Evidence map›Paper›PMID 33795350›Full record

ArticleMolecular pharmacology2021

Inhibition of Human Uracil DNA Glycosylase Sensitizes a Large Fraction of Colorectal Cancer Cells to 5-Fluorodeoxyuridine and Raltitrexed but Not Fluorouracil.

Eric S Christenson, Anthony Gizzi, Junru Cui, Matthew Egleston, Kyle J Seamon, Michael DePasquale, Benjamin Orris, Ben H Park, James T Stivers

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
0.6field-weighted citation impact, top 34% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed, 15 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 3 institutions in 1 country.

Eric S ChristensonDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (E.S.C., A.G., J.C., M.E., K.J.S., B.O., J.T.S.); Lieber Institute for Brain Development, Baltimore, Maryland (M.D.); and Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, Tennessee (B.H.P.).
Anthony GizziDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (E.S.C., A.G., J.C., M.E., K.J.S., B.O., J.T.S.); Lieber Institute for Brain Development, Baltimore, Maryland (M.D.); and Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, Tennessee (B.H.P.).
Junru CuiDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (E.S.C., A.G., J.C., M.E., K.J.S., B.O., J.T.S.); Lieber Institute for Brain Development, Baltimore, Maryland (M.D.); and Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, Tennessee (B.H.P.).
Matthew EglestonDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (E.S.C., A.G., J.C., M.E., K.J.S., B.O., J.T.S.); Lieber Institute for Brain Development, Baltimore, Maryland (M.D.); and Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, Tennessee (B.H.P.).
Kyle J SeamonDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (E.S.C., A.G., J.C., M.E., K.J.S., B.O., J.T.S.); Lieber Institute for Brain Development, Baltimore, Maryland (M.D.); and Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, Tennessee (B.H.P.).
Michael DePasqualeDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (E.S.C., A.G., J.C., M.E., K.J.S., B.O., J.T.S.); Lieber Institute for Brain Development, Baltimore, Maryland (M.D.); and Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, Tennessee (B.H.P.).
Benjamin OrrisDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (E.S.C., A.G., J.C., M.E., K.J.S., B.O., J.T.S.); Lieber Institute for Brain Development, Baltimore, Maryland (M.D.); and Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, Tennessee (B.H.P.).
Ben H ParkDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (E.S.C., A.G., J.C., M.E., K.J.S., B.O., J.T.S.); Lieber Institute for Brain Development, Baltimore, Maryland (M.D.); and Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, Tennessee (B.H.P.).
James T StiversDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (E.S.C., A.G., J.C., M.E., K.J.S., B.O., J.T.S.); Lieber Institute for Brain Development, Baltimore, Maryland (M.D.); and Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, Tennessee (B.H.P.) jstivers@jhmi.edu.
Johns Hopkins University · USJohns Hopkins Medicine · USVanderbilt University Medical Center · US

Funding

BIOCHEMISTRY, CELLULAR AND MOLECULAR BIOLOGY PROGRAMT32GM007445 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI GREEN, RACHEL · 1985 to 2021
$24.1M
TRAINING IN AREAS FUNDAMENTAL TO CANCER RESEARCHT32CA009110 · NCI · JOHNS HOPKINS UNIVERSITY · PI MATUNIS, MICHAEL J., WEERARATNA, ASHANI T · 1985 to 2025
$13.1M
Uracil Damage Recognition by Uracil DNA GlyocosylaseR01GM056834 · NIGMS · UNIVERSITY OF MD BIOTECHNOLOGY INSTITUTE · PI STIVERS, JAMES T. · 1998 to 2021
$8.3M
Mechanism of Transcriptional Downregulation of HIV Gene Expression by U/A Base Pairs in Proviral DNAF32AI150561 · NIAID · JOHNS HOPKINS UNIVERSITY · PI GIZZI, ANTHONY · 2019 to 2020
$126k
NCI NIH HHS T32 CA009110NIAID NIH HHS F32 AI150561NIGMS NIH HHS R01 GM056834NIGMS NIH HHS T32 GM007445
6 · The paper itself

Abstract

Previous short-hairpin RNA knockdown studies have established that depletion of human uracil DNA glycosylase (hUNG) sensitizes some cell lines to 5-fluorodeoxyuridine (FdU). Here, we selectively inhibit the catalytic activity of hUNG by lentiviral transduction of uracil DNA glycosylase inhibitor protein into a large panel of cancer cell lines under control of a doxycycline-inducible promoter. This induced inhibition strategy better assesses the therapeutic potential of small-molecule targeting of hUNG. In total, 6 of 11 colorectal lines showed 6- to 70-fold increases in FdU potency upon hUNG inhibition ("responsive"). This hUNG-dependent response was not observed with fluorouracil (FU), indicating that FU does not operate through the same DNA repair mechanism as FdU in vitro. Potency of the thymidylate synthase inhibitor raltitrexed (RTX), which elevates deoxyuridine triphosphate levels, was only incrementally enhanced upon hUNG inhibition (<40%), suggesting that responsiveness is associated with incorporation and persistence of FdU in DNA rather than deoxyuridine. The importance of FU/A and FU/G lesions in the toxicity of FdU is supported by the observation that dT supplementation completely rescued the toxic effects of U/A lesions resulting from RTX, but dT only increased the IC

Indexed as

Antineoplastic AgentsCell Line, TumorColorectal NeoplasmsDNA DamageDrug Screening Assays, AntitumorFloxuridineFluorouracilHumansQuinazolinesThiophenesUracil-DNA GlycosidaseAntineoplastic AgentsFloxuridineFluorouracilQuinazolinesraltitrexedThiophenesUracil-DNA Glycosidase

Identifiers

PMID33795350
PMCPMC11033954
OpenAlexW3149089593

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.