Benzamides

An increased understanding of the molecular etiology of cancer has enabled the development of novel therapies that are collectively referred to as molecular targeted agents. Unlike the drugs used in conventional chemotherapy, these agents are designed to specifically interfere with key molecular events that are responsible for the malignant phenotype. They hold great promise for widening the therapeutic window, which would provide more effective treatment options as compared with cytotoxic therapies. In addition, the targeted approach that is characteristic of these drugs provides unique opportunities for combination therapies with other anticancer agents that have non-overlapping toxicities. Targeted agents are therefore primed to become invaluable therapeutic tools in the multimodal treatment of cancer. The challenges associated with these novel targeted therapies are distinct from those faced in conventional chemotherapy. These unique challenges include the need to select appropr...

Molecular docking simulation study was carried out to design a novel series of spiro [(2H, 3H)quinazoline-2,1'-cyclohexan]-4(1H)-one derivatives as a new class of effective PARP-1 inhibitors. Spiro [2H-3,1-benzoxazine-2,1'-cyclohexan]-4(1H)-one (5) was the starting compound to synthesize the target proposed analogues. The derivatives that showed the top scores and had the best fitting in the binding sites of the target protein were selected to evaluate their in vitro anti-proliferative activity against the cultured human breast carcinoma cell line (MCF-7) using doxorubicin as a standard drug. Additionally, the compounds that exhibited the highest cytotoxic efficiency were further subjected to PARP-1 enzyme assay taking 3-aminobenzamide as the reference drug. The structures of the novel derivatives were confirmed on the bases of microanalytical and spectral data.

The mechanisms of cell killing by oxidative stress, in particular by hydrogen peroxide, are not yet well clarified. Here, we show that during recovery after H(2)O(2) treatment, apoptosis occurs in two different waves, peaking at 8 h (early) and 18 h (late) of recovery from oxidative stress. The two peaks are differentially modulated by a set of inhibitors of metabolic processes, which suggests that the first peak depends on DNA break formation, whereas the second may be correlated with H(2)O(2)-induced mitochondrial alterations.

Imatinib mesylate has become an effective agent for the treatment of chronic myeloid leukemia (CML). However, the development of drug resistance has led to examination of combination therapies. In this study, we investigated the effects of combining imatinib with immunotherapy against a murine bcr-abl+ leukemia, 12B1. We have previously shown that multiple chaperone proteins may be enriched into a vaccine form from tumor cell lysates by a free-solution isoelectric focusing method. We refer to these vaccines as chaperone-rich cell lysates (CRCLs) and have found that they are potent immunologic agents against a variety of murine tumors, including 12B1. We now demonstrate that the combination of imatinib with dendritic cells loaded with 12B1-derived CRCL yields high activation of anti-12B1-specific T cells and potent antitumor activity, resulting in tumor-free survival in up to 63% of mice with bcr-abl+ 12B1 tumors. Our data suggest that immunotherapy can be effectively combined with imatinib for the treatment of CML. © 2004 Wiley-Liss, Inc.

Oncogenic mutations in RAS or BRAF can drive the inappropriate activation of the ERK1/2. In many cases, tumour cells adapt to become addicted to this deregulated ERK1/2 signalling for their proliferation, providing a therapeutic window for tumour-selective growth inhibition. As a result, inhibition of ERK1/2 signalling by BRAF or MEK1/2 inhibitors is an attractive therapeutic strategy. Indeed, the first BRAF inhibitor, vemurafenib, has now been approved for clinical use, while clinical evaluation of MEK1/2 inhibitors is at an advanced stage. Despite this progress, it is apparent that tumour cells adapt quickly to these new targeted agents so that tumours with acquired resistance can emerge within 6–9 months of primary treatment. One of the major reasons for this is that tumour cells typically respond to BRAF or MEK1/2 inhibitors by undergoing a G1 cell cycle arrest rather than dying. Indeed, although inhibition of ERK1/2 invariably increases the expression of pro-apoptotic BCL2 fami...

A new analytical method using gas chromatography with mass spectrometry (GC–MS) for the quantitative determination of lufenuron, a benzoylphenylurea (BPU) class of insecticide, from wheat flour has been developed and applied for time-dependant residue monitoring in treated wheat flour. The analyte was extracted from wheat flour by a single step solid–liquid extraction by using ethyl acetate and subsequently cleaned up using the Primary Secondary Amine as a sorbent prior to GC–MS analysis. The present method provides sufficient sensitivity as reflected by the values of limit of detection (LOD) and limit of quantification (LOQ), 5 ng/mL (S/N ∼3) and 50 ng/mL (the lowest validation point on the calibration curve), respectively. The calibration curve showed an excellent linearity in the concentration range of 50–1000 ng/mL (r2 = 0.998). The average recovery for spiked samples at three concentrations (150, 300, and 450 ng/g) was 98.23 ± 2.52% R.S.D. The method was applied for the determination of lufenuron residues in treated wheat flour samples. Simultaneous determination of bio-efficacy of lufenuron residues was also carried out against the red flour beetle, Tribolium castaneum to correlate the actual residual effect of lufenuron as detected by the analytical method, over a period of 3 months. The findings revealed that the residual concentration of lufenuron were neither uniform nor in descending order over a period of 3 months in wheat flour, possibly because of an uneven dispersal in the treated wheat which was subsequently milled into flour, as confirmed by GC–MS analysis. However, the residues of lufenuron were sufficient to produce 100% mortality of T. castaneum larvae up to 3 months. The results have been discussed in view of the potential of lufenuron as a candidate molecule for the control of stored product pests.

Treatment of gastrointestinal stromal tumors (GIST) has been revolutioned by the recently discovered molecular mechanism responsible for the oncogenesis of this disease. In addition, due to the rapid progress at molecular and clinical level observed in the last few years, there is a need to review the current state of the art in order to delineate appropriate guidelines for the optimal management of these tumors. A panel of experts from several specialities, including medical oncology, surgery, pathology, molecular biology and imaging, were invited to participate in a meeting to present and discuss a number of pre-selected questions, and to achieve a consensus according to the categories of the National Comprehensive Cancer Network (NCCN) and the Standard Options Recommandations (SOR) of the French Federation of Cancer Centers. Generally, consensus points were from categories 2A of the NCCN and B2 of the SOR. Conventional histologic examination with immunohistochemistry for CD117, C...