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Purification of Viral DNA for the Identification of Associated Viral and Cellular Proteins
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Purification of Viral DNA for the Identification of Associated Viral and Cellular Proteins

Published on: August 31, 2017

Functional interaction between fluorodeoxyuridine-induced cellular alterations and replication of a ribonucleotide

H Petrowsky1, G D Roberts, D A Kooby

  • 1Rockefeller Research Laboratories, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

Journal of Virology
|July 4, 2001
PubMed

Insights

This study shows that fluorodeoxyuridine (FUdR) enhances the replication and cancer-killing ability of G207, an oncolytic herpes simplex virus (HSV). This occurs because FUdR increases viral ribonucleotide reductase (RR) activity, boosting viral proliferation.

Area of Science:

  • Oncolytic virotherapy
  • Molecular virology
  • Cancer therapeutics

Background:

  • G207 is an oncolytic herpes simplex virus (HSV) engineered for cancer treatment.
  • Viral ribonucleotide reductase (RR) and ICP34.5 are key viral components targeted for attenuation.
  • Cellular RR and growth arrest and DNA damage protein 34 (GADD34) can substitute for viral functions.

Purpose of the Study:

  • To investigate the effect of fluorodeoxyuridine (FUdR), a thymidylate synthetase (TS) inhibitor, on G207 bioactivity.
  • To determine if FUdR-induced changes in cellular RR and GADD34 impact G207 replication and cytotoxicity.
  • To explore the potential of combining G207 with TS inhibitors for cancer therapy.

Main Methods:

  • Treatment of cells with varying concentrations of FUdR.
  • Assessment of G207 and wild-type HSV-1 replication.
  • Evaluation of synergistic cytotoxicity between FUdR and G207.
  • Measurement of cellular RR activity and GADD34 induction.
  • Use of hydroxyurea to inhibit RR and assess its impact on viral replication.

Main Results:

  • FUdR impaired wild-type HSV-1 replication but enhanced G207 replication.
  • Combined FUdR and G207 treatment demonstrated synergistic cytotoxicity.
  • FUdR elevated cellular RR activity at 10 and 100 nM; GADD34 was induced only at 100 nM.
  • Hydroxyurea suppressed the enhanced viral replication by FUdR, indicating an RR-dependent mechanism.
  • G207 showed a growth advantage in FUdR-treated cells primarily due to RR elevation.

Conclusions:

  • The enhanced replication of G207 in FUdR-treated cells is mainly mediated by increased cellular RR activity.
  • Despite TS inhibition, elevated RR overcomes viral replication disadvantages, leading to enhanced G207 proliferation.
  • These findings support the use of RR-negative HSV mutants combined with TS inhibitors for cancer treatment.

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