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HSV-TK/GCV cancer suicide gene therapy by a designed recombinant multifunctional vector.

ABSTRACT: The objective of this research was to evaluate the efficacy of a recombinant nonviral vector for targeted delivery of a thymidine kinase (TK) suicide gene to xenograft SKOV-3 tumors. The vector was genetically engineered and used to condense the TK gene into particles of less than 100 nm. The nanoparticles were used to transfect and kill SKOV-3 cancer cells in combination with ganciclovir (GCV) in vitro. The results demonstrated that the vector could effectively kill up to 80% of the SKOV-3 cancer cells. In the next step, the ability of the vector to deliver the TK suicide gene to xenograft tumors of SKOV-3 was studied. The results demonstrated that the vector could transfect tumors and result in significant tumor size reduction during the period that GCV was administered. Administration of GCV for at least 3 weeks post transfection was of paramount importance. These results illustrate the therapeutic efficacy and application of a designed recombinant nonviral vector in cancer gene therapy.A recombinant nonviral vector is used to deliver a suicide thymidine kinase gene under gancylovir control in vitro to SKOV-3 cancer cells with 70% efficiency. Follow on testing in a xenograft tumor demonstrated tumor reduction persisting for three weeks.

SUBMITTER: Wang Y

PROVIDER: S-EPMC3024463 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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HSV-TK/GCV cancer suicide gene therapy by a designed recombinant multifunctional vector.

Wang Yuhua Y Canine Brenda F BF Hatefi Arash A

Nanomedicine : nanotechnology, biology, and medicine 20101001 2

The objective of this research was to evaluate the efficacy of a recombinant nonviral vector for targeted delivery of a thymidine kinase (TK) suicide gene to xenograft SKOV-3 tumors. The vector was genetically engineered and used to condense the TK gene into particles of less than 100 nm. The nanoparticles were used to transfect and kill SKOV-3 cancer cells in combination with ganciclovir (GCV) in vitro. The results demonstrated that the vector could effectively kill up to 80% of the SKOV-3 canc ...[more]

PMID: 20817124

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Project description:Triple-negative breast cancer (TNBC) represents approximately 20% of all breast cancers and appears resistance to conventional cytotoxic chemotherapy, demonstrating a particularly poor prognosis and a significantly worse clinical outcome than other types of cancer. Suicide gene therapy has been used for the in vivo treatment of various solid tumors in recent clinical trials. In tumor microenvironment, STAT3/NF-κB pathways are constitutively activated in stromal cells as well as in cancer stem cells (CSCs). In this study, we have cloned a novel STAT3/NF-κB-based reporter system to drive the expression of herpes simplex virus thymidine kinase (HSV-TK) against breast cancer. Lentiviral vector expressing HSV-TK under the regulation of STAT3/NF-κB fused response element was developed. In this setting, we exploited the constitutive STAT3/NF-κB activation in tumors to achieve higher transgene expression than that driven by a constitutively active CMV promotor in vivo. An orthotropic MDA-MB-231 triple negative breast cancer mouse model was used for evaluating the feasibility of STAT3-NF-κB-TK/GCV suicide gene therapy system. The basal promoter activity of Lenti-CMV-TK and Lenti-STAT3-NF-κB-TK in MDA-MB-231 cells was compared by 3H-FEAU uptake assay. The Lenti-CMV-TK showed ~5 fold higher 3H-FEAU uptake then Lenti -STAT3-NF-κB-TK. In clonogenic assay, cells expressing Lenti-CMV-TK were 2-fold more sensitive to GCV than Lenti-STAT3-NF-κB-TK transduced cells. In vitro effect of STAT3-NF-κB-induced transgene expression was determined by 10ng/mL TNF-α induction and confirmed by western blot analysis and DsRedm fluorescent microscopy. In vivo evaluation of therapeutic effect by bioluminescence and [18F]FHBG microPET imaging indicated that Lenti-STAT3-NF-κB-TK showed more tumor growth retardation than Lenti-CMV-TK when GCV (20 mg/kg) was administered. The invasiveness and expression of cancer stem cell markers were both decreased after STAT3/NF-κB-regulated HSV-TK/GCV therapy. Moreover, STAT3/NF-κB signaling targeting could further sensitize tumor cells to cisplatin. This study successfully established a theranositic approach to treat triple-negative breast cancer via STAT3-NF-κB responsive element-driven suicide gene therapy. This platform may also be an alternative strategy to handle with drug-resistant cancer cells.

Dataset Information

HSV-TK/GCV cancer suicide gene therapy by a designed recombinant multifunctional vector.

Publications

HSV-TK/GCV cancer suicide gene therapy by a designed recombinant multifunctional vector.

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