amrubicin and Stomach-Neoplasms

Idarubicin showed the superior activity against Acute Non-Lymphocytic Leukemia (ANLL) in the prospective randomized trials comparing to daunorubicin and it is judged that the analog will become the first choice in the treatment on ANLL. Anthracyclines including SM-5887, KRN-8602, ME-2303 under studies in Japan have shown comparable or superior antitumor activities and lower cardiac toxicities compared to doxorubicin in preclinical studies and therefore the results obtained in clinical trials are expected. Phase II trials of anthrapyrazoles which is an analog of mitoxantrone are in progress. Among three compounds entered it is of note that CI-941 has demonstrated an excellent activity against advanced breast cancer.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Brain Neoplasms; Carubicin; Doxorubicin; Humans; Idarubicin; Leukemia, Experimental; Leukemia, Myeloid, Acute; Menogaril; Stomach Neoplasms

Idarubicin showed the superior activity against Acute Non-Lymphocytic Leukemia (ANLL) in the prospective randomized trials comparing to daunorubicin and it is judged that the analog will become the first choice in the treatment on ANLL. Anthracyclines including SM-5887, KRN-8602, ME-2303 under studies in Japan have shown comparable or superior antitumor activities and lower cardiac toxicities compared to doxorubicin in preclinical studies and therefore the results obtained in clinical trials are expected. Phase II trials of anthrapyrazoles which is an analog of mitoxantrone are in progress. Among three compounds entered it is of note that CI-941 has demonstrated an excellent activity against advanced breast cancer.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Brain Neoplasms; Carubicin; Doxorubicin; Humans; Idarubicin; Leukemia, Experimental; Leukemia, Myeloid, Acute; Menogaril; Stomach Neoplasms

Extrapulmonary neuroendocrine carcinoma (NEC) is a rare disease, and there is no standard chemotherapy. A 73-year-old man was diagnosed with advanced gastric NEC. He received chemotherapy of irinotecan plus cisplatin, and amrubicin monotherapy. After failure of second-line chemotherapy, he received ramucirumab plus paclitaxel; this treatment was chosen because vascular endothelial growth factor 2 was strongly expressed in the tumor endothelial cells. After two cycles, his NEC had markedly reduced in size, and he continued with this treatment for over eight months. In this case, the combination of an anti-angiogenic inhibitor and a cytotoxic agent was highly effective for gastric NEC.

Topics: Aged; Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Neuroendocrine; Cisplatin; Humans; Irinotecan; Male; Paclitaxel; Ramucirumab; Stomach Neoplasms

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.

Topics: Animals; Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Camptothecin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Line, Tumor; Cisplatin; Deoxycytidine; Drug Synergism; Female; Gefitinib; Gemcitabine; Humans; In Vitro Techniques; Irinotecan; Lung Neoplasms; Mice; Mice, Nude; Quinazolines; Random Allocation; Stomach Neoplasms; Tegafur; Trastuzumab; Uracil; Vinblastine; Vinorelbine; Xenograft Model Antitumor Assays

It was reported that amrubicin hydrochloride (9-aminoanthracycline SM-5887), showed a higher therapeutic activity than doxorubicin against human tumor xenografts implanted into nude mice with a single treatment schedule. In order to find a more effective treatment schedule, the efficacy, toxicity and pharmacokinetic properties with a 5 consecutive day treatment schedule were investigated. The total amount of the maximum tolerated dose and tumor growth inhibiting activity with a 5 day schedule was found to be higher than with a single administration. High levels of amrubicinol, the active metabolite of amrubicin, was detected in the tumor tissue. It was thus assumed that the improved efficacy with the 5-day schedule resulted from the high accumulation of amrubicinol. Bone marrow suppression at the MTD with the 5 day schedule was severer than with a single dose, but recovery was rapid, similar to that following a single dose. In conclusion, it was demonstrated that a 5 day treatment schedule was more effective than a single administration.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Stomach Neoplasms; Transplantation, Heterologous

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.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Biotransformation; Breast Neoplasms; Female; Humans; Leukemia P388; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Mice, Nude; Stomach Neoplasms; Structure-Activity Relationship; Tissue Distribution; Transplantation, Heterologous; Tumor Cells, Cultured

It has been reported that the 9-aminoanthracycline amrubicin shows good efficacy in human tumor xenograft models. We studied the disposition and metabolism of amrubicin in mice, in comparison with those of doxorubicin. Amrubicinol, a 13-hydroxy metabolite of amrubicin, which is 10 to 100 times more cytotoxic than amrubicin, was detected as a major metabolite in blood and tissues, and aglycones of amrubicin were also detected. A pharmacokinetic study revealed that amrubicin had a smaller distribution volume and a shorter half-life than doxorubicin. In several normal tissues, the levels of amrubicin and amrubicinol were lower than those of doxorubicin. In contrast, the tumor levels of amrubicinol in the mice treated with amrubicin were higher than those of doxorubicin in the mice treated with that drug, in tumors that are sensitive to amrubicin. These results suggest that the potent therapeutic activity of amrubicin is caused by the selective distribution of its highly active metabolite, amrubicinol, in tumors.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Doxorubicin; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Biological; Stomach Neoplasms; Tissue Distribution; Transplantation, Heterologous

A phase II clinical trial of SM-5887, a new totally synthesized anthracycline derivative, was carried out in 13 patients with inoperable or recurrent gastric cancer. No patient had been given anthracycline previously. SM-5887 was administered by I.V. bolus with a dose of 100 mg/m2 every three weeks. Twelve of 13 cases were eligible and evaluable for the response. Of the 12 evaluated cases, 6 showed no change (NC), including one minor response (MR). The remaining 6 cases showed progressive disease (PD). Adverse effects were relatively mild in most cases and included anemia, leukocytopenia, thrombocytopenia, nausea/vomiting, phlebitis, hair loss and fever. Among them, leukocytopenia was observed most frequently.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Papillary; Adult; Aged; Anthracyclines; Antibiotics, Antineoplastic; Drug Administration Schedule; Drug Evaluation; Female; Humans; Injections, Intravenous; Leukopenia; Male; Middle Aged; Stomach Neoplasms

SM-5887, a new totally synthetic anthracycline derivative, was studied in a phase I setting. Twenty-nine evaluable courses of treatment were conducted in groups at doses increasing from 10 to 130 mg/m2. At 130 mg/m2 the median lowest WBC count was 0.7 x 10(3)/mm3 (range 0.3-1.8) and the median lowest platelet count was 57 x 10(3)/mm3 (range 4-176). Nonhematological side effects were mild gastrointestinal symptoms and hair loss. The recommended dose and schedule for a phase II setting is 100 mg/m2 every 3 weeks.

Topics: Adult; Aged; Animals; Anthracyclines; Antibiotics, Antineoplastic; Breast Neoplasms; Colonic Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred ICR; Middle Aged; Naphthacenes; Stomach Neoplasms