor effect of amrubicin as an active metabolite.…”

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Uptake and Intracellular Distribution of Amrubicin, a Novel 9‐Amino‐anthracycline, and Its Active Metabolite Amrubicinol in P388 Murine Leukemia Cells

Yamaoka¹,

Hanada²,

Ichii³

et al. 1999

Japanese Journal of Cancer Research

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Amrubicin, a 9-aminoanthracycline anti-cancer drug, and its C-13 hydroxyl metabolite amrubicinol, were examined for growth-inhibitory activity as well as cellular uptake and distribution in P388 murine leukemia cells and doxorubicin-resistant P388 cells. Also discussed are the differences in the mechanisms of action among amrubicin, amrubicinol and doxorubicin in terms of their cellular pharmacokinetic character. In P388 cells, amrubicinol was about 80 times as potent as amrubicin, and about 2 times more potent than doxorubicin in a 1-h drug exposure growth-inhibition test. A clear cross-resistance was observed to both amrubicin and amrubicinol in doxorubicin-resistant P388 cells, though the resistance index was lower for amrubicin. The intracellular concentration of amrubicinol was about 6 times and 2 times higher than those of amrubicin and doxorubicin, respectively. Compared to doxorubicin, amrubicin and amrubicinol were released rapidly after removal of the drugs from the medium. A clear correlation was found between the growth-inhibiting activity and the cellular level of amrubicin and amrubicinol in P388 cells. About 10 to 20% of amrubicin or amrubicinol taken up by the cells was detected in the cell nuclear fraction, whereas 70 to 80% of doxorubicin was localized in this fraction. These results suggest that amrubicin and amrubicinol exert cytotoxic activity via a different mechanism from that of doxorubicin.Key words: Anthracycline -Amrubicin -SM-5887 -Metabolite Amrubicin hydrochloride (SM-5887) is a completely synthetic 9-aminoanthracycline anti-cancer drug.1) It has potent antitumor activities, being more potent than doxorubicin against various mouse experimental tumors and human tumor xenografts.2) Phase II clinical trials of amrubicin for the treatment of malignant lymphoma, superficial bladder cancer, small cell lung cancer and non-small cell lung cancer are in progress.3, 4) The response rates were 25% and 79% against non-small cell lung cancer and small cell lung cancer, respectively.In our previous studies, amrubicinol, the C-13 hydroxy metabolite of amrubicin, was much more potent than the parent compound, amrubicin, and as potent as doxorubicin in inhibiting the growth of human tumor cells.5) In nude mouse-human tumor models, amrubicinol was detected in plasma, normal tissues and tumor tissues of mice treated with amrubicin. Amrubicinol was distributed more in tumor tissues than in normal tissues compared to doxorubicin, and the level of amrubicinol in the tumor correlated to the in vivo efficacy of amrubicin.6, 7) We thus suppose that amrubicinol plays an important role in the in vivo antitumor effect of amrubicin as an active metabolite.A major metabolic pathway of anthracyclines is known to be the reduction of the C-13 carbonyl group to a hydroxyl group by cytoplasmic carbonyl reductase. [8][9][10] Generally, the C-13 hydroxy metabolite of an anthracycline shows lower growth-inhibitory activity than the respective parent compound. Doxorubicinol, epirubicinol and daunorubicinol are less poten...

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Tumor‐selective Distribution of an Active Metabolite of the 9‐Aminoanthracycline Amrubicin

Cited by 46 publications

References 17 publications

Relapsed small cell lung cancer: treatment options and latest developments

Relapsed small cell lung cancer: treatment options and latest developments

Phase II study of amrubicin at a dose of 45 mg/m²in patients with previously treated small-cell lung cancer

Uptake and Intracellular Distribution of Amrubicin, a Novel 9‐Amino‐anthracycline, and Its Active Metabolite Amrubicinol in P388 Murine Leukemia Cells

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Tumor‐selective Distribution of an Active Metabolite of the 9‐Aminoanthracycline Amrubicin

Cited by 46 publications

References 17 publications

Relapsed small cell lung cancer: treatment options and latest developments

Relapsed small cell lung cancer: treatment options and latest developments

Phase II study of amrubicin at a dose of 45 mg/m2in patients with previously treated small-cell lung cancer

Uptake and Intracellular Distribution of Amrubicin, a Novel 9‐Amino‐anthracycline, and Its Active Metabolite Amrubicinol in P388 Murine Leukemia Cells

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Phase II study of amrubicin at a dose of 45 mg/m²in patients with previously treated small-cell lung cancer