Gene therapy has been investigated and used for the treatment for malignant tumors and ischemic diseases in both animal models and clinical settings. Previously, effective ulcer healing with intragastric administration of growth factors such as VEGF (vascular endothelial growth factor) and PDGF (platelet-derived growth factor) was first reported by our group. In this present study, we compared the effects of naked DNA (ND) and adenovirus (AV) transfection of VEGF and PDGF to treat chronic duodenal ulcer induced by the ulcerogen cysteamine in rats. Groups of Sprague-Dawley female rats (180–210 g) were given cysteamine-HCl (25 mg/100 g by gavage x3 with 4 hr intervals) to cause duodenal ulcers. Laparotomy on the 3rd day was performed to evaluate ulcer formation and rats with equal severity of duodenal ulcers were randomly divided into 10 groups which received either intraduodenal (i.d.) injection of 0.1 ml/rat of Tris-EDTA buffer in control group 1(G1) or 5×108 pfu/rat of adenovirus in control group 2 (G2), 1 g/rat (G3) or 100 g/rat (G4) of naked DNA of VEGF and 5×107 pfu/rat of PDGF (G5) or 5×108 pfu/rat of adenovirus vector of PDGF (G6) or VEGF (G7), respectively, and or intravenous (i.v.) injection of 200 g/rat of ND of VEGF (G8) and 5×108 pfu/rat of AV of PDGF (G9) or VEGF (G10), respectively. An additional 200 g/rat of ND of VEGF was given to G8 rats on the 7th day after cysteamine administration. Rats were euthanized on the 7th or 14th day after cysteamine and size of duodenal ulcer was measured by morphometric analysis and ulcer area was calculated by the ellipsoid formula. Mucosal scrapings of proximal duodenum were homogenized and tested for VEGF protein using Western blot analysis. The results demonstrated that no one group of rats had significant ulcer healing 7 days after cysteamine compared with controls although the tendency was towards accelerated healing using the PDGF or VEGF vectors. A significant duodenal ulcer healing was noted after 14 days in the groups with 200g/rat of ND of VEGF.i.v. (G8, p=0.0430), 5×108 pfu/rat of AV of VEGF i.v. (G7, p=0.0025), 5×107 pfu/rat i.d. (G5, p=0.0198), 5×108 pfu/rat i.d. (G6, p=0.0221 ) and 5×108 pfu/rat i.v. (G9, p=0.0300) of AV of PDGF, respectively, compared with controls. Western blot analysis showed that the 23 kDa VEGF protein (a monomeric VEGF-164 in reducing condition) decreased 14 days after cysteamine, and increased in groups with i.d. injection of either ND of VEGF, AV of VEGF or PDGF 7 days after cysteamine. In contrast, i.v. injection of AV of both VEGF and PDGF diminished 23 kDa VEGF 7 days after cysteamine, but increased it in 14 days. Conclusions: 1) Gene therapy with naked DNA of VEGF, adenovirus of VEGF or PDGF significantly accelerated chronic duodenal ulcer healing in 14 but not 7 days after the administration of duodenal ulcerogen cysteamine. 2) Increased levels of VEGF were detected by Western blotting in duodenal mucosa after both VEGF and PDGF gene therapy. 3) Thus, VEGF and PDGF gene therapy seems to be a new option to achieve a rapid duodenal ulcer healing.
This is a preview of subscription content, access via your institution