Oncolytic vaccinia virus synergizes with irinotecan in colorectal cancer

Ottolino‐Perry, Kathryn; Acuña, Sergio A.; Angarita, Fernando A.; Sellers, Clara; Zerhouni, Siham; Tang, Nan; McCart, J. Andrea

doi:10.1016/j.molonc.2015.04.009

Cited by 31 publications

(22 citation statements)

References 49 publications

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“…The mice in the control group were treated with saline containing 10% DMSO. The mice in the treatment group were given gimatecan (0.25 mg/kg, d1–d5/week, oral gavage) or irinotecan (40 mg/kg twice weekly, intraperitoneal injection) according to previous reports 45 , 46 . All of the animals were treated for 3 weeks.…”

Section: Methodsmentioning

confidence: 99%

A novel oral camptothecin analog, gimatecan, exhibits superior antitumor efficacy than irinotecan toward esophageal squamous cell carcinoma in vitro and in vivo

Zou

Chen

et al. 2018

Cell Death Dis

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Esophageal squamous cell carcinoma (ESCC) is a frequently diagnosed and deadly malignancy with few standard therapeutic options. Camptothecins are considered one of the most promising antitumor drugs. A modified lipophilic analog, gimatecan, was synthesized as a novel oral camptothecin and showed impressive effects in various tumors, but its therapeutic efficacy and mechanisms in ESCC remain unclear. This study investigated the antitumor efficacy and mechanisms of gimatecan in ECSS both in vitro and in vivo. Using ESCC cell lines, cell line-derived xenografts and patient-derived xenografts models, we evaluated gimatecan’s inhibition of tumor growth, and compared its antitumor efficacy with that of irinotecan. Topoisomerase I function and expression were assessed using the DNA relaxation assay and Western blotting, respectively. DNA damage was evaluated by Western blotting. Cell cycle progression and cell apoptosis were assessed using flow cytometry and Western blotting. Gimatecan could significantly suppress tumor growth in vivo and inhibit tumor cell proliferation in vitro, which was superior to irinotecan. Gimatecan suppressed the function and expression of topoisomerase I. It also caused DNA damage and activated the phosphorylation of multiple checkpoint gatekeepers, such as ATM, ATR, BRCA1, H2AX, CHK1, CHK2, and p53. It induced S phase arrest, enhanced the expression of p21WAF1/CIP, and suppressed the expression of CDK2 and cyclin A. Induction of apoptosis was accompanied by increases in Bax, cleaved-caspase 3 activation, cleaved-caspase 9 induction, and a decrease in Bcl-2. The molecular and phenotypic changes induced by gimatecan were stronger than that of irinotecan. In ESCC, gimatecan suppressed the expression and function of topoisomerase I, induced DNA damage and intra-S phase cell cycle arrest, and resulted in apoptosis. And the results suggest that gimatecan has higher potency in inhibiting ESCC tumor growth than irinotecan, providing a rational novel therapeutic strategy for future clinical evaluation.

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Section: Methodsmentioning

confidence: 99%

A novel oral camptothecin analog, gimatecan, exhibits superior antitumor efficacy than irinotecan toward esophageal squamous cell carcinoma in vitro and in vivo

Zou

Chen

et al. 2018

Cell Death Dis

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“…Interestingly, therapeutic benefit could be observed despite reduced viral titers. Enhanced levels of apoptosis in response to chemovirotherapeutic treatment were found to result in enhanced therapeutic efficacy and therefore outweighed detrimental decreases of the effective viral dose 29, 30. Prodrug converting strategies led to a powerful bystander effect, although viral replication was inhibited by the converted cytotoxic compound 5-FU 31, 32…”

Section: Discussionmentioning

confidence: 99%

Chemovirotherapy of Pancreatic Adenocarcinoma by Combining Oncolytic Vaccinia Virus GLV-1h68 with nab -Paclitaxel Plus Gemcitabine

Binz

Berchtold

Beil

et al. 2017

Molecular Therapy - Oncolytics

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Oncolytic viruses have proven their therapeutic potential against a variety of different tumor entities both in vitro and in vivo. Their ability to selectively infect and lyse tumor cells, while sparing healthy tissues, makes them favorable agents for tumor-specific treatment approaches. Particularly, the addition of virotherapeutics to already established chemotherapy protocols (so-called chemovirotherapy) is of major interest. Here we investigated the in vitro cytotoxic effect of the oncolytic vaccinia virus GLV-1h68 combined with dual chemotherapy with nab-paclitaxel plus gemcitabine in four human pancreatic adenocarcinoma cell lines (AsPc-1, BxPc-3, MIA-PaCa-2, and Panc-1). This chemovirotherapeutic protocol resulted in enhanced tumor cell killing in two tumor cell lines compared to the respective monotherapies. We were thereby able to show that the combination of oncolytic vaccinia virus GLV-1h68 with nab-paclitaxel and gemcitabine has great potential in the chemovirotherapeutic treatment of advanced pancreatic adenocarcinoma. However, the key to a successful combinatorial chemovirotherapeutic treatment seems to be a profound viral replication, as tumor cell lines that were non-responsive to the combination therapy exhibited a reduced viral replication in the presence of the chemotherapeutics. This finding is of special significance when aiming to achieve a virus-mediated induction of a profound and long-lasting antitumor immunity.

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“…The 5-year survival rate for metastatic colorectal cancer (mCRC) remains <30% when treated with chemotherapy with or without surgery. 29 The use of OVs is a promising therapeutic approach to fight cancer. OVs directly lyse tumor cells and some may induce systemic antitumor immunity, thus pointing to a novel therapeutic modality for CRC.…”

Section: Discussionmentioning

confidence: 99%

Antitumor effects of oncolytic herpes simplex virus type 2 against colorectal cancer in vitro and in vivo

Yin¹,

Zhao²,

Han³

et al. 2017

TCRM

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BackgroundThe incidence of colorectal cancer (CRC) is on the rise. Furthermore, late-stage diagnoses and limited efficacious treatment options make CRC a complex clinical challenge. Therefore, a new therapeutic regimen with a completely novel therapeutic mechanism is necessary for CRC. In the present study, the therapeutic efficacy of oncolytic herpes simplex virus type 2 (oHSV2) in CRC was assessed in vitro and in vivo. oHSV2 is an oncolytic agent derived from herpes simplex virus type 2 that encodes granulocyte-macrophage colony-stimulating factor.Materials and methodsWe investigated the cytopathic effects of oHSV2 in CRC cell lines using the MTT assay. Then, cell cycle progression and apoptosis of oHSV2 were examined by flow cytometry. We generated a model of CRC with mouse CRC cell CT26 in BALB/c mice. The antitumor effects and adaptive immune response of oHSV2 were assessed in tumor-bearing mice. The therapeutic efficacy of oHSV2 was compared with the traditional chemotherapeutic agent, 5-fluorouracil.ResultsThe in vitro data showed that oHSV2 infected the CRC cell lines successfully and that the tumor cells formed a significant number of syncytiae postinfection. The oHSV2 killed cancer cells independent of the cell cycle and mainly caused tumor cells necrosis. The in vivo results showed that oHSV2 significantly inhibited tumor growth and prolonged survival of tumor-bearing mice without weight loss. With virus replication, oHSV2 not only resulted in a reduction of myeloid-derived suppressor cells and regulatory T cells in the spleen, but also increased the number of mature dendritic cells in tumor-draining lymph nodes and the effective CD4+T and CD8+T-cells in the tumor microenvironment.ConclusionOur study provides the first evidence that oHSV2 induces cell death in CRC in vitro and in vivo. These findings indicate that oHSV2 is an effective therapeutic cancer candidate that causes an oncolytic effect and recruits adaptive immune responses for an enhanced therapeutic impact, thus providing a potential therapeutic tool for treatment of CRC.

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Oncolytic vaccinia virus synergizes with irinotecan in colorectal cancer

Cited by 31 publications

References 49 publications

A novel oral camptothecin analog, gimatecan, exhibits superior antitumor efficacy than irinotecan toward esophageal squamous cell carcinoma in vitro and in vivo

A novel oral camptothecin analog, gimatecan, exhibits superior antitumor efficacy than irinotecan toward esophageal squamous cell carcinoma in vitro and in vivo

Chemovirotherapy of Pancreatic Adenocarcinoma by Combining Oncolytic Vaccinia Virus GLV-1h68 with nab -Paclitaxel Plus Gemcitabine

Antitumor effects of oncolytic herpes simplex virus type 2 against colorectal cancer in vitro and in vivo

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