A gene therapy for cancer based on the angiogenesis inhibitor, vasostatin

Xiao, Fei; Yue, Wei; Yang, Li; Zhao, Xia; Tian, Li; Ding, Zhaoyang; Yuan, Shuang; Lou, Yonggen; F, Liu; Yang, Wen; Li, Jian; Deng, Heng; Kang, Bing; Mao, Ying; Su, Lei; He, Qiang; Su, Jian; Lu, Yue; T, Niu; Hou, Jianquan; Mj, Huang

doi:10.1038/sj.gt.3301788

Cited by 60 publications

(39 citation statements)

References 39 publications

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“…Previous studies have indicated that single DNA vaccination results in peak serum CRT levels at 7 days post vaccination, tapering off to near-baseline levels within 14 days post vaccination [37]. In addition, the level of serum CRT depends on the dose of CRT DNA [37].…”

Section: Discussionmentioning

confidence: 99%

Characterization of DNA vaccines encoding the domains of calreticulin for their ability to elicit tumor-specific immunity and antiangiogenesis

Cheng

Hung

Chen

et al. 2005

Vaccine

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Antigen-specific cancer immunotherapy and antiangiogenesis are feasible strategies for cancer therapy because they can potentially treat systemic tumors at multiple sites in the body while discriminating between neoplastic and non-neoplastic cells. We have previously developed a DNA vaccine encoding calreticulin (CRT) linked to human papillomavirus-16 E7 and have found that this vaccine generates strong E7-specific antitumor immunity and antiangiogenic effects in vaccinated mice. In this study, we characterized the domains of CRT to produce E7-specific antitumor immunity and antiangiogenic effects by generating DNA vaccines encoding each of the three domains of CRT (N, P, and C domains) linked to the HPV-16 E7 antigen. We found that C57BL/6 mice vaccinated intradermally with DNA encoding the N domain of CRT (NCRT), the P domain of CRT (PCRT), or the C domain of CRT (CCRT) linked with E7 exhibited significant increases in E7-specific CD8 + T cell precursors and impressive antitumor effects against E7-expressing tumors compared to mice vaccinated with wild-type E7 DNA. In addition, the N domain of CRT also showed antiangiogenic properties that might have contributed to the antitumor effect of NCRT/E7. Thus, the N domain of CRT can be linked to a tumor antigen in a DNA vaccine to generate both antigen-specific immunity and antiangiogenic effects for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Characterization of DNA vaccines encoding the domains of calreticulin for their ability to elicit tumor-specific immunity and antiangiogenesis

Cheng

Hung

Chen

et al. 2005

Vaccine

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“…It is based on the enzymatic addition of digoxigenin nucleotide to the nicked DNA by terminal deoxynucleotidyl transferase. 26 Immunostaining for VSV was performed as described previously. 5 Briefly, paraffinembedded tissue sections from the treated mice were incubated with a monoclonal antibody against VSV-glycoprotein at a 1:200 to 1:1,000 dilution (Sigma) at 4°C overnight.…”

Section: Histologic Analysismentioning

confidence: 99%

Induction of apoptosis and tumor regression by vesicular stomatitis virus in the presence of gemcitabine in lung cancer

Wei

Wang

et al. 2004

Intl Journal of Cancer

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Key words: apoptosis; vesicular stomatitis virus; gemcitabine; lung cancer; chemotherapyLung cancer accounts for about 1.5 million cases worldwide and is the leading cause of cancer-related death in both males and females. Non small cell lung cancer (NSCLC) comprises approximately 75-80% of all lung cancers. Despite aggressive approaches made in the therapy of lung cancer in the past decades, the prognosis of NSCLC remains poor, with 5-year survival rates of 5-14%, even if treated with surgery, radiotherapy and/or chemotherapy. 1-3 Efforts are therefore continuing to develop new and less toxic therapeutic approaches for the treatment of lung cancer.Vesicular stomatitis virus (VSV) is an enveloped, negativesense RNA virus and prototypic member of the family rhabdoviridae. 4 -6 It has been shown to replicate rapidly in vitro and kill selectively a variety of tumor cell lines. An essential, dose-limiting site of chemotherapy is the bone marrow while VSV can selectively kill leukemia cells when cocultured with normal bone marrow cells. 4 Furthermore, VSV exhibits the antitumor activity in both human tumor xenografts in nude mice and syngeneic tumors in the immunocompetent mice. 4,5 Gemcitabine (2Ј,2Ј-diflurodeoxycytidine) is a new deoxycytidine analogue that inhibits DNA synthesis. After cellular uptake, gemcitabine is phosphorylated to its active metabolites, which competitively inhibits DNA chain elongation, leading to DNA fragmentation and cell death. Gemcitabine has shown cytotoxic activity against a wide range of cancer cell lines in vitro and a number of murine and human tumors in vivo. [7][8][9] Gemcitabine monotherapy produced objective response in 20 -25% of patients with advanced NSCLC and has similar efficacy to cisplatin plus etoposide. 10 -12 When combined with cisplatin and/or paclitaxel or vinorelbine, gemcitabine therapy shows an objective response rates in 28 -54% and the median survival durations ranged from 38 to 61.5 weeks. [13][14][15][16][17][18] However, the treatment of advanced lung cancer still remains a challenge to medical oncologists.Because of differences in mechanisms of action and toxicity profiles, the combination of the above 2 agents may have clinical potential. The present study was designed to determine whether gemcitabine potentiates the antitumor activity of VSV in vitro using both A549 (human lung adenocarcinoma) and LLC (murine Lewis lung carcinoma) cell lines and in vivo using A549 lung cancer xenografts and the murine syngeneic Lewis lung cancer, and if so, to examine the possible mechanism in the phenomenon, as well as to provide some potential implications for the treatment of human lung cancer. MATERIAL AND METHODS Cells lines and agentsLLC cells and A549 cells were purchased from American Type Culture Collection (Rockville, MD). They were maintained in monolayer cultures in DMEM and RPMI-1640, respectively, supplemented with 10% heat-inactivated fetal bovine serum (FBS), at 37°C in a humidified atmosphere containing 5% CO 2 . Human umbilical vein endothelial cells (HU...

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“…Vasostatin specifically inhibits endothelial cell attachment to laminin and reduces subsequent endothelial cell growth induced by bFGF (201). Furthermore, gene therapy experiments with intramuscular delivery of vasostatin DNA is effective in the inhibition of angiogenesis and tumor growth in murine tumor models (202).…”

Section: Non-matrix-derived Inhibitors Of Angiogenesismentioning

confidence: 99%

“…The antiangiogenic activity is localized to a distinct region of the tumstatin molecule that is separate from the region responsible for the antitumor cell activity (90). Tumstatin has two binding sites for a v h 3 integrin, one in the NH 2 -terminal end of the molecule (containing amino acids that is associated with the antiangiogenic properties and the other in the COOHterminal end (containing amino acids [185][186][187][188][189][190][191][192][193][194][195][196][197][198][199][200][201][202][203] that is associated with the antitumor cell activity (89,91,93). The tumstatin fragment containing amino acids 54 to 132 binds to both endothelial cells and melanoma cells but only inhibits proliferation of endothelial cells, with no effect on tumor cell proliferation.…”

Section: Matrix-derived Inhibitors Of Angiogenesismentioning

confidence: 99%