View in EDS HTML Full Text PDF Full Text

Mechanism-based design of agents that selectively target drug-resistant glioma.

Saved in:
Bibliographic Details
Title: Mechanism-based design of agents that selectively target drug-resistant glioma.
Authors: Lin, Kingson, Gueble, Susan E., Sundaram, Ranjini K., Huseman, Eric D., Bindra, Ranjit S., Herzon, Seth B.
Source: Science (pre-March 2025). 7/29/2022, Vol. 377 Issue 6605, p502-511. 10p. 6 Color Photographs.
Subjects: Glioblastoma multiforme, Tumors, DNA repair, Cell death, Cancer chemotherapy, Gliomas
Abstract: Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O6-methylguanine methyl transferase (MGMT). MGMT-deficient tumors respond initially to the DNA methylation agent temozolomide (TMZ) but frequently acquire resistance through loss of the mismatch repair (MMR) pathway. We report the development of agents that overcome this resistance mechanism by inducing MMR-independent cell killing selectively in MGMT-silenced tumors. These agents deposit a dynamic DNA lesion that can be reversed by MGMT but slowly evolves into an interstrand cross-link in MGMT-deficient settings, resulting in MMR-independent cell death with low toxicity in vitro and in vivo. This discovery may lead to new treatments for gliomas and may represent a new paradigm for designing chemotherapeutics that exploit specific DNA repair defects. [ABSTRACT FROM AUTHOR]
Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
Full text is not displayed to guests.
FullText Links:
  – Type: pdflink
Text:
  Availability: 1
Header DbId: pbh
DbLabel: Psychology and Behavioral Sciences Collection
An: 158233251
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Mechanism-based design of agents that selectively target drug-resistant glioma.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Lin%2C+Kingson%22">Lin, Kingson</searchLink><br /><searchLink fieldCode="AR" term="%22Gueble%2C+Susan+E%2E%22">Gueble, Susan E.</searchLink><br /><searchLink fieldCode="AR" term="%22Sundaram%2C+Ranjini+K%2E%22">Sundaram, Ranjini K.</searchLink><br /><searchLink fieldCode="AR" term="%22Huseman%2C+Eric+D%2E%22">Huseman, Eric D.</searchLink><br /><searchLink fieldCode="AR" term="%22Bindra%2C+Ranjit+S%2E%22">Bindra, Ranjit S.</searchLink><br /><searchLink fieldCode="AR" term="%22Herzon%2C+Seth+B%2E%22">Herzon, Seth B.</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="JN" term="%22Science+%28pre-March+2025%29%22">Science (pre-March 2025)</searchLink>. 7/29/2022, Vol. 377 Issue 6605, p502-511. 10p. 6 Color Photographs.
– Name: Subject
  Label: Subjects
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Glioblastoma+multiforme%22">Glioblastoma multiforme</searchLink><br /><searchLink fieldCode="DE" term="%22Tumors%22">Tumors</searchLink><br /><searchLink fieldCode="DE" term="%22DNA+repair%22">DNA repair</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+death%22">Cell death</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+chemotherapy%22">Cancer chemotherapy</searchLink><br /><searchLink fieldCode="DE" term="%22Gliomas%22">Gliomas</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O6-methylguanine methyl transferase (MGMT). MGMT-deficient tumors respond initially to the DNA methylation agent temozolomide (TMZ) but frequently acquire resistance through loss of the mismatch repair (MMR) pathway. We report the development of agents that overcome this resistance mechanism by inducing MMR-independent cell killing selectively in MGMT-silenced tumors. These agents deposit a dynamic DNA lesion that can be reversed by MGMT but slowly evolves into an interstrand cross-link in MGMT-deficient settings, resulting in MMR-independent cell death with low toxicity in vitro and in vivo. This discovery may lead to new treatments for gliomas and may represent a new paradigm for designing chemotherapeutics that exploit specific DNA repair defects. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=158233251
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1126/science.abn7570
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 10
        StartPage: 502
    Subjects:
      – SubjectFull: Glioblastoma multiforme
        Type: general
      – SubjectFull: Tumors
        Type: general
      – SubjectFull: DNA repair
        Type: general
      – SubjectFull: Cell death
        Type: general
      – SubjectFull: Cancer chemotherapy
        Type: general
      – SubjectFull: Gliomas
        Type: general
    Titles:
      – TitleFull: Mechanism-based design of agents that selectively target drug-resistant glioma.
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Lin, Kingson
      – PersonEntity:
          Name:
            NameFull: Gueble, Susan E.
      – PersonEntity:
          Name:
            NameFull: Sundaram, Ranjini K.
      – PersonEntity:
          Name:
            NameFull: Huseman, Eric D.
      – PersonEntity:
          Name:
            NameFull: Bindra, Ranjit S.
      – PersonEntity:
          Name:
            NameFull: Herzon, Seth B.
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 29
              M: 07
              Text: 7/29/2022
              Type: published
              Y: 2022
          Identifiers:
            – Type: issn-print
              Value: 00368075
          Numbering:
            – Type: volume
              Value: 377
            – Type: issue
              Value: 6605
          Titles:
            – TitleFull: Science (pre-March 2025)
              Type: main
ResultId 1