5-fluorouracil and gemcitabine potentiate the efficacy of oncolytic herpes viral gene therapy in the treatment of pancreatic cancer. Academic Article uri icon

Overview

MeSH

  • Cell Line, Tumor
  • Combined Modality Therapy
  • Genetic Vectors
  • Humans
  • Oncolytic Viruses
  • Reverse Transcriptase Polymerase Chain Reaction
  • Virus Replication

MeSH Major

  • Antineoplastic Agents
  • Deoxycytidine
  • Fluorouracil
  • Genetic Therapy
  • Herpesvirus 1, Human
  • Pancreatic Neoplasms

abstract

  • Oncolytic herpes viruses are attenuated, replication-competent viruses that selectively infect, replicate within, and lyse cancer cells and are highly efficacious in the treatment of a wide variety of experimental cancers. The current study seeks to define the pharmacologic interactions between chemotherapeutic drugs and the oncolytic herpes viral strain NV1066 in the treatment of pancreatic cancer cell lines. The human pancreatic cancer cell lines Hs 700T, PANC-1, and MIA PaCa-2 were treated in vitro with NV1066 at multiplicities of infection (MOI; ratio of the number of viral particles per tumor cell) ranging from 0.01 to 1.0 with or without 5-fluorouracil (5-FU) or gemcitabine. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Viral replication was measured using a standard plaque assay. Six days after combination therapy, 76% of Hs 700T cells were killed compared with 43% with NV1066 infection alone (MOI = 0.1) or 0% with 5-FU alone (2 micromol/L) (P < .01). Isobologram and combination-index analyses confirmed a strongly synergistic pharmacologic interaction between the agents at all viral and drug combinations tested (LD5 to LD95) in the three cell lines. Dose reductions up to 6- and 78-fold may be achieved with combination therapy for NV1066 and 5-FU, respectively, without compromising cell kill. 5-FU increased viral replication up to 19-fold compared with cells treated with virus alone. Similar results were observed by combining gemcitabine and NV1066. We have demonstrated that 5-FU and gemcitabine potentiate oncolytic herpes viral replication and cytotoxicity across a range of clinically achievable doses in the treatment of human pancreatic cancer cell lines. The potential clinical implications of this synergistic interaction include improvements in efficacy, treatment-associated toxicity, tolerability of therapeutic regimens, and quality of life. These data provide the cellular basis for the clinical investigation of combined oncolytic herpes virus therapy and chemotherapy in the treatment of pancreatic cancer.

publication date

  • November 2005

has subject area

  • Antineoplastic Agents
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Deoxycytidine
  • Fluorouracil
  • Genetic Therapy
  • Genetic Vectors
  • Herpesvirus 1, Human
  • Humans
  • Oncolytic Viruses
  • Pancreatic Neoplasms
  • Reverse Transcriptase Polymerase Chain Reaction
  • Virus Replication

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC1373688

Digital Object Identifier (DOI)

  • 10.1016/j.gassur.2005.06.024

PubMed ID

  • 16269377

Additional Document Info

start page

  • 1068

end page

  • 77; discussion 1077-9

volume

  • 9

number

  • 8