Safety and Efficacy of Everolimus With Exemestane vs. Exemestane Alone in Elderly Patients With HER2-Negative,Hormone Receptor–Positive Breast Cancer in BOLERO-2

BackgroundPostmenopausal women with hormone receptor–positive (HR⁺) breast cancer in whom disease progresses or there is recurrence while taking a nonsteroidal aromatase inhibitor (NSAI) are usually treated with exemestane (EXE), but no single standard of care exists in this setting. The BOLERO-2 trial demonstrated that adding everolimus (EVE) to EXE improved progression-free survival (PFS) while maintaining quality of life when compared with EXE alone. Because many women with HR⁺ advanced breast cancer are elderly, the tolerability profile of EVE plus EXE in this population is of interest.Patients and MethodsBOLERO-2, a phase III randomized trial, compared EVE (10 mg/d) and placebo (PBO), both plus EXE (25 mg/d), in 724 postmenopausal women with HR⁺ advanced breast cancer recurring/progressing after treatment with NSAIs. Safety and efficacy data in elderly patients are reported at 18-month median follow-up.ResultsBaseline disease characteristics and treatment histories among the elderly subsets (≥ 65 years, n = 275; ≥ 70 years, n = 164) were generally comparable with younger patients. The addition of EVE to EXE improved PFS regardless of age (hazard ratio, 0.59 [≥ 65 years] and 0.45 [≥ 70 years]). Adverse events (AEs) of special interest (all grades) that occurred more frequently with EVE than with PBO included stomatitis, infections, rash, pneumonitis, and hyperglycemia. Elderly EVE-treated patients had similar incidences of these AEs as did younger patients but had more on-treatment deaths.ConclusionAdding EVE to EXE offers substantially improved PFS over EXE and was generally well tolerated in elderly patients with HR⁺ advanced breast cancer. Careful monitoring and appropriate dose reductions or interruptions for AE management are recommended during treatment with EVE in this patient population.     

Structural relationships of stemona alkaloids: assessment of species-specific accumulation trends for exploiting their biological activities

On the basis of a comparison of 42 Stemona samples, representing eight different species collected and cultivated in Thailand, species-specific accumulation trends of Stemona alkaloids were analyzed. An overview was achieved by comparative HPLC analyses of methanolic crude extracts of underground parts coupled with diode array or evaporative light scattering detectors. All major compounds were isolated and their structures elucidated by NMR and MS analyses. Protostemonine- and stichoneurine-type derivatives dominated, from which the latter characterize S. tuberosa and S. phyllantha accumulating species-specific isomers of tuberostemonine (3). The widespread S. curtisii and S. collinsiae clearly deviate by protostemonine-type derivatives dominated by stemofoline (10) and/or didehydrostemofoline (11). Further diversification within this structural type results from a mutual accumulation of derivatives with a pyrrolo- or pyridoazepine nucleus, leading to chemical variability in S. curtisii and S. aphylla.     

Inhibitory effects of Phyllanthus amarus and its major lignans on human microsomal cytochrome P450 activities: evidence for CYP3A4 mechanism-based inhibition

Phyllanthus amarus has long been used as a herbal medicine in several countries. Phytochemicals in herbal medicine may interact with cytochromes P450 (CYP) and thus raise the potential of herb-drug interactions; therefore, the inhibitory effects of P. amarus and its major phytochemicals phyllanthin and hypophyllanthin on CYP isoforms were determined using human liver microsomes and selective substrates. Both ethanolic and aqueous extracts of P. amarus inhibited CYP1A2, CYP2D6, CYP2E1 and CYP3A4 in a dose-dependent manner. Compared to known CYP3A inhibitors, the IC(50) values of the ethanolic and aqueous extracts on testosterone 6β-hydroxylation were higher than that of ketoconazole but were lower than those of erythromycin and clarithromycin. Both extracts were weak inhibitors of CYP1A2, CYP2D6 and CYP2E1. In addition, phyllanthin and hypophyllanthin were potent mechanism-based inhibitors of CYP3A4 with K(I) values of 1.75 ± 1.20 μM and 2.24 ± 1.84 μM and k(inact) values of 0.18 ± 0.05 min(-1) and 0.15 ± 0.06 min(-1), respectively. The k(inact)/K(I) ratios of these lignans were higher than those reported for some therapeutic drugs that act as mechanism-based inhibitors of CYP3A4. These results suggest that co-administration of P. amarus with drugs that are metabolized by CYP3A4 may potentially result in herb-drug interactions.     

Localization of anti-lipopolysaccharide factor (ALFPm3) in tissues of the black tiger shrimp, Penaeus monodon, and characterization of its binding properties

Anti-lipopolysaccharide factor (ALF) is an antimicrobial peptide originally identified from horseshoe crabs and recently found in several shrimp species. ALFPm3, the most abundant isoform in the black tiger shrimp, Penaeus monodon, has been shown to possess a broad spectrum of antimicrobial activity against Gram-negative and Gram-positive bacteria, and filamentous fungi. In this study, a potential role for ALFPm3 in the shrimp innate immunity was revealed by examining the distribution of the protein in shrimp tissues in response to Vibrio harveyi challenge. Immunohistochemistry using anti-ALFPm3 antibody showed that the ALFPm3 protein is primarily localized in hemocytes and the positive cells observed at the injection site and in the cephalothorax are infiltrating hemocytes that migrate into shrimp tissues after bacterial injection. A rapid increase in the number of hemocytes producing ALFPm3 observed in V. harveyi-injected shrimp suggests a likely important function of the protein in defense against invading pathogens. ALFPm3 was shown to be able to bind to Gram-negative and Gram-positive bacterial cells and their major cell wall components, lipopolysaccharide (LPS) and lipoteichoic acid (LTA), respectively. The results suggested that ALFPm3 performs its antibacterial activity by binding to component(s) of the bacterial cell wall.     

Gemcitabine and split-dose paclitaxel or docetaxel in metastatic breast cancer: a randomised phase II study

PurposeThe purpose was to evaluate the activity and toxicity of split-dose paclitaxel or docetaxel in combination with gemcitabine in patients with metastatic breast cancer (MBC) who had previously received anthracyclines.Patients and methodsA total of 210 patients were randomly assigned to one of three treatment arms: gemcitabine 1250 mg/m² Days 1 and 8 and paclitaxel 175 mg/m² as a 3-h infusion on Day 1 (GP1); gemcitabine 1000 mg/m² Days 1 and 8 and paclitaxel 100 mg/m² as a 1-h infusion on Days 1 and 8 (GP2); gemcitabine 1000 mg/m² Days 1 and 8 and docetaxel 40 mg/m² as a 1-h infusion on Days 1 and 8 (GD). Cycles were repeated every 3 weeks.ResultsFor the 204 patients evaluable for response assessment, the response rates were 48.6% for GP1, 52.2% for GP2, and 52.3% for GD. Median response duration, time to treatment failure, and time to progression (TTP) were similar in each arm. Median TTP for GP1, GP2 and GD was 7.5, 7.0 and 7.4 months, respectively. For the 208 patients evaluable for safety, the most common grade 3/4 toxicity for each regimen was neutropaenia, with 64%, 57%, and 68% for GP1, GP2, and GD, respectively. Grade 4 neutropaenia, grade 3/4 anaemia, febrile neutropaenia, and diarrhoea were more common in the docetaxel arm, as was the use of intravenous antibiotics and blood transfusions.ConclusionThe study confirmed the high activity of gemcitabine–taxane combinations in MBC. Split-dose paclitaxel had similar activity and toxicity to the 3-weekly administration. The split-dose docetaxel regimen had similar activity to the paclitaxel combinations though associated with higher toxicity.     

Randomized, double-blinded, placebo-controlled trial of ondansetron plus dexamethasone with or without metoclopramide as antiemetic prophylaxis in patients receiving high-dose cisplatin in medical practice

Purposes  

Ondansetron plus dexamethasone are standard antiemetic agents for highly emetogenic chemotherapy. Metoclopramide is a dopamine antagonist, which may enhance efficacy of ondansetron and dexamethasone. The objective of this study was to assess the efficacy and tolerability of metoclopramide added to standard antiemetic regimen for prophylaxis of cisplatin-induced emesis.     

Expression and characterization of a fusion protein‐containing cyclodextrin glycosyltransferase from Paenibacillus sp. A11

A recombinant cyclodextrin glycosyltransferase (CGTase) gene fused with thioredoxin (Trx), hexa‐histidine (His₆) and S‐protein (S) at the N terminus and a proline‐rich peptide (PRP) at the C terminus, was constructed using the wild‐type gene from Paenibacillus sp. A11, the pET‐32a vector and Escherichia coli BL21(DE3) as the host cell. The expression levels and enzyme characteristics of the Trx‐His₆‐CGTase‐PRP fusion protein, the recombinant CGTase without fusion peptides, and the wild‐type CGTase were compared. The maximum specific activity for the Trx‐His₆‐CGTase‐PRP fusion enzyme was 2.7 fold higher than that of the non‐fusion form at the optimal IPTG concentration. The Trx‐His₆‐CGTase‐PRP fusion protein was purified to homogeneity by starch adsorption and Ni‐NTA affinity chromatography, with a specific activity of 2,268 units/mg protein at a 61% yield. The ease of purification and the higher enzyme yield were obtained with the fusion form when compared to the non‐fusion and wild‐type enzymes. The fusion enzyme was superior than its wild‐type counterpart in terms of stability against high temperature and organic solvents. Moreover, the fusion enzyme could catalyze the synthesis of cyclodextrins in 20% (v/v) dimethylformamide with a higher product yield of CD₇ and CD₈ compared to that of the wild‐type enzyme in the same buffer‐solvent system. (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)