Systemic proliferative changes and clinical signs in cynomolgus monkeys administered a recombinant derivative of human epidermal growth factor.
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 EGF(1-48) (rhEGF(1-48)). This report documents clinical findings and structural effects in the remaining epithelium-containing tissues of these animals. Two monkeys/sex/dose received rhEGF(1-48) by intravenous bolus at 0 (vehicle), 10, 100, 500 (females only), or 1,000 microg/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 1,000 microg/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 microg/kg and greater; small thymuses seen sporadically at all doses; and enlarged adrenals and small thyroids in males at 1,000 microqg/kg. Respective organ-to-brain weight ratios at 500 and 1,000 microg/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 microg/kg. Changes to renal collecting ducts were present at 10 microg/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, rhEGF(1-48) was a pantrophic epithelial mitogen in cynomolgus monkeys when used intravenously at suprapharmacologic doses.
Reindel
J F
JF
Drug Safety Evaluation, Pfizer Global Research and Development, Ann Arbor, Michigan 48105, USA.
Gough
A W
AW
Pilcher
G D
GD
Bobrowski
W F
WF
Sobocinski
G P
GP
de la Iglesia
F A
FA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004064:Digestive System / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000633:toxicity*; D004848:Epithelium / Q000187:drug effects* / Q000473:pathology; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D006984:Hypertrophy / Q000139:chemically induced / Q000473:pathology; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D008934:Mitogens / Q000008:administration & dosage / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D010446:Peptide Fragments / Q000008:administration & dosage / Q000633:toxicity*; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000633:toxicity*; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology
D008934:Mitogens; D010446:Peptide Fragments; D011994:Recombinant Proteins; C102344:epidermal growth factor (1-48); D004815:Epidermal Growth Factor