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: 2.55). 07/2006; 13(6):619-27. DOI: 10.1038/sj.cgt.7700938
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostaglandins derived from the cyclooxygenase (COX) pathway and epoxyeicosatrienoic acids (EETs) from the cytochrome P450/soluble epoxide hydrolase (sEH) pathway are important eicosanoids that regulate angiogenesis and tumorigenesis. COX-2 inhibitors, which block the formation of prostaglandins, suppress tumor growth, whereas sEH inhibitors, which increase endogenous EETs, stimulate primary tumor growth and metastasis. However, the functional interactions of these two pathways in cancer are unknown. Using pharmacological inhibitors as probes, we show here that dual inhibition of COX-2 and sEH synergistically inhibits primary tumor growth and metastasis by suppressing tumor angiogenesis. COX-2/sEH dual pharmacological inhibitors also potently suppress primary tumor growth and metastasis by inhibiting tumor angiogenesis via selective inhibition of endothelial cell proliferation. These results demonstrate a critical interaction of these two lipid metabolism pathways on tumorigenesis and suggest dual inhibition of COX-2 and sEH as a potential therapeutic strategy for cancer therapy.
    Proceedings of the National Academy of Sciences 07/2014; 111(30). DOI:10.1073/pnas.1410432111 · 9.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Corneal transplantation is the oldest and one of the most successful transplant procedures with a success rate in many studies in excess of 90%. The high success rate is mainly due to the relatively immune-privileged status of the eye and the fact that the cornea is largely avascular. However, the success rate in patients with failed grafts is much lower such that regrafting is frequently the top indication for corneal transplantation in many centres. Neovascularisation is the most important risk factor for rejection, as it allows access of the immune system to the donor tissue, compromising immune privilege of the graft/eye. We have developed a process to modify donor corneal tissue to prevent rejection by a single exposure to a gene therapy vector prior to surgery (EncorStat®). The vector used is based on clinically-relevant EIAV-derived lentiviral platform and contains genes for two potently angiostatic genes, endostatin and angiostatin. We show that incubation of rabbit, primate and human corneal tissue with EIAV vector mediates strong, stable expression in the corneal endothelium. We have optimised this process to maximize transduction and, once this is complete, maximize the removal of free vector prior to transplant. Rabbit corneas treated with two different anti-angiogenic expression vectors (EIAV-EndoAngio and to a lesser extent EIAV-Endo:k5) significantly suppressed neovascularisation in a rabbit model of corneal rejection. As a result, corneal opacity, oedema and inflammatory infiltrates were reduced in these corneas. This study demonstrates that angiogenesis is a suitable target to prevent corneal rejection, and provides the first proof-of-concept data for the development of EncorStat®, an ex vivo gene therapy treatment to prevent corneal rejection.
    Human gene therapy 01/2014; 25(5). DOI:10.1089/hum.2013.079 · 3.62 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background:Endostatin, a fragment of collagen XVIII, is an endogenous angiogenesis inhibitor with anti-tumour functions. However, elevated circulating endostatin concentrations have been found in several human cancers including colorectal cancer (CRC).Methods:Serum endostatin levels were measured by enzyme-linked immunoassay from a series of 143 patients with CRC and from 84 controls, and correlated with detailed clinicopathological features of CRC, serum leukocyte differential count and C-reactive protein (CRP) levels.Results:Patients with CRC had higher serum endostatin levels than the controls (P=0.005), and high levels associated with age, tumour invasion through the muscularis propria and poor differentiation, but not with metastases. Endostatin levels showed a positive correlation with the markers of systemic inflammatory response and a negative correlation with the densities of tumour-infiltrating mast cells and dendritic cells. Collagen XVIII was expressed in tumour stroma most strikingly in blood vessels and capillaries, and in the muscle layer of the bowel wall.Conclusions:Elevated endostatin levels in CRC correlate with systemic inflammation and invasion through the muscularis propria. Increased endostatin level may be a result of invasion-related cleavage of collagen XVIII expressed in the bowel wall. The negative correlations between serum endostatin and intratumoural mast cells and immature dendritic cells may reflect angiogenesis inhibition by endostatin.British Journal of Cancer advance online publication, 19 August 2014; doi:10.1038/bjc.2014.456
    European Journal of Cancer 08/2014; 111(8). DOI:10.1038/bjc.2014.456 · 4.82 Impact Factor

Full-text (2 Sources)

Available from
Jun 10, 2014