A gene transfer comparative study of HSA-conjugated antiangiogenic factors in a transgenic mouse model of metastatic ocular cancer

Abstract

Different antiangiogenic and antimetastatic recombinant adenoviruses were tested in a transgenic mouse model of metastatic ocular cancer (TRP1/SV40 Tag transgenic mice), which is a highly aggressive tumor, developed from the pigmented epithelium of the retina. These vectors, encoding amino-terminal fragments of urokinase plasminogen activator (ATF), angiostatin Kringles (K1-3), endostatin (ES) and canstatin (Can) coupled to human serum albumin (HSA) were injected to assess their metastatic and antiangiogenic activities in our model. Compared to AdCO1 control group, AdATF-HSA did not significantly reduce metastatic growth. In contrast, mice treated with AdK1-3-HSA, AdES-HSA and AdCan-HSA displayed significantly smaller metastases (1.1971.19, 0.8771.5, 0.4370.56 vs controls 4.0475.12 mm 3 ). Moreover, a stronger inhibition of metastatic growth was obtained with AdCan-HSA than with AdK1-3-HSA (P ¼ 0.04). Median survival was improved by 4 weeks. A close correlation was observed between the effects of these viruses on metastatic growth and their capacity to inhibit tumor angiogenesis. Our study indicates that systemic antiangiogenic factors production by recombinant adenoviruses, particularly Can, might represent an effective way of delaying metastatic growth via inhibition of angiogenesis.

Collagens in the developing and diseased nervous system

“…Although not much is known about how these factors are involved in the regulation of angiogenesis, one should mention that three anti-angiogenic fragments called arresten, canstatin and tumstatin are derived from collagen IV [87,88]. Interestingly, canstatin has been shown to have an inhibitory property with regard to tumour growth in an animal model of ocular cancer with brain metastasis [89]. In addition to angiogenesis defects, neuronal ectopia is observed in mice lacking both the a1 and a2 isoforms of collagen IV due to the disruption of the pial basement membrane [90].…”

Anti-angiogenic gene therapy of cancer: Current status and future prospects

“…Ovarian cancer (Wu et al, 2006) Proteolitic fragments Angiostatin Adenoviral vectors Glioma and breast carcinoma (Griscelli et al, 1998); breast cancer (Gyorffy et al, 2001); Lewis lung carcinoma (Kuo et al, 2001); prostate cancer (Raikwar et al, 2005); hepatoma (Schmitz et al, 2004); ocular cancer (Frau et al, 2006 (Feldman et al, 2000); colon carcinoma ; Lewis lung carcinoma (Kuo et al, 2001;Sauter et al, 2000); mammary tumor (Calvo et al, 2002); malignant ascites (Wu et al, 2004); oral squamous cells (Fukumoto et al, 2005); nasopharyngeal carcinoma (Li et al, 2006a) …”

Cutaneous melanoma in genetically modified animals

“…Similarly, another pigment cell‐specific promoter, Tyrp1, was used to target SV40 T antigen ( Tyrp1 :: SV40Tag ) or the artificial ret oncogene ( Tyrp1 :: Ret ) to pigment cells (Penna et al., 1998; Schmidt et al., 1999). Metastasizing and vascularized tumors were reproducibly found in the RPE of Tyrp1 :: SV40Tag mice, favoring this model to exploit antiangiogenic treatments (Bouquet et al., 2003; Foletti et al., 2002; Frau et al., 2007; Penna et al., 1998; Rousseau et al., 2004). Ret is a receptor tyrosine kinase, and a Ret/PTC rearrangement is found in some human tumors, but not in melanoma, leading to the constitutive activation of the Ras/Raf pathway (Edery et al., 1997).…”