Two-Week Aflibercept or Erlotinib Administration Does Not Induce Changes in Intestinal Morphology in Male Sprague– Dawley Rats But Aflibercept Affects Serum and Urine Metabolic Profiles Richard A. Forsgård * , Vannina G Marrachelli †, ‡ , Jere Lindén § , Rafael Frias ¶ , Maria Carmen Collado # , Riitta Korpela * , Daniel Monleon † , Thomas Spillmann ** and Pia Österlund ††, ‡‡ * Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; † Health research Institute INCLIVA, Metabo- lomics and Molecular Imaging Lab, Valencia, Spain; ‡ Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain; § FCLAP, Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Finland; ¶ Comparative Medicine, Karolinska Institutet, Stockholm, Sweden; # Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain; ** Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland; †† Department of Oncology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; ‡‡ Department of Oncology, Tampere University Hospital, Tampere, Finland Abstract Gastrointestinal toxicity is a frequently observed adverse event during cancer treatment with traditional chemother- apeutics. Currently, traditional chemotherapeutics are often combined with targeted biologic agents. These biologics, however, possess a distinct toxicity profile, and they may also exacerbate the adverse effects of traditional chemotherapeutics. In this study, we aimed to characterize the gastrointestinal and metabolic changes after a 2-week treatment period with aflibercept, an antiangiogenic VEGFR decoy, and with erlotinib, a tyrosine-kinase inhibitor. Male rats were treated either with aflibercept or erlotinib for 2 weeks. During the 2-week treatment period, the animals in the aflibercept group received two subcutaneous doses of 25 mg/kg aflibercept. The erlotinib group got 10 mg/kg of erlotinib by oral gavage every other day. The control groups were treated similarly but received either saline injections or oral gavage of water. Intestinal toxicity was assessed by measuring intestinal permeability and by histological analyses of intestinal tissues. Metabolic changes were measured with 1 H nuclear magnetic resonance in serum and urine. Neither aflibercept nor erlotinib induced changes in intestinal permeability or intestinal tissue morphology. However, aflibercept treatment resulted in stunted body weight gain and altered choline, amino acid, and lipid metabolism. Two-week treatment with aflibercept or erlotinib alone does not induce observable changes in gastrointestinal morphology and function. However, observed aflibercept-treatment related metabolic changes suggest alterations in intestinal microbiota, nutrient intake, and adipose tissue function. The metabolic changes are also interesting in respect to the systemic effects of aflibercept and their possible associations with adverse events caused by aflibercept administration. Translational Oncology (2019) 12, 1122–1130 Introduction Gastrointestinal (GI) toxicity is a common and well-known adverse effect of chemotherapy [1]. Chemotherapeutic drugs such as 5- fluorouracil (5-FU) and irinotecan are associated with a variety of GI symptoms such as diarrhea, abdominal pain, weight loss, and www.transonc.com Translational Oncology Volume 12 Number 8 August 2019 pp. 1122–1130 1122 Address all correspondence to: Richard Forsgård, Faculty of Medicine, Pharmacology, P.O. Box 63, FI-00014, University of Helsinki, Finland. E-mail: richard.forsgard@helsinki.fi Received 29 January 2019; Revised 27 April 2019; Accepted 28 April 2019 © 2019 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). 1936-5233/19 https://doi.org/10.1016/j.tranon.2019.04.019