Phase I and pharmacologic study of irinotecan and amrubicin in advanced non-small cell lung cancer

Yanaihara, Tomoko; Yokoba, Masanori; Onoda, Shoichi; Yamamoto, Michiko; Ryuge, Shinichiro; Hagiri, Shintaro; Katagiri, Masayuki; Wada, Mayuko; Mitsufuji, Hisashi; Kubota, Minoru; Arai, Setsuo; Kobayashi, Hirosuke; Yanase, Nobuo; Abe, Tadashi; Masuda, Noriyuki

doi:10.1007/s00280-006-0279-5

Cited by 14 publications

(18 citation statements)

References 24 publications

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“…The incidence of pulmonary toxicity observed in this trial was higher than that in our previous trial without G-CSF support (20 % versus 9.1 %, respectively) ( Table 4) [32]. Higher age (C55 years old), poor performance status, smoking, recent non-small-cell lung cancer diagnosis, reduced normal lung on CT scan, preexisting chronic interstitial lung disease, and concurrent cardiac disease are known to be risk factors for interstitial lung disease [14].…”

Section: Discussioncontrasting

confidence: 78%

“…Neutropenia, neutropenic fever, ileus, and diarrhea were the DLTs. Although use of prophylactic rhG-CSF support did not completely eliminate neutropenia, use of rhG-CSF allowed the dose of amrubicin to be raised 40 % above that in the original regimen (25 mg/m 2 amrubicin and 60 mg/m 2 CPT-11) [32]. The dose of amrubicin was 78 % of that recommended for single-agent administration as an intravenous injection on days 1-3 in patients without prior chemotherapy.…”

Section: Discussionmentioning

confidence: 98%

“…Amrubicin was commenced at 30 mg/m 2 intravenously on days 1-3, which was the highest dose evaluated in our previous phase I study without rhG-CSF support [32]. In the present study, the dose of amrubicin was escalated in increments of 5 mg/m 2 in successive patient cohorts until MTD was reached, while CPT-11 was given at a fixed dose of 60 mg/m 2 intravenously over 90 min on days 1 and 8.…”

Section: Dosage and Dose Escalation Proceduresmentioning

confidence: 98%

“…The development of a new topoisomerase II inhibitor, amrubicin, has led to renewed interest in a combination of topoisomerase I and II inhibitors. Although myelosuppression, especially leukopenia, was one of the major dose-limiting toxicities (DLTs) in our previous phase I and pharmacokinetic trial of a combination of these agents [32], neutropenia associated with this drug combination can be alleviated by the administration of recombinant human granulocyte colonystimulating factor (rhG-CSF) [3].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Phase I trial of irinotecan and amrubicin with granulocyte colony-stimulating factor support in extensive-stage small-cell lung cancer

Asakuma

Yamamoto

Wada

et al. 2012

Cancer Chemother Pharmacol

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Section: Discussioncontrasting

confidence: 78%

Section: Discussionmentioning

confidence: 98%

Section: Dosage and Dose Escalation Proceduresmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Phase I trial of irinotecan and amrubicin with granulocyte colony-stimulating factor support in extensive-stage small-cell lung cancer

Asakuma

Yamamoto

Wada

et al. 2012

Cancer Chemother Pharmacol

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“…9) Therefore, combination treatment with irinotecan and amrubicin offers a potentially promising chemotherapy regimen for refractory or relapsed lung cancer. [10][11][12][13] According to the results of another clinical study, combination chemotherapy with irinotecan and amrubicin was well tolerated but produced only a modest antitumor effect in advanced NSCLC. 14) In this study, we investigated the efficacy of combination therapy with irinotecan and amrubicin for human lung cancer in vivo and in vitro.…”

mentioning

confidence: 99%

Efficacy of Combination Treatment and Influence of Schedule with Irinotecan and Amrubicin in Human Lung Carcinoma Cells in Vivo and in Vitro

Shishido

Furuta

Matsuzaki

et al. 2010

Biological & Pharmaceutical Bulletin

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Lung cancer is one of the leading causes of cancer death worldwide, 1) including in Japan.2) Although much work has been done to enable earlier detection, most cases are already advanced on initial presentation, and further improvement is still required in both diagnosis and treatment. Irinotecan is recognized as one of the most important drugs in the treatment of solid tumors, and chemotherapy combining irinotecan with cisplatin has shown great promise in the treatment of small-cell lung cancer (SCLC).3,4) However, platinumbased regimens are often associated with severe, dose-limiting, systemic toxicities, a factor which hampers their efficacy. The fact is that lung cancer still remains notoriously difficult to treat. Therefore, there is an urgent need to develop more effective combination chemotherapies with novel agents active against lung cancer.Amrubicin, a completely synthetic 9-aminoanthracycline derivative and anthracyclin analog, is the latest anticancer agent in the treatment of SCLC and non-small cell lung cancer (NSCLC) in Japan, and has demonstrated excellent single-agent activity against extensive-stage SCLC (ES-SCLC).5) It has also shown promising antitumor activity against advanced NSCLC, with acceptable toxicity.6) The combination of amrubicin and cisplatin demonstrated an impressive response rate and median survival time in patients with previously untreated ES-SCLC, 7) indicating the potential of this regimen.Irinotecan is a DNA topoisomerase I (topo I) inhibitor. On the other hand, amrubicin, and especially its 13-hydroxy metabolite, amrubicinol, exhibit antitumor activity through interacting with DNA by intercalation, thus inhibiting DNA topoisomerase II (topo II) by stabilizing the cleavable complex.8) The combination of topo I and topo II inhibitors such as irinotecan and etoposide has been reported to be effective against SCLC. 9) Therefore, combination treatment with irinotecan and amrubicin offers a potentially promising chemotherapy regimen for refractory or relapsed lung cancer. [10][11][12][13] According to the results of another clinical study, combination chemotherapy with irinotecan and amrubicin was well tolerated but produced only a modest antitumor effect in advanced NSCLC. 14) In this study, we investigated the efficacy of combination therapy with irinotecan and amrubicin for human lung cancer in vivo and in vitro. The in vivo anticancer effect was evaluated using an LX-1 xenograft model in mice. The in vitro combination effect of SN-38, the active metabolite of irinotecan, 15) and amrubicinol on proliferation of A549 and PC-6 was analyzed by the combination index method of Chou and Talalay 16) to determine whether synergy was obtained with simultaneous and sequential combination treatment. We also characterized the cell cycle events associated with simultaneous and sequential treatment with the two drugs. ,10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione hydrochloride (amrubicin) and amrubicinol hydrochloride (amrubicinol) were kindly provided by Dainippon Sumitomo Pharma C...

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Simple and sensitive HPLC method for determination of amrubicin and amrubicinol in human plasma: application to a clinical pharmacokinetic study

Ando¹,

Makino²,

Tamura³

et al. 2009

Biomedical Chromatography

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A simple and sensitive high-performance liquid chromatographic (HPLC) method was developed for determination of amrubicin and its metabolite amrubicinol in human plasma. After protein precipitation with methanol without evaporation procedure, large volume samples were injected and separated by two monolithic columns with a guard column. The mobile phase consisted of tetrahydrofuran-dioxane-water (containing 2.3 mM acetic acid and 4 mM sodium 1-octanesulfonate; 2:6:15, v/v/v). Wavelengths of fluorescence detection were set at 480 nm for excitation and 550 nm for detection. Under these conditions, linearity was confirmed in the 2.5-5000 ng/mL concentration range of both compounds. The intra- and inter-day precision and intra- and inter-day accuracy for both compounds were less than 10%. The method was successfully applied to a clinical pharmacokinetic study of amrubicin and amrubicinol in cancer patients.

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Phase I and pharmacologic study of irinotecan and amrubicin in advanced non-small cell lung cancer

Cited by 14 publications

References 24 publications

Phase I trial of irinotecan and amrubicin with granulocyte colony-stimulating factor support in extensive-stage small-cell lung cancer

Phase I trial of irinotecan and amrubicin with granulocyte colony-stimulating factor support in extensive-stage small-cell lung cancer

Efficacy of Combination Treatment and Influence of Schedule with Irinotecan and Amrubicin in Human Lung Carcinoma Cells in Vivo and in Vitro

Simple and sensitive HPLC method for determination of amrubicin and amrubicinol in human plasma: application to a clinical pharmacokinetic study

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