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Recombinant Human Epidermal Growth Factor1-48-Induced Structural Changes in the Digestive Tract of Cynomolgus Monkeys (Macaca fascicularis)Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company, Ann Arbor, Michigan 48105
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company, Ann Arbor, Michigan 48105
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company, Ann Arbor, Michigan 48105
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company, Ann Arbor, Michigan 48105
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company, Ann Arbor, Michigan 48105 To determine the cellular effects and potential toxicity of exogenously administered recombinant human epidermal growth factor1-48 (EGF1-48) in primates, intravenous bolus injections were given to 2 cynomolgus monkeys per sex at 0 (vehicle control). 10, 100, 500 (females only), and 1,000 µg/kg/day (males only) for up to 2 wk. Males given the suprapharmacologic dose of 1,000 µg/kg did not tolerate treatment and were necropsied after 5 days of dosing. All other monkeys completed the 2-wk study. Necropsy findings included enlarged, discolored, pale tan livers at 500 µg/kg and greater, firm, thickened pancreata in 500-µg/kg females, and enlarged salivary glands at all doses. Relative liver weights were increased at 500 and 1,000 µg/kg; mean salivary gland weights in all dose groups were greater than in controls. Histopathologic changes were primarily those of diffuse epithelial cell hypertrophy and hyperplasia in liver (hepatocytes and biliary tract), pancreas, salivary glands, tongue, esophagus, stomach, small and large intestine, and gallbladder. Alterations were dose-related in intensity and occurred in at least some tissues at the lowest dose. In gastric glands, colon crypts, pancreatic ducts, biliary tract, and salivary glands, differentiated epithelial cells were replaced by cells of less differentiated phenotype. These morphologic alterations were consistent with exuberant proliferation induced by this epithelial mitogen. The extent of the proliferative response in tissues of the digestive tract attests to the potency of this fragment of human EGF1-53 in primates. Furthermore, the epithelial proliferation was significantly greater than that reported previously in EGF-treated rodents.
Key Words: Nonhuman primate • epithelium • epithelial hyperplasia • gastrointestinal system • stomach • salivary gland • liver • pancreas • intestine • cell differentiation • toxicity • intravenous
Toxicologic Pathology, Vol. 24, No. 6,
669-680 (1996) This article has been cited by other articles:
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