Systemic Proliferative Changes and Clinical Signs in Cynomolgus Monkeys Administered a Recombinant Derivative of Human Epidermal Growth Factor

Abstract

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.

Fetal and Neonatal Goiter in Cynomolgus Monkeys Following Administration of the Antithyroid Drug Thiamazole at High Doses to Dams During Pregnancy

“…This observation suggests that administration of thiamazole to dams just before delivery strongly induces histopathological changes in the follicular epithelium of the thyroid gland in the fetal cynomolgus monkey. Although TSH and thyroid hormones were not assessed in the present study, the morphologic features of the thyroid glands from treated fetuses were consistent with enhanced resorption of colloid through TSH stimulation 17 .…”

Metformin regulates atrial SK2 and SK3 expression through inhibiting the PKC/ERK signaling pathway in type 2 diabetic rats

“…During the last two weeks, the Met group was further randomly divided into three groups: metformin-treated only (Met), the phorbol 12-myristate 13-acetate (PMA, a PKC agonist) treatment group (PMA), and the recombinant human epidermal growth factor (rh-EGF, an ERK agonist) treatment group (EGF). The PMA group rats were given a intraperitoneal injection of 2 μg/kg PMA (Abcam, Cambridge, UK) in dimethylsulfoxide (DMSO; Santa Cruz Biotech, Santa Cruz, CA, USA) every other day for two weeks [19]; the EGF group was given a tail vein injection of 10 μg/kg rh-EGF (R&D Systems, Minneapolis, MN, USA) in distilled water every day for two weeks [20]; and the Con, DM, and Met groups were injected with an equal volume of the same liquid. Body weight, FBG, and FINS were monitored again before the rats were sacrificed by intraperitoneal injection with 100 mg/kg pentobarbital sodium, and the atrial tissues were rapidly isolated after the sacrifice.…”

Assessing the mammary gland of nonhuman primates: effects of endogenous hormones and exogenous hormonal agents and growth factors

“…Recombinant human epidermal growth factor has been reported to produce multi‐system epithelial proliferative changes in cynomolgus monkeys, affecting most markedly the kidneys but also other tissues including the mammary glands (Reindel et al, 2001). In this study, Reindel et al (2001) exposed adult female cynomolgus monkeys to 10, 100, or 500 µg/day and males to 10, 100, or 1,000 µg/day of recombinant truncated N‐terminal 48 amino acid fragment of human epidermal growth factor, for 2 weeks. Mild proliferative changes in the ductal and acinar epithelium of the mammary gland were induced by the 500‐µg dose in females, and mild to marked changes were induced by the 1,000‐µg dose in males, as a component of the multi‐systemic epithelial proliferative response.…”