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991.
Pinkerton AB Vernier JM Schaffhauser H Rowe BA Campbell UC Rodriguez DE Lorrain DS Baccei CS Daggett LP Bristow LJ 《Journal of medicinal chemistry》2004,47(18):4595-4599
Herein we disclose the discovery of a new class of positive allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2), phenyl-tetrazolyl acetophenones, e.g. 1-(2-hydroxy-3-propyl-4-[4-[4-(2H-tetrazol-5-yl)phenoxy]butoxy]phenyl) ethanone (4). These potentiators were shown to have no effect in the absence of glutamate as well as no effect at mGlu3 or the other mGlu receptors. The compounds were also evaluated in rodent models with potential relevance for schizophrenia, and 4 was shown to have activity in the inhibition of ketamine-induced norepinephrine release and ketamine-induced hyperactivity. This represents the first example of the efficacy of mGlu2 receptor potentiators in these models. 相似文献
992.
Deprez E Barbe S Kolaski M Leh H Zouhiri F Auclair C Brochon JC Le Bret M Mouscadet JF 《Molecular pharmacology》2004,65(1):85-98
Styrylquinoline derivatives (SQ) efficiently inhibit the 3'-processing activity of integrase (IN) with IC50 values of between 0.5 and 5 microM. We studied the mechanism of action of these compounds in vitro. First, we used steady-state fluorescence anisotropy to assay the effects of the SQ derivatives on the formation of IN-viral DNA complexes independently of the catalytic process. The IC50 values obtained in activity and DNA-binding tests were similar, suggesting that the inhibition of 3'-processing can be fully explained by the prevention of IN-DNA recognition. SQ compounds act in a competitive manner, with Ki values of between 400 and 900 nM. In contrast, SQs did not inhibit 3'-processing when IN-DNA complexes were preassembled. Computational docking followed or not by molecular dynamics using the catalytic core of HIV-1 IN suggested a competitive inhibition mechanism, which is consistent with our previous data obtained with the corresponding Rous sarcoma virus domain. Second, we used preassembled IN-preprocessed DNA complexes to assay the potency of SQs against the strand transfer reaction, independently of 3'-processing. Inhibition occurred even if the efficiency was decreased by about 5- to 10-fold. Our results suggest that two inhibitor-binding modes exist: the first one prevents the binding of the viral DNA and then the two subsequent reactions (i.e., 3'-processing and strand transfer), whereas the second one prevents the binding of target DNA, thus inhibiting strand transfer. SQ derivatives have a higher affinity for the first site, in contrast to that observed for the diketo acids, which preferentially bind to the second one. 相似文献
993.
Long-term radioiodine retention and regression of liver cancer after sodium iodide symporter gene transfer in wistar rats 总被引:6,自引:0,他引:6
Faivre J Clerc J Gérolami R Hervé J Longuet M Liu B Roux J Moal F Perricaudet M Bréchot C 《Cancer research》2004,64(21):8045-8051
Radioiodine therapy of nonthyroid cancers after sodium iodide symporter (NIS) gene delivery has been proposed as a potential application of gene therapy. However, it seems to be precluded by the rapid efflux of taken up iodine from most transduced xenografted tumors. We present an in vivo kinetic study of NIS-related hepatic iodine uptake in an aggressive model of hepatocarcinoma induced by diethylnitrosamine in immunocompetent Wistar rats. We followed the whole-body iodine distribution by repeated imaging of live animals. We constructed a rat NIS (rNIS) adenoviral vector, Ad-CMV-rNIS, using the cytomegalovirus (CMV) as a promoter. Injected in the portal vein in 5 healthy and 25 hepatocarcinoma-bearing rats and liver tumors in 9 hepatocarcinoma-bearing rats, Ad-CMV-rNIS drove expression of a functional NIS protein by hepatocytes and allowed marked (from 20 to 30% of the injected dose) and sustained (>11 days) iodine uptake. This contrasts with the massive iodine efflux found in vitro in human hepatic tumor cell lines. In vivo specific inhibition of NIS by sodium perchlorate led to a rapid iodine efflux from the liver, indicating that the sustained uptake was not attributable to an active retention mechanism but to permanent recycling of the effluent radioiodine via the high hepatic blood flow. Radioiodine therapy after Ad-CMV-rNIS administration achieved a strong inhibition of tumor growth, the complete regression of small nodules, and prolonged survival of hepatocarcinoma-bearing rats. This demonstrates for the first time the efficacy of NIS-based radiotherapy in a relevant preclinical model of nonthyroid human carcinogenesis. 相似文献
994.
APC mutations are infrequent but present in human lung cancer 总被引:3,自引:0,他引:3
Since it is well established that inactivation of p53 is involved in pathogenesis of breast cancer, it seems to be reasonable to assume that p53 genetic polymorphism at codon 72 (p53Arg72Pro) which affects the function of p53 might have an influence on breast cancer risk. Thus, in the present study, we have studied the association of p53Arg72Pro polymorphism with breast cancer risk. A case–control study was conducted with 191 breast cancer patients and 218 healthy female controls. p53Arg72Pro polymorphism was examined in their association with breast cancer risk after adjustment for the epidemiological risk factors. Relationship between p53Arg72Pro polymorphism and clinicopathological characteristics of breast cancers was also studied. In addition, frequency of somatic p53 mutation was compared according to the genotype of p53Arg72Pro polymorphism. p5372Pro/Pro homozygotes showed a significant increase in the risk of estrogen receptor (ER) positive breast cancer (adjusted odds ratio (OR)=2.04, P=0.04) as compared with p5372Arg/Arg homozygotes, whereas such an association was not found between p5372Pro/Pro homozygotes and ER negative breast cancer risk. Subset analysis according to menopausal status showed that p5372Pro/Pro homozygotes were significantly associated with ER positive breast cancer risk in postmenopausal women (adjusted OR=3.42, P=0.01) but not in premenopausal women. Frequency of ER positive tumors was significantly (p<0.01) higher in breast cancer patients with p5372Pro/Pro genotype (82.8%) than those with p5372Arg/Arg genotype (54.5%). Mutational analysis of p53 in tumors showed that p5372Pro/Pro homozygotes had a lower frequency of p53 mutation (3.5%) than p5372Arg/Arg homozygotes (10.5%). It is suggested that p53Arg72Pro polymorphism is associated with ER positive breast cancer risk, especially, in postmenopausal women. The higher frequency of p53 somatic mutation in p5372Arg/Arg homozygotes than p5372Pro/Pro homozygotes is consistent with the thesis that the function of p5372Pro/Pro is impaired so that a further alteration of p53 gene is less required in p5372Pro/Pro homozygotes than p5372Arg/Arg homozygotes. 相似文献
995.
Diéras V Guastalla JP Ferrero JM Curé H Weber B Winckel P Lortholary A Mayer F Paraiso D Magherini E Pujade-Lauraine E 《Cancer chemotherapy and pharmacology》2004,53(6):489-495
Purpose A multicenter phase II study to evaluate the antitumor effect and safety of docetaxel in combination with cisplatin as first-line chemotherapy for advanced ovarian cancer.Methods Enrolled in the study were 45 patients who were to receive six courses of docetaxel 75 mg/m2 plus cisplatin 75 mg/m2 every 21 days with hydration and steroid prophylaxis after initial debulking surgery. Imaging techniques and radiography were used to assess clinical tumor response, and second-look surgery was required for patients with complete clinical responses and for those without clinically measurable disease.Results The overall clinical response rate in 29 patients with clinically measurable disease was 58% (41% complete response). A complete pathologic response was seen in 9 of 34 patients who underwent second-look laparotomy, while microscopic disease was found in 10 patients. The median time to progression was 14.4 months (95% CI 8.4–20.4 months), with a median overall survival of 43 months (95% CI 21.1–65.0 months). Patients received a median number of six cycles at a dose intensity of 98%. Grade 3–4 neutropenia was seen in 80% of patients, but was manageable. No patients withdrew because of fluid retention.Conclusions The combination of docetaxel with cisplatin confers high clinical and pathologically verified tumor response rates and is well tolerated in the first-line management of advanced ovarian cancer. 相似文献
996.
Huang H Okamoto Y Yokoo H Heppner FL Vital A Fevre-Montange M Jouvet A Yonekawa Y Lazaridis EN Kleihues P Ohgaki H 《Oncogene》2004,23(35):6012-6022
The histological diagnosis of low-grade astrocytomas and oligodendrogliomas (WHO grade II) is often challenging, particularly in cases that show both astrocytic and oligodendroglial differentiation. We carried out gene expression profiling on 17 oligodendrogliomas (93% with LOH 1p and/or 19q) and 15 low-grade astrocytomas (71% with a TP53 mutation), using a cDNA array containing 1176 cancer-related genes. In oligodendrogliomas, 40 genes showed on average higher expression (at least a two-fold increase) than in astrocytomas, including DES, TDGF1, TGF-beta, GABA-BR1A, Histone H4, CDKN1A, PCDH43, Rho7 and Jun-D, while 39 genes were expressed at lower levels (at least a two-fold decrease), including JNK2, ITGB4, JNK3A2, RhoC, IFI-56K, AAD14 and EGFR. Immunohistochemistry revealed nuclear staining of Jun-D in oligodendrogliomas, in contrast to the immunoreactivity of cytoplasm and cell processes in low-grade astrocytomas. Partial least-squares analysis of the 79 genes at least two-fold differentially expressed between oligodendrogliomas and low-grade astrocytomas demonstrated perfect separation of oligodendrogliomas from low-grade astrocytomas and normal cerebral white matter. Clustering analysis based on the entire gene set divided the 17 subjects with oligodendrogliomas into two subgroups with significantly different survival (log-rank test, P=0.0305; survival to 5-years, 80 vs 0%, P=0.048). These results demonstrate that oligodendrogliomas and low-grade astrocytomas differ in their gene expression profiles, and that there are subgroups of oligodendroglioma with distinct expression profiles related to clinical outcome. 相似文献
997.
Mouret-Reynier MA Abrial CJ Ferrière JP Amat S Curé HD Kwiatkowski FG Feillel VA Lebouëdec G Penault-Llorca FM Chollet PJ 《Clinical breast cancer》2004,5(4):303-307
This study investigated the efficacy and tolerability of FEC 100 (epirubicin 100 mg/m2 with 5-fluorouracil 500 mg/m2 and cyclophosphamide 500 mg/m2) every 21 days as neoadjuvant chemotherapy in women with stage I-III primary operable breast cancer. Forty patients were treated with 6 cycles of FEC 100, followed by surgery and radiation therapy. In addition, most patients also received an adjuvant treatment for residual disease (11 chemotherapies and 31 tamoxifen). After 6 cycles of FEC 100, the overall clinical response rate of 75% (CI 95%, 61.6-88.4) was achieved, 22.5% of which were complete responses. Breast conservation was achieved in 70% of patients. A pathologic complete response was confirmed in 6 patients (15%; CI 95%, 3.9-26.1) using Chevallier's classification and in 10 patients (25%; CI 95%, 11.6-38.4) using Sataloff's classification. After a median follow-up of 29.5 months, 3 metastatic relapses were observed. The principal toxicity of FEC 100 was myelosuppression; 51.3% of patients developed grade 3/4 neutropenia. Neoadjuvant FEC 100 was both effective and well tolerated in patients with early-stage operable breast cancer. 相似文献
998.
Baumert H Fromont G Adorno Rosa J Cahill D Cathelineau X Vallancien G 《Journal of endourology / Endourological Society》2004,18(2):173-176
PURPOSE: To describe the experience of a single surgeon with his first 100 laparoscopic radical prostatectomies and determine the impact of the learning curve on the surgical margin status according to the rate of nervesparing procedures. PATIENTS AND METHODS: Between December 2000 and April 2002, 100 laparoscopic radical prostatectomies were performed by one surgeon without any selection of patients and without the help of any other surgeon. The procedures were divided in four groups of 25 consecutive cases. There was no significant difference among the groups in terms of age, clinical and pathological stage, or Gleason score. Nerve-sparing (NS) dissection was performed when the procedure was easy. Positive surgical margins (SM+) were measured and classified according to their location. RESULTS: The overall rate of SM+ was 12.8% in pT2 and 31.8% in pT3 tumors. The SM+ rate was not significantly different among the groups. In contrast, the number of NS dissections (49 patients) increased from group 1 to group 4. Both the positive margin length and the rate of multiple positive margins were significantly lower in the 50 most recent patients. CONCLUSION: Nerve-sparing surgery was performed with increasing frequency during this learning curve without compromising the surgical margins. The results suggest that experience could lead to a decrease of both the positive margin length and the rate of multiple positive margins. The impact on cancer control and potency is under evaluation. 相似文献
999.
Thivat E Durando X D'Incan M Cure H Mouret-Reynier MA Madelmont JC Souteyrand P Chollet P 《Anti-cancer drugs》2005,16(9):1003-1007
Nitrosoureas possess some anti-tumor activity as a single agent in metastatic melanoma (MM). In a phase II trial, we evaluated the anti-tumor effects of cystemustine chemotherapy, a new nitrosourea, as a second-line treatment. Patients were required to have histologic evidence of disseminated MM and had failed in first-line chemotherapy. Treatment comprised cystemustine given at a dose of 60 mg/m every 2 weeks by a 15-min infusion. From February 1997 to September 1999, 22 patients (median age 66 years) were enrolled and were assessable. Two complete responses, one partial response, three stable diseases and 16 progressions were observed, giving an overall response rate of 13.6%. Median duration of response was 10 months (range 4-63). Median survival of responders and non-responders was 11 and 4 months, respectively. However, hematological toxicity, particularly thrombopenia, was a limiting factor for one-third of patients. We conclude that cystemustine at 60 mg/m is active in patients who progressed after one line of chemotherapy in advanced disease, and offers the possibility of complete responses and long durations of these responses. 相似文献
1000.
Amé-Thomas P Deschaseaux F Mauny F Bulabois CE Lamy T Hervé P Cahn JY Fest T 《Experimental hematology》2005,33(3):318-328
OBJECTIVE: We hypothesized that the presence of tumor cells in bone marrow (BM) could alter hematopoietic progenitor cell functions. Therefore, we evaluated phenotypic and in vitro functional properties of BM-derived CD34+ progenitors issued from untreated and newly diagnosed patients presenting a mature B-lymphoproliferative disorder (LPD) involving the BM (Inv+). PATIENTS AND METHODS: In vitro proliferation and differentiation capacities of primitive and committed progenitors were evaluated by cobblestone area-forming cell (CAFC) and colony-forming cell (CFC) assays, and ex vivo cell expansion. Migratory capacities of CD34+ cells were explored by chemotaxis assays using a CXCL12alpha gradient. RESULTS: Our results showed that CD34+ cells from Inv+ patients overexpressed CD117 and had a significant decrease of week-3 and -6 CAFC, and CFC frequencies, compared to cells obtained from healthy volunteers and LPD patients without BM involvement (Inv-). In addition, progenitors from Inv+ patients maintained a significantly decreased CFC capacity after ex vivo cell expansion, compared to healthy volunteers. However, the former cells held their migratory capacity in response to CXCL12alpha. CONCLUSION: Functional defects of primitive and committed CD34+ progenitors detected among LPD patients with BM tumor involvement suggest either that tumor cells may induced bystander effects on progenitors or that "unusual" CD34+ cells may exist in the BM that could belong to the proliferating tumor tissue. 相似文献