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871.
Bilodeau MT Balitza AE Koester TJ Manley PJ Rodman LD Buser-Doepner C Coll KE Fernandes C Gibbs JB Heimbrook DC Huckle WR Kohl N Lynch JJ Mao X McFall RC McLoughlin D Miller-Stein CM Rickert KW Sepp-Lorenzino L Shipman JM Subramanian R Thomas KA Wong BK Yu S Hartman GD 《Journal of medicinal chemistry》2004,47(25):6363-6372
A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution. 相似文献
872.
Lützhøft HC Foged C Rasmussen SR Lehmann S Olsen H 《Journal of pharmaceutical sciences》2004,93(5):1142-1153
Radiolabeled compounds can be used for alleviating the degradation pathways and mass balance of drug products in the solid formulation, because it provides a very sensitive and specific method of locating and measuring particular compounds. The present study utilizes this methodology on levormeloxifene-a partial oestrogen receptor agonist-in the solid dosage form. It demonstrates how radiotracers can be used as a supplement to conventional analytical methods to investigate the degradation pathways and mass balance of drug substances as well as how they can be useful to cross validate the traditional analytical methods developed for the determination of uniformity of content, assay, and purity. To decrease the study time, pilot studies-in which the product was stored at high pressures of molecular oxygen and elevated temperatures-were performed. Conditions mimicking the degradation processes taking place under standard storage conditions of the drug substance were found, and these super-enhanced stress conditions were applied. The study time was thereby dramatically decreased. The produced degradation products were studied by liquid chromatography with mass spectrometric detection. The most important degradation pathway was ascribed to the oxidation of the pyrrolidine nitrogen atom in levormeloxifene to an N-oxide derivative of the drug substance. 相似文献
873.
Alpha1a-adrenergic receptors (alpha1aARs) are present intracellularly and at the cell surface in cultured and natural cell models, where they are subject to agonist-mediated desensitization and internalization. To explore alpha1aAR trafficking, a hemagglutinin (HA)-tagged alpha1aAR/enhanced green fluorescent protein (EGFP) fusion protein was expressed in rat-1 fibroblasts and tracked by EGFP fluorescence and antibody labeling of surface receptors. Confocal analysis of antibody-labeled surface receptors revealed unexpected constitutive internalization in the absence of agonist stimulation. In partial agreement, the inverse agonist prazosin also caused a modest 20 +/- 2% increase in surface receptor levels, suggesting a partial block of constitutive internalization caused by decreased basal activation. However, prazosin was unable to prevent internalization of antibody-tagged surface receptors observed by confocal microscopy or cause obvious redistribution of intracellular receptor to the surface, suggesting that the alpha1aAR is internalizing even in a basal-inactive state. In contrast to the alpha1aAR, surface labeling of an HA-tagged alpha1b-EGFP fusion protein did not result in any apparent constitutive internalization. Constitutive internalization of the alpha1aAR seems to occur alongside reversible agonist-induced internalization, and both seem to involve clathrin-mediated endocytosis but not degradation in lysozymes. Surface receptor density must be maintained by recycling, because the protein synthesis inhibitor cycloheximide has no effect on total or surface receptor density in agonist-treated or untreated cells for 6 h. Constitutive agonist-independent trafficking of alpha1aARs may provide a novel mechanism by which an internal pool of alpha1aARs are maintained and recycled to allow continuous agonist-induced signaling. 相似文献
874.
Lehmann D Nelsen J Ramanath V Newman N Duggan D Smith A 《Journal of clinical pharmacology》2004,44(8):861-865
Tamoxifen is a selective estrogen receptor modulator used in estrogen receptor-positive breast cancer. Tamoxifen is metabolized to an extremely potent antiestrogen by cytochrome P450 (CYP) 2D6, 2C9, and 3A isoforms. The selective serotonin reuptake inhibitors (SSRIs) are potent inhibitors of these CYPs. Since the prevalence of depression in breast cancer patients is nearly triple that of the general population, it is likely that a subgroup of breast cancer patients will receive long-term treatment with both an SSRI and tamoxifen. A case control design was used to investigate the possibility that a resultant decrease in production of the 4-hydroxy metabolite from chronic inhibition results in the attenuation of the antitumor effect of tamoxifen. Twenty-eight patients without recurrences of breast cancer (controls) were matched to an equal number of cases (recurrences) by cancer stage and year of diagnosis. Data were analyzed on all chronic medication exposure (> 3 months) in both cases and controls classified as to their status as CYP 2D6, 2C9, and 3A inhibitors, substrates, or inducers. No significant difference was found for CYP inhibitor or substrate exposure between cases and controls. Indeed, controls showed a slightly greater exposure to inhibitors of the relevant CYP isoforms compared to cases. These results suggested a trend toward the null hypothesis. It is unlikely that the effect of chronic exposure to potent CYP isoform inhibitors affects the antitumor effect of tamoxifen and its 4-hydroxy metabolite, supporting the safety of the continued practice of concomitant SSRI administration to breast cancer patients with depression. 相似文献
875.
Fareed J Hoppensteadt D Schultz C Ma Q Kujawski MF Neville B Messmore H 《Current pharmaceutical design》2004,10(9):983-999
Ever since the introduction of low molecular weight heparins (LMWHs) for clinical use, one of the major questions raised relates to product interchangeability and the differences between each of the individual LMWH preparations. Although differences between various commercially available products have been described in terms of molecular weight profile and biologic properties, very limited information on the direct comparison of individual products in a defined clinical setting is available at this time. European Pharmacopeia (EP) and the World Health Organization (WHO) have developed guidelines to characterize these agents in terms of molecular weight and biologic profiles. On a gravimetric basis, these potency assignments differ for anti-Xa and anti-IIa activities in terms of U potency per mg. The relative distribution of various molecular weight components has also been reported to vary. The oligosaccharide composition, microstructural differences in terms of specific sugars and the presence of unique structural features and the interaction with endogenous mediators such as antithrombin (AT) and heparin cofactor II (HC II) also differ. At equivalent anti-Xa levels, the amount of the anti-IIa activity and anticoagulant activity differs. Since the bioavailability and relative pharmacokinetics of the anti-Xa and anti-IIa effects are different, the specific pharmacodynamic effects of these drugs also differ. A large preclinical data base is now available on the differences between various LMWHs. However, only limited clinical data is available in the current literature. To date, the LMWHs have been primarily used for the management of post-surgical DVT. Only smaller dosages (30-40 mg or 2,500 to 4,000 anti-Xa U total dose) have been used. In these studies, because of the low dose and subcutaneous route of administration, the differences in clinical effects are rather small. Since LMWHs are now developed for therapeutic use, where relatively higher doses are used, these pharmacokinetic/pharmacodynamic differences will become more apparent. The reported differences in the clinical efficacy of LMWHs in such indications as unstable angina may be due to their pharmacologic properties and molecular composition. There are also major differences in the non-anticoagulant actions of these agents such as their ability to interact with growth factors and antithrombotic effects. Based on the available literature, it can be concluded that each product exhibits individuality. 相似文献
876.
Zebrack BJ Eshelman DA Hudson MM Mertens AC Cotter KL Foster BM Loftis L Sozio M Oeffinger KC 《Cancer》2004,100(4):843-850
BACKGROUND: Most children diagnosed with cancer are surviving into adulthood but are not receiving adequate or appropriate follow-up health care. However, to the authors' knowledge, there is little literature published to date exploring potential barriers to long-term risk-based follow-up care for young adult survivors of childhood cancer. METHODS: In the current study, using a modified Delphi technique, young adult cancer survivors identified barriers to utilizing appropriate follow-up care and offered suggestions for ways to enhance health care in this young adult population. RESULTS: Major barriers to health care were found to be a lack of knowledge on the part of both physicians and survivors regarding long-term health issues related to cancer. Suggestions to enhance care included self-advocacy training for survivors and advanced training for primary care physicians who may treat childhood cancer survivors as they transition into adulthood. CONCLUSIONS: The results of the current study are consistent with reports that young adult survivors of childhood cancer need or desire information regarding their medical histories, psychosocial support, and social advocacy. 相似文献
877.
The superior prognostic value of humoral factors compared with molecular proliferation markers in renal cell carcinoma 总被引:2,自引:0,他引:2
Lehmann J Retz M Nürnberg N Schnöckel U Raffenberg U Krams M Kellner U Siemer S Weichert-Jacobsen K Stöckle M 《Cancer》2004,101(7):1552-1562
BACKGROUND: The American Joint Committee on Cancer and the Union Internationale Contre le Cancer have acknowledged routine laboratory parameters, such as serum calcium, alkaline phosphatase, hemoglobin, and the erythrocyte sedimentation rate (ESR), as predictors of survival in patients with renal cell carcinoma. The predictive value of these parameters compared with proliferation markers, such as Ki-67, proliferating cell nuclear antigen (PCNA), topoisomerase II-alpha, and p100, has not been determined. METHODS: Forty-eight consecutive patients who underwent nephrectomy for nonmetastatic renal cell carcinoma between 1990 and 1994 were observed up to 120 months postoperatively. Ten of 48 patients developed tumor progression 6-69 months after surgery. Routine preoperative laboratory parameters as well as tumor-specific data were assessed. Findings were compared with tumor proliferation indices, which were obtained by immunohistochemical staining for nuclear antigens Ki-67, PCNA, topoisomerase II-alpha, and p100 in paraffin embedded tumor tissue. RESULTS: Univariate and multivariate statistical analyses demonstrated superiority of routine laboratory values compared with tumor proliferation indices in predicting progression-free survival and disease-specific death. The best predictor after tumor size and symptomatic presentation was ESR (P < 0.0001), with ESR values > 70 mm at 2 hours indicating a significantly poorer prognosis. Only the proliferation marker Ki-67 reached univariate significance at a threshold of 7%. CONCLUSIONS: Routine laboratory parameters, such as alkaline phosphatase, lactate dehydrogenase, thrombocyte count, and especially ESR, provided superior long-term prognostic information for patients with nonmetastatic renal cell carcinoma compared with the molecular tumor proliferation markers Ki-67, PCNA, topoisomerase II-alpha, and p100. 相似文献
878.
Pitha-Rowe I Petty WJ Feng Q Koza-Taylor PH Dimattia DA Pinder L Dragnev KH Memoli N Memoli V Turi T Beebe J Kitareewan S Dmitrovsky E 《Cancer research》2004,64(21):8109-8115
Retinoids, natural and synthetic derivatives of vitamin A, are active in cancer therapy and chemoprevention. We reported previously that all-trans-retinoic acid (RA) treatment prevented carcinogen-induced transformation of immortalized human bronchial epithelial (HBE) cells. To identify cancer chemopreventive mechanisms, immortalized (BEAS-2B), carcinogen-transformed (BEAS-2B(NNK)), and RA-chemoprevented (BEAS-2B(NNK/RA)) HBE cells were used to conduct microarray analyses independently. Species increased in chemoprevented as compared with immortalized HBE cells (group I) and those augmented in chemoprevented as compared with transformed HBE cells (group II) included known RA-target genes as well as previously unrecognized RA-target genes in HBE cells. Unexpectedly, both groups were also enriched for interferon-stimulated genes. One interferon-stimulated gene of particular interest was UBE1L, the ubiquitin-activating enzyme E1-like protein. UBE1L expression was also induced after prolonged RA-treatment of immortalized HBE cells. UBE1L mRNA was shown previously as repressed in certain lung cancer cell lines, directly implicating UBE1L in lung carcinogenesis. Notably, UBE1L immunoblot expression was reduced in a subset of malignant as compared with adjacent normal lung tissues that were examined. Immunohistochemical analyses were performed using a new assay developed to detect this species using rabbit polyclonal anti-UBE1L antibodies independently raised against the amino- or carboxyl-termini of UBE1L. Studies done on paraffin-embedded and fixed tissues revealed abundant UBE1L, but low levels of cyclin D1 expression in the normal human bronchial epithelium, indicating an inverse relationship existed between these species. To study this further, cotransfection into HBE cells of wild-type or mutant UBE1L species was accomplished. In a dose-dependent manner, wild-type but not mutant UBE1L species repressed cyclin D1 expression. This implicated UBE1L in a retinoid chemoprevention mechanism involving cyclin D1 repression described previously. Taken together, these findings directly implicate UBE1L as a candidate-pharmacologic target for lung cancer chemoprevention. These findings also provide a mechanistic basis for the tumor suppressive effects of UBE1L through cyclin D1 repression. 相似文献
879.
Elevated levels and distinct patterns of expression of A-type cyclins and their associated cyclin-dependent kinases in male germ cell tumors 总被引:4,自引:0,他引:4
Liao C Li SQ Wang X Muhlrad S Bjartell A Wolgemuth DJ 《International journal of cancer. Journal international du cancer》2004,108(5):654-664
Aberrant expression of several key regulators controlling the G1/S phase of the cell cycle has been implicated in human male germ cell tumorigenesis. Given the critical role of cyclin A2 at both the G1/S and G2/M transitions and the essential role for cyclin A1 in male germ cell development, our present study focused on the involvement of the A-type cyclins in the transformation and progression of male germ cell tumors (GCTs). The expression of the A-type cyclins and their catalytic partners Cdk1 and Cdk2 was examined in all types and stages of human male GCTs, including carcinoma in situ(CIS), seminoma and non-seminoma GCTs, along with normal testis samples. Elevated levels of cyclin A2, Cdk1 and Cdk2 were detected in the majority of GCTs and were correlated with the invasiveness of the tumors (p < 0.05). Cyclin A1 expression was virtually undetectable in CIS and seminoma, but was aberrantly expressed in all non-seminomatous GCTs. Cyclin A2 expression was strongly correlated with that of its catalytic partners Cdk1 and Cdk2 in all types of testicular tumors examined (p < 0.05), whereas a strong correlation between cyclin A1 and Cdk1 or Cdk2 was only seen in non-seminomatous GCTs (p < 0.05). Histone kinase activities of cyclin A1/Cdks and cyclin A2/Cdks were found to be elevated in tumors. Our data suggest that aberrant expression of A-type cyclins and their Cdks is a significant factor in male germ cell tumorigenesis. The abundant ectopic expression of cyclin A1 in non-seminomatous GCTs and its absence in CIS and seminomas is likely linked to the tumor transformation and progression and may be relevant to clinical prognosis. 相似文献
880.