5-Fluorouracil and gemcitabine potentiate the efficacy of oncolytic herpes viral gene therapy in the treatment of pancreatic cancer |
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Authors: | David?P?Eisenberg Prasad?S?Adusumilli Karen?J?Hendershott Zhenkun?Yu Michael?Mullerad Mei-Ki?Chan Ting-Chao?Chou Email author" target="_blank">Yuman?FongEmail author |
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Institution: | (1) Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, 10021 New York, NY;(2) Preclinical Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York |
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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 βmol/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.
Presented at the Forty-Sixth Annual Meeting of The Society for Surgery of the Alimentary Tract, Chicago, Illinois, May 141-18,
2005 (oral presentation).
Supported in part by training grant T 32 CA09501 (D.P.E. and K.J.H.), AACR-AstraZeneca Cancer Research and Prevention fellowship
(P.S.A), grants RO1 CA 76416 and RO1 CA/DK80982 (Y.F.) from the National Institutes of Health, grant BC024118 from the U.S.
Army (Y.F.), grant IMG0402501 from the Susan G. Komen Foundation (Y.F.), and grant 032047 from Flight Attendant Medical Research
Institute (Y.F.). |
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Keywords: | Herpes simplex virus NV1066 synergism viral oncolysis |
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