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  1. Article: Can inhibiting dihydropyrimidine dehydrogenase limit hand-foot syndrome caused by fluoropyrimidines?

    Yen-Revollo, Jane L / Goldberg, Richard M / McLeod, Howard L

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2008  Volume 14, Issue 1, Page(s) 8–13

    Abstract: Hand-foot syndrome (HFS) is a cutaneous adverse event that occurs in some patients treated with fluoropyrimidines. Although it is not life threatening, HFS can severely disrupt the daily lives of patients. HFS appears more frequently with 5-fluorouracil ( ...

    Abstract Hand-foot syndrome (HFS) is a cutaneous adverse event that occurs in some patients treated with fluoropyrimidines. Although it is not life threatening, HFS can severely disrupt the daily lives of patients. HFS appears more frequently with 5-fluorouracil (5-FU) delivered by continuous infusion or with the 5-FU oral derivative capecitabine than with bolus 5-FU therapy. HFS is a leading cause of treatment interruption, dosage reduction, or, even, therapy discontinuation for patients on a capecitabine regimen. Interestingly, addition of a dihydropyrimidine dehydrogenase (DPD) inhibitor, such as uracil, 5-chloro-2,4-dihydroxypyridine, or eniluracil, to the fluoropyrimidine treatment regimen significantly diminishes the incidence of HFS. DPD inhibitors were initially combined with fluoropyrimidines to increase the efficacy of the drugs by impairing the DPD-mediated catabolism of 5-FU. However, with the accumulating findings from clinical trials that show the benefits of DPD inhibition on decreasing the risk of HFS, consideration should be given to changing the recommendations for the treatment of cancer patients with fluoropyrimidines to include DPD inhibitor components as standard therapy.
    MeSH term(s) Antineoplastic Agents/adverse effects ; Dihydrouracil Dehydrogenase (NADP)/antagonists & inhibitors ; Enzyme Inhibitors/therapeutic use ; Fluorouracil/adverse effects ; Foot Dermatoses/chemically induced ; Foot Dermatoses/enzymology ; Foot Dermatoses/prevention & control ; Hand Dermatoses/chemically induced ; Hand Dermatoses/enzymology ; Hand Dermatoses/prevention & control ; Humans ; Syndrome
    Chemical Substances Antineoplastic Agents ; Enzyme Inhibitors ; Dihydrouracil Dehydrogenase (NADP) (EC 1.3.1.2) ; Fluorouracil (U3P01618RT)
    Language English
    Publishing date 2008-01-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-07-1225
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4223: Show issues Location:
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  2. Article ; Online: Race does not explain genetic heterogeneity in pharmacogenomic pathways.

    Yen-Revollo, Jane L / Auman, J Todd / McLeod, Howard L

    Pharmacogenomics

    2008  Volume 9, Issue 11, Page(s) 1639–1645

    Abstract: Introduction: Polymorphic alleles in the human genome have been identified as affecting numerous drug responses. Currently, genotyping of all patients before starting a drug regimen is impractical. Since many polymorphisms occur at varying rates in ... ...

    Abstract Introduction: Polymorphic alleles in the human genome have been identified as affecting numerous drug responses. Currently, genotyping of all patients before starting a drug regimen is impractical. Since many polymorphisms occur at varying rates in different racial groups, we investigated whether a patient's race could predict presence of drug-relevant genetic variants well enough to be used as a substitute for individual genotyping.
    Methods: We performed hierarchical clustering and principal components analysis on tagSNPs from three pathways (irinotecan, 5-fluorouracil and insulin) across 270 individuals from four racial groups available from the International HapMap Project.
    Results: For the drug pathways, irinotecan and 5-fluorouracil, individuals from each race were widely dispersed, although several subclusters consisted entirely of individuals from a single racial group. Principal components analysis confirmed race was not a major contributor to the SNP data variance. Interestingly, individuals tended to cluster more by race across the endogenous insulin signaling pathway SNPs.
    Conclusions: Most genetic variation was determined by individual variation, not racial grouping, indicating race is not adequate as a surrogate to individualized therapy.
    MeSH term(s) Camptothecin/analogs & derivatives ; Camptothecin/pharmacokinetics ; Camptothecin/pharmacology ; Cluster Analysis ; Continental Population Groups/genetics ; Databases, Genetic ; Fluorouracil/pharmacokinetics ; Fluorouracil/pharmacology ; Genetic Heterogeneity ; Humans ; Insulin/pharmacokinetics ; Insulin/pharmacology ; Irinotecan ; Metabolic Clearance Rate ; Pharmacogenetics/methods ; Pharmacogenetics/statistics & numerical data ; Polymorphism, Single Nucleotide ; Principal Component Analysis
    Chemical Substances Insulin ; Irinotecan (7673326042) ; Fluorouracil (U3P01618RT) ; Camptothecin (XT3Z54Z28A)
    Language English
    Publishing date 2008-11-19
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2019513-8
    ISSN 1744-8042 ; 1462-2416
    ISSN (online) 1744-8042
    ISSN 1462-2416
    DOI 10.2217/14622416.9.11.1639
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5247: Show issues Location:
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  3. Article: Association of thymidylate synthase variants with 5-fluorouracil cytotoxicity.

    Peters, Eric J / Kraja, Aldi T / Lin, Shiow J / Yen-Revollo, Jane L / Marsh, Sharon / Province, Michael A / McLeod, Howard L

    Pharmacogenetics and genomics

    2009  Volume 19, Issue 5, Page(s) 399–401

    Abstract: Identifying relevant cytotoxicity genes using an ex-vivo lymphoblastoid cell line (LCLs) model has distinct advantages for pharmacogenomic discovery studies of cancer chemotherapy, including standardized treatment conditions, availability of large ... ...

    Abstract Identifying relevant cytotoxicity genes using an ex-vivo lymphoblastoid cell line (LCLs) model has distinct advantages for pharmacogenomic discovery studies of cancer chemotherapy, including standardized treatment conditions, availability of large numbers of samples, and publicly available genotypic data. However, there is little proof of principal data to confirm the promise of this approach. One of the known targets of 5-fluorouracil (5-FU) treatment is thymidylate synthase (TYMS). We hypothesized that genetic variants in TYMS would alter cytotoxicity because of 5-FU treatment using a LCL model system. LCLs from the Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees (N=427) were treated with eight concentrations of 5-FU for 72 h, and cytotoxicity was determined using an Alamar Blue assay. For a subset of the 30 International Haplotype Mapping project (HapMap) trios, genotype data for 46 single-nucleotide polymorphism (SNP) variants encompassing the TYMS gene were downloaded from the HapMap website. Using a mixed models approach, each SNP was tested for association to 5-FU cytotoxicity in the subset of HapMap trios. Putatively associated SNPs (P<0.01), were then genotyped in the remaining LCLs in the CEPH pedigrees and tested for association. Two intronic SNPs in TYMS (rs2847153 and rs2853533) were significantly associated (P<0.01) with 5-FU cytotoxicity in the HapMap subset using the mixed models approach. After genotyping these SNPs in the full CEPH pedigrees, the associations with cytotoxicity showed a more reliable significance (P<0.0005), as a result of the increase in sample size. These results highlight the importance of the TYMS gene variants in response to 5-FU treatment. Furthermore, they provide additional biological validation of the relevance of LCLs as a model for pharmacogenomic gene discovery in cancer chemotherapy.
    MeSH term(s) Antimetabolites, Antineoplastic/adverse effects ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Drug-Related Side Effects and Adverse Reactions/genetics ; Fluorouracil/adverse effects ; Humans ; Pedigree ; Polymorphism, Single Nucleotide/physiology ; Thymidylate Synthase/genetics
    Chemical Substances Antimetabolites, Antineoplastic ; Thymidylate Synthase (EC 2.1.1.45) ; Fluorouracil (U3P01618RT)
    Language English
    Publishing date 2009-04-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Validation Study
    ZDB-ID 2175826-8
    ISSN 1744-6880 ; 1744-6872 ; 0960-314X
    ISSN (online) 1744-6880
    ISSN 1744-6872 ; 0960-314X
    DOI 10.1097/FPC.0b013e328329fdec
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3660: Show issues Location:
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  4. Article ; Online: Cumulative genetic risk predicts platinum/taxane-induced neurotoxicity.

    McWhinney-Glass, Sarah / Winham, Stacey J / Hertz, Daniel L / Yen Revollo, Jane / Paul, Jim / He, Yijing / Brown, Robert / Motsinger-Reif, Alison A / McLeod, Howard L

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2013  Volume 19, Issue 20, Page(s) 5769–5776

    Abstract: Purpose: The combination of a platinum and taxane are standard of care for many cancers, but the utility is often limited due to debilitating neurotoxicity. We examined whether single-nucleotide polymorphisms (SNP) from annotated candidate genes will ... ...

    Abstract Purpose: The combination of a platinum and taxane are standard of care for many cancers, but the utility is often limited due to debilitating neurotoxicity. We examined whether single-nucleotide polymorphisms (SNP) from annotated candidate genes will identify genetic risk for chemotherapy-induced neurotoxicity.
    Patients and methods: A candidate-gene association study was conducted to validate the relevance of 1,261 SNPs within 60 candidate genes in 404 ovarian cancer patients receiving platinum/taxane chemotherapy on the SCOTROC1 trial. Statistically significant variants were then assessed for replication in a separate 404 patient replication cohort from SCOTROC1.
    Results: Significant associations with chemotherapy-induced neurotoxicity were identified and replicated for four SNPs in SOX10, BCL2, OPRM1, and TRPV1. The population attributable risk for each of the four SNPs ranged from 5% to 35%, with a cumulative risk of 62%. According to the multiplicative model, the odds of developing neurotoxicity increase by a factor of 1.64 for every risk genotype. Patients possessing three risk variants have an estimated OR of 4.49 (2.36-8.54) compared to individuals with 0 risk variants. Neither the four SNPs nor the risk score were associated with progression-free survival or overall survival.
    Conclusions: This study shows that SNPs in four genes have a significant cumulative association with increased risk for the development of chemotherapy-induced neurotoxicity, independent of patient survival.
    MeSH term(s) Antineoplastic Agents/adverse effects ; Antineoplastic Agents/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Bridged-Ring Compounds/adverse effects ; Bridged-Ring Compounds/therapeutic use ; Case-Control Studies ; Female ; Genetic Association Studies ; Genotype ; Humans ; Nervous System Diseases/chemically induced ; Nervous System Diseases/genetics ; Odds Ratio ; Ovarian Neoplasms/complications ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/mortality ; Platinum/adverse effects ; Platinum/therapeutic use ; Polymorphism, Single Nucleotide ; Taxoids/adverse effects ; Taxoids/therapeutic use
    Chemical Substances Antineoplastic Agents ; Bridged-Ring Compounds ; Taxoids ; taxane (1605-68-1) ; Platinum (49DFR088MY)
    Language English
    Publishing date 2013-08-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-13-0774
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4223: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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