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Targeted therapy for Epstein-Barr virus-associated gastric carcinoma using low-dose gemcitabine-induced lytic

Hyun Gyu Lee1, Hyemi Kim1,2, Eun Jung Kim3

  • 1Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea.

Oncotarget
|October 2, 2015
PubMed

Insights

Gemcitabine can activate Epstein-Barr virus (EBV) replication in gastric cancer cells, enabling combination therapy with ganciclovir (GCV). This novel strategy targets viral enzymes for potential EBV-associated gastric cancer treatment.

Area of Science:

  • Oncology
  • Virology
  • Pharmacology

Background:

  • Epstein-Barr virus (EBV) is present in EBV-associated gastric cancers (EBVaGCs), suggesting targeted therapy potential.
  • Ganciclovir (GCV) efficacy is limited to the viral lytic cycle, requiring EBV-encoded thymidine kinase (TK)/protein kinase (PK) expression.

Purpose of the Study:

  • To identify novel therapeutic strategies for EBV-associated gastric cancers.
  • To evaluate gemcitabine as a lytic inducer for combination therapy with GCV.

Main Methods:

  • Screening of the Johns Hopkins Drug Library identified gemcitabine.
  • In vitro and in vivo studies using EBVaGC cells and a mouse model.
  • Evaluation of gemcitabine's lytic induction via the ATM/p53 pathway.
  • Utilized a [125I] fialuridine (FIAU)-based imaging system for in vivo lytic activation.

Main Results:

  • Gemcitabine was identified as a potent lytic inducer in EBVaGC cells.
  • Gemcitabine activates the ATM/p53 genotoxic stress pathway, inducing viral lytic replication.
  • Combination treatment with gemcitabine and GCV demonstrated efficacy in an EBVaGC mouse model.

Conclusions:

  • Gemcitabine acts as a lytic inducer in EBVaGC by activating the ATM/p53 pathway.
  • The combination of gemcitabine and GCV offers a promising targeted anti-tumor strategy for EBVaGCs.
  • This approach leverages viral enzyme targeting for novel therapeutic development in EBVaGC.
Keywords:
EBVaGC mouse modelEpstein-Barr virus-associated gastric carcinomaataxia telangiectasia-mutatedgemcitabinep53

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