Abstract
The tissue distribution of a novel antitumor anthracycline antibiotic, amrubicin, was studied using seven human tumor xenografts implanted into nude mice, in order to identify the principal factors determining its therapeutic efficacy. We found a good correlation between the level of the metabolite amrubicinol in the tumor and the in vivo efficacy. High metabolic activity of amrubicin to amrubicinol was detected in tumor tissue homogenates, especially in cell lines highly sensitive to amrubicin in vivo. In contrast to amrubicin, the administration of amrubicinol showed less tumor‐selective toxicity in these human tumor xenograft models. These data indicate that the tumor‐selective metabolism of amrubicin to amrubicinol resulted in a tumor‐selective disposition of amrubicinol, leading to good efficacy in in vivo experimental therapeutic models.
Keywords: Anthracycline, Amrubicin, SM‐5887, Active metabolite, Pharmacokinetics
Full Text
The Full Text of this article is available as a PDF (93.7 KB).
REFERENCES
- 1. ) Ishizumi , K. , Ohashi , N. and Tanno , N.Stereospecific total synthesis of 9‐aminoanthracyclines: (+)‐9‐amino‐9‐deoxydaunomycin and related compounds . J. Org. Chem. , 50 , 4477 – 4485 ( 1987. ). [Google Scholar]
- 2. ) Morisada , S. , Yanagi , Y. , Noguchi , T. , Kashiwazaki , Y. and Fukui , M.Antitumor activities of a novel 9‐aminoanthracycline (SM‐5887) against mouse experimental tumors and human tumor xenografts . Jpn. J. Cancer Res. , 80 , 69 – 76 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. ) Yokota , S. , Negoro , S. , Yana , T. , Takada , Y. , Fukuoka , M.and The West Japan Lung Cancer Group. Phase II study of amrubicin (SM‐5887), a novel 9‐aminoanthracycline, in previously untreated patients with extensive‐stage small‐cell lung cancer (ES‐SCLC): a trial of The West Japan Lung Cancer Group . 8th World Conference on Lung Cancer , A1756 ( 1997. ). [Google Scholar]
- 4. ) Hiraki , S. , Shinkai , T. , Furuse , K. , Fukuoka , M. , Ohnoshi , T. , Kimura , I.and The SM‐5887 Lung Cancer Study Group. A phase II of SM‐5887, a novel 9‐aminoanthracycline, for non‐small cell lung cancer . 18th International Congress of Chemotherapy , æ 726 ( 1993. ). [Google Scholar]
- 5. ) Takigawa , N. , Ohnoshi , T. , Ueoka , H. , Kiura , K. and Kimura , I.Comparison of antitumor activity of new anthracycline analogues, ME2303, KRN8602, and SM5887 using human lung cancer cell lines . Acta Med. Okayama , 46 , 249 – 256 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 6. ) Yamaoka , T. , Hanada , M. , Ichii , S. , Morisada , S. , Noguchi , T. and Yanagi , Y.Cytotoxicity of amrubicin, a novel 9‐aminoanthracycline, and its active metabolite amrubicinol on human tumor cells . Jpn. J. Cancer Res. , 89 , 1061 – 1067 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. ) Noguchi , T. , Ichii , S. , Morisada , S. , Yamaoka , T. and Yanagi , Y.Tumor‐selective distribution of an active metabolite of the 9‐aminoanthracycline amrubicin . Jpn. J. Cancer Res. , 89 , 1068 – 1073 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. ) Ueyama , Y. and Tamaoki , N.Properties of human tumor lines used in anticancer drug susceptibility panels . In“The Nude Mouse and Anticancer Drug Evaluation ,” ed. Nomura T. , Sakurai Y. and Inaba M. , pp. 7 – 28 ( 1996. ). Japanese Journal of Cancer and Chemotherapy Publishers Inc. , Tokyo . [Google Scholar]
- 9. ) Inaba , M.Experimental treatment protocols . In “ The Nude Mouse and Anticancer Drug Evaluation ,” ed. Nomura T. , Sakurai Y. and Inaba M. , pp. 43 – 45 ( 1996. ). Japanese Journal of Cancer and Chemotherapy Publishers Inc. , Tokyo . [Google Scholar]
- 10. ) Matsushita , Y. , Iguchi , H. , Kiyosaki , T. , Tone , H. and Ishikura , T.A high performance liquid chromatographic method of analysis of 4′‐O‐tetrahydropyranyladriamycin and their metabolites in biological samples . J. Antibiot. , 36 , 880 – 886 ( 1983. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Ohara , H. , Miyabe , Y. , Deyashiki , Y. , Matsuura , K. and Hara , A.Reduction of drug ketones by dihydrodiol dehydrogenases, carbonyl reductase and aldehyde reductase of human liver . Biochem. Pharmacol. , 50 , 221 – 227 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Wirth , H. and Wermuth , B.Immunohistochemical localization of carbonyl reductase in human tissues . J. Histochem. Cytochem. , 40 , 1857 – 1863 ( 1992. ). [DOI] [PubMed] [Google Scholar]