Cancer cells as targets for lentivirus-mediated gene transfer and gene therapy

Pellinen, Riikka; Hakkarainen, Tanja; Wahlfors, Tiina; Tulimäki, Kirsi; Ketola, Anna; Tenhunen, Anni; Salonen, Tuula; Wahlfors, Jarmo

doi:10.3892/ijo.25.6.1753

Cited by 30 publications

(42 citation statements)

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“…However, lentivirus vectors have not been studied widely as gene transfer vehicles for cancerous cells for obvious reasons. 17 (1) they have potential to permanently transduce unwanted tissue; (2) their transduction efficiency has not been considered high enough for cancer gene therapy; (3) it is still widely thought that the safety profile of lentivirus vectors cannot validate their clinical use. Clearly, more studies are needed before it can be advanced into clinical practice.…”

Section: Discussionmentioning

confidence: 99%

“…Pellinen et al also reported that Gene transfer efficiency analysis four days later revealed that lentivirus was able to transfect almost ten times more tumor cells than the adenovirus(with equal number of biologically active viruses) in vivo. 17 The capability of lentiviruses to integrate and reside permanently in the target cell genome is indeed and undesired feature for cancer gene therapy. However, this would not be problematic in our studies, for the target KB cells are destroyed due to action of lentiviral vector.…”

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confidence: 99%

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Lentivirus-mediated gene therapy by suppressing survivin in BALB/c nude mice bearing oral squamous cell carcinoma

Jiang¹,

Li²,

Zeng³

et al. 2006

Cancer Biology & Therapy

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Despite advances in surgery, radiotherapy, and chemotherapy, the long-term survival rates with oral squamous cell carcinoma (OSCC) have not significantly improved. Gene therapy for OSCC is currently under investigation in clinical trials. Lentivirus vector is considered to be a promising gene delivery tool, but their value in cancer gene therapy has not been studied thoroughly. Survivin is overexpressed in OSCC, making it a promising target for gene therapy. This study was conducted to determine whether lentivirus-mediated gene therapy by suppressing survivin could be exploited in the treatment of OSCC. A lentivirus vector encoding short hairpin RNA (shRNA) targeting survivin was constructed and transfected into KB cells in vitro. The results showed that survivin was persistently and markedly reduced by lentivirus-mediated RNA interference (RNAi); the growth of KB cells was decreased by 34.2% on day 5; the apoptosis rate induced by vincristine (VCR) was increased by 29.8% and caspase-3 activity was also significantly increased; the IC 50 value of adriamycin (ADM) were 0.09 µg/ml, which indicated that survivin-knockout KB cells were 2.1 times more susceptible to ADM than the control; the clonogenic survival rate at 6 Gy of X ray was 3.7%, less than 15.3% of the control. In the xenograft model, the development of tumors as well as the growth of established tumors was inhibited by transfection of lentivirus. Our study indicates that lentivirus-mediated gene therapy is an attractive strategy in the treatment of OSCC and justifies the use of lentivirus in cancer gene therapy studies.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Lentivirus-mediated gene therapy by suppressing survivin in BALB/c nude mice bearing oral squamous cell carcinoma

Jiang¹,

Li²,

Zeng³

et al. 2006

Cancer Biology & Therapy

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“…Supernatants containing TAT-TK-GFP and TK-GFP lentiviral vectors were collected 48 h post-transfection and concentrated at 50 000 Â g for 90 min. Lentiviral vector transducing unit (TU) titers were determined in 293T cells using flow cytometry (FACSCalibur, Becton Dickinson, San Jose, CA, USA) as described earlier by Pellinen et al 20 and particle titers were determined using p24 assay (ALLIANCE HIV-1 p24 ELISA Kit, Perkin Elmer Life Sciences, Boston, MA, USA) according to the manufacturer's instructions.…”

Section: Viral Vectorsmentioning

confidence: 99%

Characterization of HIV-1 TAT peptide as an enhancer of HSV-TK/GCV cancer gene therapy

et al. 2008

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Cancer suicide gene therapy based on herpes simplex virus type I thymidine kinase (HSV-TK) and ganciclovir (GCV) suffers from the lack of efficacy in clinical use, which is mostly due to low gene-transfer efficiency and absence of bystander effect in tumors. We have previously demonstrated the enhancement of GCV cytotoxicity by fusing the HSV-TK with the cell penetrating peptide from HIV-1 transactivator protein transduction domain (TAT PTD). Despite the earlier promising results, we found that the triple fusion protein HIV-1 transactivator protein transduction domain-thymidine kinase suicide gene-green fluorescent protein marker gene (TAT-TK-GFP) increased GCV cytotoxicity only in 3/12 of different human tumor cell lines. Extended GCV exposure enhanced the cytotoxic effect of HSV-TK/GCV gene therapy, but the difference between TK-GFP and TAT-TK-GFP was not statistically significant. The modest improvement on cell killing mediated by TAT PTD in Chinese hamster ovary cells appeared to be associated with cellsurface heparan sulfate proteoglycan (HSPG) composition. However, TAT-mediated increased cell death did not correlate with the density of cell-surface HSPG expression in different tumor cell lines. In conclusion, although some degree of enhancement by TAT was shown in certain tumor cells in vitro, it is unlikely that TAT peptide linked to a suicide protein could be a useful booster of in vivo gene therapy trials.

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“…However, the fetal case report following adenovirus gene transfer (75) indicated against this strategy in humans. As other than adenovirus gene transfer vectors, it has been shown that osteosarcoma cell lines were good targets for lentiviral transduction with favorable gene transfer efficiency (76,77). After the development of a successful and safe delivery of the therapeutic gene, this strategy demonstrates great potential activity to modulate the prognosis of patients with osteosarcoma.…”

Section: Gene Therapy Eliciting Immune Response In Tumor-bearing Hostmentioning

confidence: 99%

Osteosarcoma: Current status of immunotherapy and future trends (Review)

Mori¹,

Rédini²,

Cherrier³

et al. 2006

Oncol Rep

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Abstract. Osteosarcoma is the most common primary bone tumor and represents a major therapeutic challenge in medical oncology. While the use of aggressive chemotherapy has drastically improved the prognosis of the patients with nonmetastatic osteosarcomas, the very poor prognosis of patients with metastasis have led to the exploration of new, more effective and less toxic treatments, such as immunotherapy for curing osteosarcoma. Compared to the numerous reports describing successful immunotherapy for other solid tumors, the number of reports concerning immunotherapy for osteosarcoma is low. However, this therapeutic strategy opens new areas for the treatment of osteosarcoma. In this review, the reasons for delay and all elements essential to develop immunotherapy concerning osteosarcoma are defined. Several pieces of evidence strongly support the potential capability of new therapies such as cellular therapy and gene therapy to eradicate osteosarcoma. Thus, clinical human trials using peptides, cytokines and dendritic cells have been performed. Tumor-infiltrating lymphocytes and some tumor antigens have been identified in osteosarcoma and resulted in an important breakthrough in cellular immunotherapy. Also, RANKL/RANK/OPG, the key regulator of bone metabolism, is a hot spot in this field as therapeutic tools. Immunotherapy for osteosarcomas has great potential, promising improvement in the survival rate and better quality of life for the patients.

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Cancer cells as targets for lentivirus-mediated gene transfer and gene therapy

Cited by 30 publications

References 0 publications

Lentivirus-mediated gene therapy by suppressing survivin in BALB/c nude mice bearing oral squamous cell carcinoma

Lentivirus-mediated gene therapy by suppressing survivin in BALB/c nude mice bearing oral squamous cell carcinoma

Characterization of HIV-1 TAT peptide as an enhancer of HSV-TK/GCV cancer gene therapy

Osteosarcoma: Current status of immunotherapy and future trends (Review)

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