Endostatin therapy reveals a U-shaped curve for antitumor activity

Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Cancer Gene Therapy (Impact Factor: 2.42). 07/2006; 13(6):619-27. DOI: 10.1038/sj.cgt.7700938
Source: PubMed


Developing continuous systemic delivery of endostatin has been a goal of many laboratories. We have employed a method of gene therapy utilizing different viral constructs. Here, we report that a new serotype of adeno-associated viruses, which incorporates canine endostatin, provides dose-dependent transgene expression in the circulation after intramuscular injection in mice. Elevated levels of endostatin remained stable in the circulation for at least 4 months. In vitro assays determined that the protein expressed was biologically active. Antitumor activities of the above construct demonstrated a U-shape curve, where the maximum activity was observed within a certain critical concentration range. These data suggest that an optimum dose range may be required to achieve therapeutic efficacy in large animal models.

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Available from: David Zurakowski, May 19, 2014
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    • "Considering that BPA has been described as a xenoestrogen, it is interesting to note that Vandenberg et al. (2006) found that mice exposed to estradiol exhibited a non monotonic dose response for mammary gland morphology. Other classes of compounds, most notably the angiogenesis inhibitors, have also reported nonmonotonic therapeutic dose responses (Benelli et al. 2003; Bruns et al. 2004; Celik et al. 2005; Humar et al. 2002; Lalani et al. 2004; Motegi et al. 2002; Panigrahy et al. 2002; Slaton et al. 1999; Tjin Tham Sjin et al. 2005, 2006; Trinh et al. 2000; Yamaguchi et al. 1999). Given that our data suggest a potential role for BPA in tumor angiogenesis because of the significant increases in tumor volume and the incidence of metastasis, future research efforts focusing on this connection are warranted. "
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    ABSTRACT: Bisphenol A (BPA) is a synthetic compound used to produce plastics and epoxy resins. BPA can leach from these products in appreciable amounts, resulting in nearly ubiquitous daily exposure to humans. Whether BPA is harmful to humans, especially when administered orally in concentrations relevant to humans, is a topic of debate. In this study, we investigated the role of chronic oral exposure to BPA during adulthood on mammary carcinogenesis by using a transgenic mouse model that spontaneously develops tumors through overexpression of wild-type erbB2 [mouse mammary tumor virus (MMTV)-erbB2]. MMTV-erbB2 mice were exposed to 0, 2.5, 25, 250, or 2,500 µg BPA/L drinking water from 56 until 112 days of age (for mechanism of action) or 252 days of age (for tumorigenesis). Cellular and molecular mechanisms of BPA action in the mammary gland were investigated via immunohistochemistry and immunoblotting. Only low doses of BPA significantly decreased tumor latency and increased tumor multiplicity, tumor burden, and the incidence of metastasis. All BPA doses significantly increased the cell proliferation index, but only the higher doses also increased the apoptotic index in the mammary gland. At the molecular level, 25 µg BPA/L, but not 2,500 µg BPA/L, increased phosphorylation of erbB2, erbB3, insulin-like growth factor 1 receptor, and Akt in the mammary gland. Low, but not high, BPA doses significantly accelerated mammary tumorigenesis and metastasis in MMTV-erbB2 mice. The combined ratio of cell proliferation and apoptosis indices and alterations in protein expression best predicted the ability of each dose of BPA to alter tumorigenesis in this model.
    Environmental Health Perspectives 11/2011; 119(11):1604-9. DOI:10.1289/ehp.1103850 · 7.98 Impact Factor
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    • "Nowadays, animal experiments in vivo have been carried out. The clinical evaluation, however, calls for more deep research about the gene transduction system with better efficiency, specificity and safety (Tjin et al, 2006). The comprehensive therapy involving muti-genes transduction can inhibit the tumor in different stages, which may result in more conspicuous curative effect (Liu et al, 2009). "
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    ABSTRACT: The aim of the present study was to investigate the anti-tumor effect of a pEgr-1-endostatin-TNF-α recombinant plasmid induced by ionizing radiation. Three hundred and twenty mice bearing Lewis lung carcinomas were divided into four experimental groups: blank control, irradiation treatment, plasmid treatment and plasmid combined irradiation treatment. Twenty-four hours after the recombinant plasmid was injected locally into the tumors of the mice, they were irradiated with 10 Gy γ -rays. The concentration of TNF-α and endostatin in the serum of mice was measured by ELISA and tumor growth in each group was compared. The tumor microvessel density was examined by H and E staining and immunohistochemistry analysis of CD31 positive cells. Radiation could induce the expression of pEgr-1-endostatin-TNFα. The levels of endostatin and TNF-α could express steadily for about 4 weeks, with concentrations of 52.6 ± 4.19 and 12.0 ± 0.87 ng/ml respectively, in the second week in combined therapy group and maintained at relative higher level in the fourth week than other groups (F=29.7, P>0.05). Compared with the control group, the tumor micro vessel density was significantly depressed (P>0.05) and tumor growth was significantly inhibited (5907.2 ± 78.6 mm3 vs. 763.5 ± 12.3 mm3, P >0.05). The expression of pEgr-1-endostatin-TNF-α could be induced in mice in vivo and exhibited more significant anti-tumor and anti-angiogenesis effects than irradiation alone.
    Asian Pacific journal of cancer prevention: APJCP 01/2011; 12(11):2933-7. · 2.51 Impact Factor
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    • "For both tumor types, an increase in dosage to 1000 mg/kg/day resulted in elevated circulating endostatin levels in excess of 100 ng/ml and was correlated with reduced therapeutic efficacy of endostatin. In addition Tjin Tham Sijn et al., found that, for BxPC-3 tumor-bearing mice, the optimal circulating concentration of endostatin to achieve anti-tumor effects was between Hormesis and anti-angiogenic therapy 126-175 ng/ml, but that therapeutic efficacy was lost at higher endostatin dosages, where circulating concentrations were increased to 580 ng/ml (Tjin Tham Sjin et al. 2006). These data suggest that endostatin displays maximal anti-tumor effects only when circulating concentrations are within a low dose range. "
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    ABSTRACT: Tumor angiogenesis, the growth of new blood vessels into tumors, facilitates tumor growth and thus represents an attractive therapeutic target. Numerous experimental angiogenesis inhibitors have been characterised and subsequently trialled in patients. Some of these agents have failed to show any substantial activity in patients. In contrast, others have been more successful, but even these provide only a few months extra patient survival. Recent work has focused on understanding the effects of anti-angiogenic agents on tumor biology and has revealed a number of new findings that may help to explain the limited efficacy of angiogenesis inhibitors. Herein, I review the evidence that hormetic dose-responses (i.e. bell-shaped and U-shaped dose-response curves) are often observed with anti-angiogenic agents. Agents reported to exhibit these types of dose-response include: 5-fluorouracil, ATN-161, bortezomib, cisplatin, endostatin, enterostatin, integrin inhibitors, interferon-α, plasminogen activator-1 (PAI-1), rapamycin, rosiglitazone, statins, thrombospondin-1, TGF-α1 and TGF-α3. Hormesis may also be relevant for drugs that target the vascular endothelial growth factor (VEGF) signalling pathway and for metronomic chemotherapy. Here I argue that hormetic dose-responses present a challenge for the clinical translation of several anti-angiogenic agents and discuss how these problems might be circumvented.
    Dose-Response 07/2010; 8(3):253-84. DOI:10.2203/dose-response.09-049.Reynolds · 1.22 Impact Factor
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