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  • American Association for Cancer Research (AACR)  (2)
  • 1
    Online Resource
    Online Resource
    A Novel Orally Bioavailable Inhibitor of Kinase Insert Domain-Containing Receptor Induces Antiangiogenic Effects and Prevents Tumor Growth in Vivo
    American Association for Cancer Research (AACR) ; 2004
    In:  Cancer Research Vol. 64, No. 2 ( 2004-01-15), p. 751-756
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 64, No. 2 ( 2004-01-15), p. 751-756
    Abstract: A strategy for antagonizing vascular endothelial growth factor (VEGF) -induced angiogenesis is to inhibit the kinase activity of its receptor, kinase insert domain-containing receptor (KDR), the first committed and perhaps the last unique step in the VEGF signaling cascade. We synthesized a novel ATP-competitive KDR tyrosine kinase inhibitor that potently suppresses human and mouse KDR activity in enzyme (IC50 = 7.8–19.5 nm) and cell-based assays (IC50 = 8 nm). The compound was bioavailable in vivo, leading to a dose-dependent decrease in basal- and VEGF-stimulated KDR tyrosine phosphorylation in lungs from naïve and tumor-bearing mice (IC50 = 23 nm). Pharmacokinetics and pharmacodynamics guided drug dose selection for antitumor efficacy studies. HT1080 nude mice xenografts were treated orally twice daily with vehicle, or 33 or 133 mg/kg of compound. These doses afforded trough plasma concentrations approximately equal to the IC50 for inhibition of KDR autophosphorylation in vivo for the 33 mg/kg group, and higher than the IC99 for the 133 mg/kg group. Chronic treatment at these doses was well-tolerated and resulted in dose-dependent inhibition of tumor growth, decreased tumor vascularization, decreased proliferation, and enhanced cell death. Antitumor efficacy correlated with inhibition of KDR tyrosine phosphorylation in the tumor, as well as in a surrogate tissue (lung). Pharmacokinetics and pharmacodynamics assessment indicated that the degree of tumor growth inhibition correlated directly with the extent of inhibition of KDR tyrosine phosphorylation in tumor or lung at trough. These observations highlight the need to design antiangiogenic drug regimens to ensure constant target suppression and to take advantage of PD end points to guide dose selection.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-03-2871
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2004
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Testing the Circadian Gene Hypothesis in Prostate Cancer: A Population-Based Case-Control Study
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 24 ( 2009-12-15), p. 9315-9322
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 24 ( 2009-12-15), p. 9315-9322
    Abstract: Circadian genes are responsible for maintaining the ancient adaptation of a 24-hour circadian rhythm and influence a variety of cancer-related biological pathways, including the regulation of sex hormone levels. However, few studies have been undertaken to investigate the role of circadian genes in the development of prostate cancer, the most common cancer type among men (excluding nonmelanoma skin cancer). The current genetic association study tested the circadian gene hypothesis in relation to prostate cancer by genotyping a total of 41 tagging and amino acid–altering single nucleotide polymorphisms (SNP) in 10 circadian-related genes in a population-based case-control study of Caucasian men (n = 1,308 cases and 1,266 controls). Our results showed that at least one SNP in nine core circadian genes (rs885747 and rs2289591 in PER1; rs7602358 in PER2; rs1012477 in PER3; rs1534891 in CSNK1E; rs12315175 in CRY1; rs2292912 in CRY2; rs7950226 in ARNTL; rs11133373 in CLOCK; and rs1369481, rs895521, and rs17024926 in NPAS2) was significantly associated with susceptibility to prostate cancer (either overall risk or risk of aggressive disease), and the risk estimate for four SNPs in three genes (rs885747 and rs2289591 in PER1, rs1012477 in PER3, and rs11133373 in CLOCK) varied by disease aggressiveness. Further analyses of haplotypes were consistent with these genotyping results. Findings from this candidate gene association study support the hypothesis of a link between genetic variants in circadian genes and prostate cancer risk, warranting further confirmation and mechanistic investigation of circadian biomarkers in prostate tumorigenesis. [Cancer Res 2009;69(24):9315–22]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-09-0648
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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