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  • 1
    Online Resource
    Online Resource
    Polymorphisms in Genes Related to Oxidative Stress ( CAT, MnSOD, MPO , and eNOS ) and Acute Toxicities from Radiation Therapy following Lumpectomy for Breast Cancer
    American Association for Cancer Research (AACR) ; 2006
    In:  Clinical Cancer Research Vol. 12, No. 23 ( 2006-12-01), p. 7063-7070
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 12, No. 23 ( 2006-12-01), p. 7063-7070
    Abstract: Purpose: Because radiotherapy exerts cytotoxic effects via generation of massive oxidative stress, we hypothesized that catalase, manganese superoxide dismutase, myeloperoxidase (MPO), and endothelial nitric oxide synthase (eNOS) genotypes might result in greater risk of radiotoxicity. Experimental Design: Cases (n = 446) were Caucasian women with breast cancer who received radiotherapy following lumpectomy. Genotypes were determined by matrix-assisted laser desorption/ionization time-of-flight. The development of acute reactions (moist desquamation) associated with genotypes was modeled using the Cox proportional hazards model, accounting for cumulative biologically effective radiation dose. Results: Genotypes associated with higher levels of reactive oxygen species (ROS) were not associated with risk of radiotoxicity. However, relationships between overweight/obesity [body mass index (BMI), & gt;25] and radiotoxicity risk seemed to be modified by eNOS and MPO genotypes associated with higher generation of nitric oxide and ROS, respectively. Women with high BMI ( & gt;25) and eNOS GG genotypes were at more than a 6-fold increase in risk (hazard ratio, 6.39; 95% confidence interval, 2.53-16.15) compared with those with BMI & lt;25, and for MPO, those with high BMI ( & gt;25) and GG genotypes also had greater risk of radiotoxicity (hazard ratio, 3.61; 95% confidence interval, 1.78-7.35) compared with those with BMI & lt;25. Overweight/obesity was not a strong risk factor among women with other eNOS and MPO genotypes. Exploratory analysis using classification and regression trees indicated that total number of risk alleles contributed, in part, to acute toxicity outcomes among a subgroup of women. Conclusions: Associations between BMI and radiotoxicity risk may be most apparent among women with genotypes related to higher levels of oxidative stress. Regression trees may be useful in future studies to examine the contributions of multiple factors to individual susceptibility to adverse effects of cancer treatment.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-06-0039
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 2
    Online Resource
    Online Resource
    Leflunomide Induces Apoptosis in Fludarabine-Resistant and Clinically Refractory CLL Cells
    American Association for Cancer Research (AACR) ; 2012
    In:  Clinical Cancer Research Vol. 18, No. 2 ( 2012-01-15), p. 417-431
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 2 ( 2012-01-15), p. 417-431
    Abstract: Purpose: Environmental conditions in lymph node proliferation centers protect chronic lymphocytic leukemia (CLL) cells from apoptotic triggers. This situation can be mimicked by in vitro stimulation with CD40 ligand (CD40L) and interleukin 4 (IL-4). Our study investigates the impact of the drug leflunomide to overcome apoptosis resistance of CLL cells. Experimental Design: CLL cells were stimulated with CD40L and IL-4 and treated with fludarabine and the leflunomide metabolite A771726. Results: Resistance to fludarabine-mediated apoptosis was induced by CD40 activation alone stimulating high levels of BCL-XL and MCL1 protein expression. Apoptosis resistance was further enhanced by a complementary Janus-activated kinase (JAK)/STAT signal induced by IL-4. In contrast, CLL proliferation required both a CD40 and a JAK/STAT signal and could be completely blocked by pan-JAK inhibition. Leflunomide (A771726) antagonized CD40L/IL-4–induced proliferation at very low concentrations (3 μg/mL) reported to inhibit dihydroorotate dehydrogenase. At a concentration of 10 μg/mL, A771726 additionally attenuated STAT3/6 phosphorylation, whereas apoptosis of CD40L/IL-4–activated (“resistant”) CLL cells was achieved with higher concentrations (IC50: 80 μg/mL). Apoptosis was also effectively induced by A771726 in clinically refractory CLL cells with and without a defective p53 pathway. Induction of apoptosis involved inhibition of NF-κB activity and loss of BCL-XL and MCL1 expression. In combination with fludarabine, A771726 synergistically induced apoptosis (IC50: 56 μg/mL). Conclusion: We thus show that A771726 overcomes CD40L/IL-4–mediated resistance to fludarabine in CLL cells of untreated as well as clinically refractory CLL cells. We present a possible novel therapeutic principle for attacking chemoresistant CLL cells. Clin Cancer Res; 18(2); 417–31. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-11-1049
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
    Online Resource
    Online Resource
    Association between Polymorphisms in the DNA Repair Genes, XRCC1, APE1 , and XPD and Acute Side Effects of Radiotherapy in Breast Cancer Patients
    American Association for Cancer Research (AACR) ; 2005
    In:  Clinical Cancer Research Vol. 11, No. 13 ( 2005-07-01), p. 4802-4809
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 11, No. 13 ( 2005-07-01), p. 4802-4809
    Abstract: Purpose: Several DNA repair gene polymorphisms have been described, which affect DNA repair capacity and modulate cancer susceptibility. We evaluated the association of six polymorphisms in the DNA repair genes: XRCC1 (Arg194Trp, Arg280His, and Arg399Gln), APE1 (Asp148Glu), and XPD (Lys751Gln and Asp312Asn), with the risk of acute skin reactions following radiotherapy. Design: We conducted a prospective study of 446 female patients with breast cancer who received radiotherapy after breast-conserving surgery. Individual genetic polymorphisms were determined using melting point analysis of sequence-specific hybridization probes. The development of acute skin reactions (moist desquamation) associated with DNA repair gene polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Results: Overall, the development of acute toxicity, which presented in 77 patients, was not associated with the genetic variants studied, although the hazard ratios (HR) were generally below 1. Risks were however differential by body mass index. Among normal-weight patients only, both carriers of the APE1 148Glu and the XRCC1 399Gln alleles had decreased risk of acute skin reactions after radiotherapy (HR, 0.49 and 0.51, respectively). The results for XRCC1 were confirmed by haplotype analysis. When considering joint effects, we observed that compared with homozygote carriers of the wild-type allele in both genes, the risk was most strongly reduced in carriers of both APE1 148Glu and XRCC1 399Gln alleles with normal weight [HR, 0.19; 95% confidence interval (95% CI), 0.06-0.56] but not in those with overweight (HR, 1.39; 95% CI, 0.56-3.45; Pinteraction = 0.009). Conclusion: The XRCC1 399Gln or APE1 148Glu alleles may be protective against the development of acute side effects after radiotherapy in patients with normal weight.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-04-2657
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 4
    Online Resource
    Online Resource
    The Immune Checkpoint Regulator PD-L1 Is Highly Expressed in Aggressive Primary Prostate Cancer
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 8 ( 2016-04-15), p. 1969-1977
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 8 ( 2016-04-15), p. 1969-1977
    Abstract: Purpose: Therapies targeting the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway promote anti-tumor immunity and have shown promising results in various tumors. Preliminary data further indicate that immunohistochemically detected PD-L1 may be predictive for anti-PD-1 therapy. So far, no data are available on PD-L1 expression in primary prostate cancer. Experimental Design: Following validation of a monoclonal antibody, immunohistochemical analysis of PD-L1 expression was performed in two independent, well-characterized cohorts of primary prostate cancer patients following radical prostatectomy (RP), and resulting data were correlated to clinicopathological parameters and outcome. Results: In the training cohort (n = 209), 52.2% of cases expressed moderate to high PD-L1 levels, which positively correlated with proliferation (Ki-67, P & lt; 0.001), Gleason score (P = 0.004), and androgen receptor (AR) expression (P & lt; 0.001). Furthermore, PD-L1 positivity was prognostic for biochemical recurrence [BCR; P = 0.004; HR, 2.37; 95% confidence interval (CI), 1.32–4.25]. In the test cohort (n = 611), moderate to high PD-L1 expression was detected in 61.7% and remained prognostic for BCR in univariate Cox analysis (P = 0.011; HR, 1.49; 95% CI, 1.10–2.02). The correlation of Ki-67 and AR with PD-L1 expression was confirmed in the test cohort (P & lt; 0.001). In multivariate Cox analysis of all patients, PD-L1 was corroborated as independently prognostic for BCR (P = 0.007; HR, 1.46; 95% CI, 1.11–1.92). Conclusions: We provide first evidence that expression of the therapy target PD-L1 is not only highly prevalent in primary prostate cancer cells but is also an independent indicator of BCR, suggesting a biologic relevance in primary tumors. Further studies need to ascertain if PD-1/PD-L1–targeted therapy might be a treatment option for hormone-naïve prostate cancers. Clin Cancer Res; 22(8); 1969–77. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-2042
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 5
    Online Resource
    Online Resource
    Activation of Phosphatidylinositol-3′-kinase/AKT Signaling Is Essential in Hepatoblastoma Survival
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 14 ( 2009-07-15), p. 4538-4545
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 14 ( 2009-07-15), p. 4538-4545
    Abstract: Purpose: Hepatoblastoma represents the most frequent malignant liver tumor in childhood. The phosphatidylinositol-3′-kinase (PI3K)/AKT pathway is crucial in downstream signaling of multiple receptor tyrosine kinases of pathogenic importance in hepatoblastoma. Increased PI3K/AKT signaling pathway activity and activating mutations of PIK3CA, encoding a PI3K catalytic subunit, have been reported in different childhood tumors. The current study was done to analyze the role of PI3K/AKT signaling in hepatoblastoma. Experimental Design: Immunohistochemical stainings of (Ser473)-phosphorylated (p)-AKT protein, its targets p-(Ser9)-GSK-3β and p-(Ser2448)-mTOR, as well as the cell cycle regulators Cyclin D1, p27KIP1, and p21CIP1 were done and the PIK3CA gene was screened for mutations. In vitro, two hepatoblastoma cell lines treated with the PI3K inhibitor LY294002 were analyzed for AKT and GSK-3β phosphorylation, cell proliferation, and apoptosis. Additionally, simultaneous treatments of hepatoblastoma with LY294002 and cytotoxic drugs were carried out. Results: Most tumors strongly expressed p-AKT, p-GSK-3β, and p-mTOR; subgroups showed significant Cyclin D1, p27KIP1, and p21CIP1 expression. One hepatoblastoma carried an E545A mutation in the PIK3CA gene. In vitro, PI3K inhibition diminished hepatoblastoma cell growth being accompanied by reduced AKT and GSK-3β phosphorylation. Flow cytometry and 4', 6-diamidino-2-phenylindole stainings showed that PI3K pathway inhibition leads to a substantial increase in apoptosis and a decrease in cellular proliferation linked to reduced Cyclin D1 and increased p27KIP1 levels. Simultaneous treatment of hepatoblastoma cell lines with LY294002 and cytotoxic drugs resulted in positive interactions. Conclusions: Our findings imply that PI3K signaling plays an essential role in growth control of hepatoblastoma and might be successfully targeted in multimodal therapeutic strategies.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-08-2878
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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