title: Amrubicin, a novel 9-aminoanthracycline, enhances the antitumor activity of chemotherapeutic agents against human cancer cells in vitro and in vivo.
abstract: Amrubicin, a completely synthetic 9-aminoanthracycline derivative, is an active agent in the treatment of untreated extensive disease-small-cell lung cancer and advanced non-small-cell lung cancer. Amrubicin administered intravenously at 25 mg/kg substantially prevented the growth of five of six human lung cancer xenografts established in athymic nude mice, confirming that amrubicin as a single agent was active in human lung tumors. To survey which antitumor agent available for clinical use produces a synergistic interaction with amrubicin, we examined the effects in combinations with amrubicinol, an active metabolite of amrubicin, of several chemotherapeutic agents in vitro using five human cancer cell lines using the combination index (CI) method of Chou and Talalay. Synergistic effects were obtained on the simultaneous use of amrubicinol with cisplatin, irinotecan, gefitinib and trastuzumab, with CI values after 3 days of exposure being <1. Additive effect was observed with the combination containing vinorelbine with CI values indistinguishable from 1, while the combination of amrubicinol with gemcitabine was antagonistic. All combinations tested in vivo were well tolerated. The combinations of cisplatin, irinotecan, vinorelbine, trastuzumab, tegafur/uracil, and to a lesser extent, gemcitabine with amrubicin caused significant growth inhibition of human tumor xenografts without pronouncedly enhancing body weight loss, compared with treatment using amrubicin alone at the maximum tolerated dose. Growth inhibition of tumors by gefitinib was not antagonized by amrubicin. These results suggest that amrubicin appears to be a possible candidate for combined use with cisplatin, irinotecan, vinorelbine, gemcitabine, tegafur/uracil or trastuzumab.
authors.affiliation: Pharmacology Research Laboratories, Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugadenaka, Konohana-ku, Osaka 554-0022, Japan. mitsuharu-hanada@ds-pharma.co.jp
authors.forename: Mitsuhara
authors.initials: M
authors.lastname: Hanada
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Noguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamaoka
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000737:chemistry / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D018288:Carcinoma, Small Cell / Q000188:drug therapy; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D066298:In Vitro Techniques; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D011799:Quinazolines / Q000627:therapeutic use; D011897:Random Allocation; D013274:Stomach Neoplasms / Q000188:drug therapy; D005641:Tegafur / Q000627:therapeutic use; D000068878:Trastuzumab; D014498:Uracil / Q000627:therapeutic use; D014747:Vinblastine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077235:Vinorelbine; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D018943:Anthracyclines; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D011799:Quinazolines; C116173:amrubicinol; D003841:Deoxycytidine; D005641:Tegafur; D014498:Uracil; D014747:Vinblastine; D000077146:Irinotecan; C055866:amrubicin; D000068878:Trastuzumab; D002945:Cisplatin; D000077235:Vinorelbine; D000077156:Gefitinib; D002166:Camptothecin; D000093542:Gemcitabine