bms184476 and Lung-Neoplasms

The taxanes are among the most active cytotoxic agents in oncology and are widely used in adjuvant and advanced treatment settings in multiple tumor types. Paclitaxel and docetaxel are standard therapies in advanced non-small-cell lung cancer (NSCLC) and are increasingly used in earlier treatment settings. The taxanes are generally well tolerated but can be associated with severe, irreversible (and rarely life-threatening) toxicity. Premedication and special infusion sets are necessary to reduce the risk of hypersensitivity reactions. Newer taxanes are in development designed to improve the therapeutic index and ease of administration. Several agents have completed phase I/II clinical trials and are in phase III testing. Many other novel taxanes are at earlier stages of development and appear promising as single agents and in combination regimens. Safer and more effective taxanes could replace paclitaxel and docetaxel as standard treatments in NSCLC.

Topics: Antineoplastic Agents, Phytogenic; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cross-Linking Reagents; Docetaxel; Humans; Lung Neoplasms; Paclitaxel; Taxoids

The purpose of this study was to evaluate the tolerability and efficacy of BMS-184476, an analog of paclitaxel, in patients with advanced non-small-cell lung cancer (NSCLC) progressing or relapsing following at least one prior chemotherapy regimen.. Fifty-six previously treated advanced NSCLC patients received BMS-184476 at a dose of 60 mg/m(2) administered intravenously over 1 h every 21 days.. The median number of cycles delivered per patient was five (range one to 17). Dose reduction was required in only 3.8% of cycles. Grade 4 neutropenia occurred in 19.6% of patients, but no grade 4 thrombocytopenia or anemia was reported. Febrile neutropenia was observed in only two (3.6%) patients and there were no life-threatening events. Grade 3/4 peripheral sensory-motor neuropathy was reported in 9% of patients. Other non-hematological toxicities, such as nausea and vomiting, myalgia and arthralgia, diarrhea, and mucositis, were uncommon. Partial responses were observed in eight (14.3%) patients and stable disease in 33 (58.9%). Median progression-free survival was 3.7 months [95% confidence interval (CI) 2.7-5.4] and median overall survival was 10 months (95% CI 6-13.4).. BMS-184476 was well tolerated at the dose of 60 mg/m(2) and showed evidence of antitumor activity in previously treated NSCLC.

Topics: Adult; Aged; Carcinoma, Non-Small-Cell Lung; Female; Gastrointestinal Diseases; Humans; Lung Neoplasms; Male; Middle Aged; Survival Analysis; Taxoids

To evaluate the novel taxane analogs, BMS-184476 and BMS-188797, as potential radiosensitizers in vitro and in vivo.. Human H460 lung cancer cells were incubated with either paclitaxel or a taxane analog and irradiated at various times. Surviving fractions were then determined using a clonogenic assay. Three different schedules were used: (A) 1-h drug incubation with radiation at t = 8 h, (B) 1-h drug incubation with radiation at t = 24 h, (C) 24-h drug incubation with radiation immediately after. Cell cycle redistribution by taxanes alone was measured with propidium iodide and flow cytometry. Percent apoptosis was also measured using 7-aminoactinomycin D (7-AAD) staining with flow cytometry. For in vivo studies, H460 cell xenografts were used in nude mice. Tumors were grown s.c. on the flank and then treated with BMS-184476 (10 mg/kg i.p. injection, Days 0, 2, and 4) and/or radiation (2 Gy/day, Days 0-4). Tumor growth delay was then measured for each treatment group.. The mean in vitro radiation dose enhancement ratios of BMS-184476, BMS-188797, and paclitaxel were 1.76, 1.49, and 1.31 for Schedules A, B, and C, respectively. Isobologram analysis showed that BMS-184476 was synergistic with radiation using Schedule A. Treatment with taxanes caused an increase in the percentage of G2/M cells at the time of irradiation. The mean fold increases in the %G2/M above control values for all three drugs were 5.6, 2.5, and 1.7 for Schedules A, B, and C, respectively. The combined effects of taxanes plus radiation on the induction of apoptosis were additive for all three drugs. In vivo studies showed that BMS-184476 can enhance the effects of fractionated radiotherapy, with an average enhancement factor of 1.66 obtained from three independent experiments.. These results demonstrated that the novel taxane analogs, BMS-184476 and BMS-188797, can enhance the effects of radiation in human lung cancer cells both in vitro and in vivo. These data also support the hypothesis that a G2/M block is involved in the radiosensitization caused by the taxanes.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle; Humans; Interphase; Lung Neoplasms; Paclitaxel; Radiation-Sensitizing Agents; Taxoids; Tumor Cells, Cultured