Table 3.
EGF preclinical safety studies
| Study goal | Reference | Animal sp. | Dose / route | Findings |
|---|---|---|---|---|
| Broad toxicological evaluation of EGF | (70) | Rats, mice, monkeys | Dose scale up to 3 mg/kg for 4 weeks. IV/SC | Hyperplasia and hypertrophy of most epithelial and mesenchymal structures of internal organs and the skin. Cellular growth and proliferation were not associated with altered differentiation |
| Effect of chronic administration of EGF especially at the urinary tract | (79) | Minipigs | EGF 30 μg/kg/day for 4 weeks SC | An EGF‐mediated growth effect was observed in ureters, kidneys and heart. A milder enlargement was also found in pancreas, esophagus, salivary glands and lungs. Pre‐malignant or malignant lesions were not detected |
| Impact of chronic treatment with EGF on the esophageal epithelia in pigs and rats | (80) | Minipigs rats | EGF 30 and 150 μg/kg/day / 4 weeks SC | Significant thickening of the esophageal mucosa in both species, without the occurrence of changes in the normal pattern of cellular differentiation |
| Impact of chronic systemic treatment with EGF in the mucosal surface of the small intestine | (81) | Rats | EGF 150 μg/kg for 4 weeks SC | EGF treatment for 1–4 weeks caused a time‐dependent increase in intestinal weight. The growth was characterised by increased wall thickness, increased cross‐sectional area and reduced wall stiffness |
| Impact of chronic treatment with EGF in the growth of the urinary tract | (82) | Rats | EGF 150 μg/kg for 4 weeks SC | Ureters enlargement and urothelial hypercellularity not associated to changes in the epithelial differentiation pattern according to lectin histochemistry |
| Effect of prolonged systemic treatment with EGF in the luminal surface and colonic mass | (83) | Rats | EGF 150 μg/kg for 4 weeks SC | Systemic treatment with EGF for 1 week increased the luminal surface area relatively more than the mass of the colon. Treatment for more than 1 week caused a colonic mass increase in a time‐dependent manner. No malignant changes are reported |
| Effects of long‐term EGF treatment on the normal rat colon | (84) | Rats | EGF 150 μg/kg for 4 weeks SC | EGF has a stimulating role on the mucosa and luminal surface area of the entire functioning colon and a trophic effect on the submucosa of the distal colon |
| Effects of chronic administration of EGF on the levels of endogenous EGF | (85) | Rats | EGF at 150 μg/kg for 4 weeks SC | Chronic systemic treatment with EGF causes growth of the SMG with concomitantly reduced contents of EGF, and growth of the kidneys with unchanged content and excretion of EGF |
| Effects of chronic treatment with EGF in the urinary tract | (86) | Minipigs | EGF at 30 μg/kg/day × 4 weeks SC | Treatment with EGF induces the growth of all wall layers in the urinary tract with remarkable hyperplastic and hypertrophic changes of the smooth muscle cells in the muscular coat |
| Impact of chronic systemic treatment with EGF induces gastric physiological changes | (87) | Minipigs | EGF at 30 mg/kg/day for 4 weeks SC | EGF‐induced increase in serum gastrin, increased the number of antral G‐cells, and decreased the density of antral D‐cells. The acidity of gastric fluid was reduced, and the protein concentration increased |
| Effect of EGF systemic treatment in pancreatic ductal proliferation | (88) | Minipigs | EGF at 30 mg/kg/day for 5 weeks. Later 3 weeks of recovery SC | Interlobular ducts appeared hyperplastic, with increased number of PCNA positive cells. The epithelia of these ducts were increased in height, with accumulations of glycoconjugates in the columnar cells and in an increased number of goblet cells |
| Effect of EGF in polyps formation and its progression to cancer in MIN mice. | (78) | MIN mice | EGF by osmotic mini‐pumps (6·7 μg/day) for 28 days | EGF did not stimulate the appearance of polyps nor its transformation to malignant tumours |
| The effects of intra‐colonic EGF on mucosal growth and carcinogenesis | (72) | Mice | EGF (12 nM) in saline solution, rectal, 24 weeks | Showed that the intra‐colonic treatment with EGF did not strengthen the carcinogenic effect of the chemical azoxymethane. EGF does not promote colonic carcinogenesis in this model |
| Effect of EGF on experimental ulcerative mucositis by cancer chemotherapy. | (71) | Hamster | EGF 0·5 μl/h × 2 weeks | EGF leads to sensitise tumour cells under the effects of anti‐neoplastic agents |
| Effect of EGF on rat stomach chemical carcinogenesis | (89) | Rats | EGF 10μg/ml/day x 30 weeks with carcinogen MNNG | The findings suggest a possible enhancing effect of EGF on stomach carcinogenesis in rats |
| Effect of EGF on the development of salivary gland carcinomas | (90) | Mice | EGF 2 μg/ml/day × 8 weeks with carcinogen DMBA | EGF does not promote tumour induction in mouse salivary gland carcinogenesis assay |
| Effect of EGF administration on chemically induced tumours | (91) | Hamster | EGF + DMBA × 6weeks | Results suggest that EGF applied from the luminal side of the mucosa stimulates tumour formation in the hamster cheek pouch and forestomach |
| Effect of EGF in pancreatic and bronchial cancer when administered with a chemical carcinogen | (92) | Hamsters | EGF (5 μg) three injections/week × 3weeks + 19 weeks of N‐nitroso‐bis(2‐oxopropyl)amine | EGF increased the incidence of animals with bronchial cancer doubled. Suggested as a cocarcinogen as a result of its mitogenic activity |
EGF, epidermal growth factor; mg, milligram; mcg, microgram; IV, intravenous; SC, subcutaneous; SMG, submandibular gland; MNNG, N‐methyl‐N’‐nitro‐N‐nitro‐soguanidine; DMBA, dimethyl‐1,2‐benzanthracene.