Systemic Proliferative Changes and Clinical Signs in Cynomolgus Monkeys Administered a Recombinant Derivative of Human Epidermal Growth Factor
| Autor: | J. F. Reindel, Gregg Sobocinski, Alexander W. Gough, Gary D. Pilcher, Walter F. Bobrowski, Felix A. de la Iglesia |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Pathology medicine.medical_specialty 040301 veterinary sciences Urinary Bladder Uterus Blood Pressure 030209 endocrinology & metabolism Thymus Gland Biology Kidney Toxicology Epithelium Pathology and Forensic Medicine 0403 veterinary science 03 medical and health sciences 0302 clinical medicine Seminal vesicle Toxicity Tests medicine Animals Endocrine system Molecular Biology Hyperplasia Urinary bladder Dose-Response Relationship Drug Epidermal Growth Factor Stomach Thyroid Prostate Hypertrophy Organ Size 04 agricultural and veterinary sciences Cell Biology medicine.disease Peptide Fragments Recombinant Proteins Macaca fascicularis medicine.anatomical_structure Injections Intravenous Female Mitogens Digestive System Cell Division |
| Zdroj: | Toxicologic Pathology. 29:159-173 |
| ISSN: | 1533-1601 0192-6233 |
| Popis: | Epidermal growth factor (EGF) effects have been explored extensively in vivo in rodents, but little is known about trophic responses in nonhuman primates. A previous publication reports the hyperplastic epithelial/parenchymal changes noted in the digestive tract (tongue, esophagus, stomach, intestine, liver, gallbladder, pancreas, and salivary glands) of adult cynomolgus monkeys treated with recombinant human EGF1-48 (rhEGF1-48). This report documents clinical findings and structural effects in the remaining epithelium-containing tissues of these animals. Two monkeys/sex/dose received rhEGF1-48 by intravenous bolus at 0 (vehicle), 10, 100, 500 (females only), or 1,000 μg/kg/day (males only) daily for up to 2 weeks. Treatment- and dose-related clinical findings included emesis, fecal alterations (soft feces and diarrhea), lacrimation, nasal discharge, hypoactivity, transient hypotension, and salivation after dosing. Male monkeys administered 1000 μg/kg became moribund after 5 days of treatment and were necropsied. All other monkeys completed the 2-week treatment period. Necropsy findings in nongastrointestinal tissues were: enlarged, pale kidneys at 100 μ g/kg and greater; small thymuses seen sporadically at all doses; and enlarged adrenals and small thyroids in males at 1,000 μg/kg. Respective organ-to-brain weight ratios at 500 and 1,000 μg/kg for kidneys were 1.5- and 2.6-fold greater and for heart were 1.7- and 1.3-fold greater than controls. Microscopically, pronounced dose-related epithelial hypertrophy and hyperplasia were evident in kidney, urinary bladder, skin (epidermis and adnexa), mammary gland, prostate, seminal vesicles, epididymis, uterus, cervix, vagina, thyroid, thymus, tonsillar crypts, cornea, trachea, and pulmonary airways. Epitheliotrophic effects were conspicuous in many tissues at 100 to 1,000 μg/kg. Changes to renal collecting ducts were present at 10 μg/kg, suggesting that kidneys were a relatively sensitive target. Proliferative alterations were not apparent in testes, intraocular structures, brain ependyma and choroid plexus at any dose. Aside from the noted exceptions, rhEGF1-48 was a pantrophic epithelial mitogen in cynomolgus monkeys when used intravenously at suprapharmacologic doses. |
| Databáze: | OpenAIRE |
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