(E)-5-(2-bromovinyl)-2'-deoxyuridine potentiates ganciclovir-mediated cytotoxicity on herpes simplex virus-thymidine...

Area of Science:

• Oncology
• Gene Therapy
• Virology

Background:

• Tumor cells genetically modified to express herpes simplex virus thymidine kinase (HSV-tk) are sensitive to specific antiherpes drugs.
• Enhancing the efficacy of HSV-tk based gene therapy for cancers like glioma is an ongoing challenge.

Purpose of the Study:

• To investigate if co-administering two prodrugs, (E)-5-(2-bromovinyl)-2 '-deoxyuridine (BVDU) and ganciclovir (GCV), can improve tumor cell killing in HSV-tk expressing cell lines.
• To evaluate the bystander effect in co-cultures of HSV-tk positive and negative cells.

Main Methods:

• HSV-tk expressing and non-expressing tumor cell lines were treated with BVDU and GCV, alone and in combination.
• Cytotoxicity was measured in single-cell cultures and co-cultures of HSV-tk(+) and HSV-tk(-) cells.
• Potential mechanisms of BVDU cytotoxicity, including thymidylate synthase inhibition and DNA incorporation, were assessed.

Main Results:

• Combination therapy with BVDU and GCV significantly enhanced GCV-mediated cancer cell killing by up to tenfold in 8 out of 12 cell lines.
• BVDU potentiated GCV cytotoxicity even at concentrations with minimal individual effect.
• Enhanced bystander cell killing was observed in co-cultures when BVDU was present with GCV.
• BVDU's cytotoxic effects (thymidylate synthase inhibition, DNA incorporation) were observed in all HSV-tk expressing cells, irrespective of direct cytotoxicity.

Conclusions:

• Simultaneous administration of two distinct prodrugs metabolized by the same enzyme (HSV-tk) can substantially increase the effectiveness of gene therapy.
• The findings challenge existing notions of BVDU's mechanism of action in HSV-tk expressing cells.
• This dual-prodrug strategy holds promise for improving outcomes in HSV-tk based cancer gene therapy.