5-Fluorouracil and Gemcitabine Potentiate the Efficacy of Oncolytic Herpes Viral Gene Therapy in the Treatment of Pancreatic Cancer

Eisenberg, David P.; Adusumilli, Prasad S.; Hendershott, Karen; Yu, Zhenkun; Mullerad, Michael; Chan, Mei-Ki; Chou, Ting‐Chao; Fong, Yuman

doi:10.1016/j.gassur.2005.06.024

Cited by 53 publications

(50 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…32,33 A recent study indicated that 5-FU potentiated herpes simplex virus cytotoxic effects primarily through increasing viral replication by 19-fold. 44 While our manuscript was in preparation, a relevant study on utilizing VV for controlling ovarian cancer models in mice was published. The study by Hung et al 45 has applied a wild-type and a tk gene-deleted VV and showed good efficacy for treating the tumor models.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic virotherapy for ovarian carcinomatosis using a replication-selective vaccinia virus armed with a yeast cytosine deaminase gene

et al. 2007

View full text Add to dashboard Cite

In this study, we assessed the ability of a highly tumor-selective oncolytic vaccinia virus armed with a yeast cytosine deaminase gene to infect and lyse human and murine ovarian tumors both in vitro and in vivo. The virus vvDD-CD could infect, replicate in and effectively lyse both human and mouse ovarian cancer cells in vitro. In two different treatment schedules involving either murine MOSEC or human A2780 ovarian carcinomatosis models, regional delivery of vvDD-CD selectively targeted tumor cells and ovarian tissue, effectively delaying the development of either tumor or ascites and leading to significant survival advantages. Oncolytic virotherapy using vvDD-CD in combination with the prodrug 5-fluorocytosine conferred an additional long-term survival advantage upon tumor-bearing immunocompetent mice. These findings demonstrate that a tumor-selective oncolytic vaccinia combined with gene-directed enzyme prodrug therapy is a highly effective strategy for treating advanced ovarian cancers in both syngeneic mouse and human xenograft models. Given the biological safety, tumor selectivity and oncolytic potency of this armed oncolytic virus, this dual therapy merits further investigation as a promising new treatment for metastatic ovarian cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Oncolytic virotherapy for ovarian carcinomatosis using a replication-selective vaccinia virus armed with a yeast cytosine deaminase gene

et al. 2007

View full text Add to dashboard Cite

show abstract

“…36,37 A recent study indicated that low doses of 5-FU potentiated herpes simplex virus cytotoxic effects primarily through increasing viral replication by 19-fold. 38 Clearly, the timing of prodrug administration will be a key factor in the overall efficacy; administration too early in the course of vaccinia infection could be counterproductive, preventing virus replication and thus limiting both the oncolytic effect, and the amount and distribution of the prodrug-activating enzyme. However, with optimum timing, prodrug activation is expected to kill more cells, or do so more rapidly although the tumor is smaller, than could be achieved by viral oncolysis alone.…”

Section: Oncolytic Vaccinia Virus Expressing Fcu1 J Foloppe Et Almentioning

confidence: 99%

Targeted delivery of a suicide gene to human colorectal tumors by a conditionally replicating vaccinia virus

et al. 2008

View full text Add to dashboard Cite

We have generated a thymidine kinase gene-deleted vaccinia virus (VV) (Copenhagen strain) that expressed the fusion suicide gene FCU1 derived from the yeast cytosine deaminase and uracil phosphoribosyltransferase genes. Intratumoral inoculation of this thymidine kinase genedeleted VV encoding FCU1 (VV-FCU1) in the presence of systemically administered prodrug 5-fluorocytosine (5-FC) produced statistically significant reductions in the growth of subcutaneous human colon cancer in nude mice compared with thymidine kinase gene-deleted VV treatments or with control 5-fluorouracil alone. A limitation of prodrug therapies has often been the requirement for the direct injection of the virus into relatively large, accessible tumors. Here we demonstrate vector targeting of tumors growing subcutaneously following systemic administration of VV-FCU1. More importantly we also demonstrate that the systemic injection of VV-FCU1 in nude mice bearing orthotopic liver metastasis of a human colon cancer, with concomitant administration of 5-FC, leads to substantial tumor growth retardation. In conclusion, the insertion of the fusion FCU1 suicide gene potentiates the oncolytic efficiency of the thymidine kinase gene-deleted VV and represents a potentially efficient means for gene therapy of distant metastasis from colon and other cancers.

show abstract

“…Gemcitabine belongs to the antimetabolites interfering with the cell cycle progression. In several studies gemcitabine was combined with other established anticancer drugs like 5-FU, cisplatin, docetaxel and radiotherapy to address or to overcome the extraordinary resistance of pancreatic carcinoma to chemotherapy (Eisenberg et al, 2005;Ko and Tempero, 2005;Pipas et al, 2005).…”

mentioning

confidence: 99%

Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells

et al. 2006

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease and one of the cancer entities with the lowest life expectancy. Beside surgical therapy, no effective therapeutic options are available yet. Here, we show that 4-phenylbutyrate (4-PB), a known and welltolerable inhibitor of histone deacetylases (HDAC), induces up to 70% apoptosis in all cell lines tested (Panc 1, T4M-4, COLO 357, BxPc3). In contrast, it leads to cell cycle arrest in only half of the cell lines tested. This drug increases gap junction communication between adjacent T3M-4 cells in a concentration-dependent manner and efficiently inhibits cellular export mechanisms in Panc 1, T4M-4, COLO 357 and BxPc3 cells. Consequently, in combination with gemcitabine 4-PB shows an overadditive effect on induction of apoptosis in BxPc3 and T3M-4 cells (up to 4.5-fold compared to single drug treatment) with accompanied activation of Caspase 8, BH3 interacting domain death agonist (Bid) and poly (ADP-ribose) polymerase family, member 1 (PARP) cleavage. Although the inhibition of the mitogen-activated protein kinase-pathway has no influence on fulminant induction of apoptosis, the inhibition of the JNK-pathway by SP600125 completely abolishes the overadditive effect induced by the combined application of both drugs, firstly reported by this study.

show abstract

5-Fluorouracil and Gemcitabine Potentiate the Efficacy of Oncolytic Herpes Viral Gene Therapy in the Treatment of Pancreatic Cancer

Cited by 53 publications

References 25 publications

Oncolytic virotherapy for ovarian carcinomatosis using a replication-selective vaccinia virus armed with a yeast cytosine deaminase gene

Oncolytic virotherapy for ovarian carcinomatosis using a replication-selective vaccinia virus armed with a yeast cytosine deaminase gene

Targeted delivery of a suicide gene to human colorectal tumors by a conditionally replicating vaccinia virus

Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells

Contact Info

Product

Resources

About