NE US Academic Publishers Advances in Animal and Veterinary Sciences November 2021 | Volume 9 | Issue 11 | Page 1978 INTRODUCTION H epatocellular carcinoma (HCC) represents approximately 90% of primary liver cancers (Galle et al., 2018). Diethylnitrosamine (DEN) is found in foods such as smoked or dried fsh, cheese, soybeans, cured meat, and groundwater (El-Tabl et al., 2019). DEN is a potent liver carcinogen in experimental animals that initiate the stages of carcinogenesis throughout a time of promoting cell proliferation that goes together with the liver cells’ necrosis and destroys DNA integrity (Shahat et al., 2015). HCC in experimental animals is either induced by oral, intravenous, or intraperitoneal administration with diethylnitrosamine, the dose and duration of the carcinogen administration infuenced the occurrence and the latent period of the liver tumor (Khazaei et al., 2018). 5-fuoropyrimidine-2, 4(1H,3H)-dione (Fluorouracil) (5-FU) has been used for years as one of the frst-line chemotherapy for the treatment of cancers (Zhang et al., 2008). 5-FU treatment resulted in a high incidence of toxicity (Lee et al., 2015). Terapeutic doses of 5-FU in tumor treatment led to many toxic and side efects produced by DNA damage that in turn led to stimulation of apoptosis (Grem, 2000). Natural extracts had been used to augment the efcacy of 5-FU in chemotherapy, lessen their side efects as well as reduce the duration of treatment, and the anticipated dose (Grem, 2000). Resveratrol (RES) is a polyphenol substance found in by various plants such as grapes, peanuts, plums, and red wine has used in the treatment of obesity, and infammation (Chachay et al., 2011). RES has a possible efect against a number of diseases, among them its ability to achieve both chemo-preventive and therapeutic efects against Research Article Abstract | Toxicity and resistance to chemotherapeutic drugs remain major obstacles to successful therapy. We researched the ameliorative impacts of combining natural agent-like resveratrol with a chemotherapeutic drug-like 5-fuorouracil to improve its efcacy and reduce its side efect severity. Our results indicated that RES and 5-FU had a therapeutic impact against Diethylnitrosamine-induced HCC, and the best result was gained when both had been used together, they retain normal liver structure and functions also decreased the cytotoxic impact of 5-FU. RES remarkably reduced most of the efects induced by DEN, as they suppressed the signifcant increased relative liver weight, the hepatic nodules number and their relative volumes, the raised levels of serum liver function tests, and increased the depression of T. protein, albumin, globulin, liver homogenates antioxidants indicating their antioxidant efect. Furthermore, it showed alterations in the expression of the levels of some infammatory cytokines in serum, and immunoreactivities (Bax, CK18, and CA19-9) in the liver sections of the HCC group when compared with other groups. Dual-treatment of the phytochemical substance and the antitumor drug had an observantly therapeutic and immune-modulatory efcacy against HCC as they together have less toxicity than pharmaceutical agents. Keywords | Chemotherapeutic Drug, Hepatocellular Carcinoma, Infammatory Cytokines, Resveratrol, 5-Fluorouracil AMANY E. NOFAL 1 *, REDA M. FAY YAD 2 Enhanced Efect of Resveratrol on Hepatocellular Carcinoma of Rats Treated with 5-Fluorouracil Received | June 09, 2021; Accepted | July 08, 2021; Published | October 01, 2021 *Correspondence | Amany E. Nofal, Zoology Department, Faculty of Science, Menoufa University, Egypt; Email: nofal83@yahoo.com Citation | Nofal AE, Fayyad RM (2021). Enhanced efect of resveratrol on hepatocellular carcinoma of rats treated with 5-fuorouracil. Adv. Anim. Vet. Sci. 9(11): 1978-1988. DOI | http://dx.doi.org/10.17582/journal.aavs/2021/9.11.1978.1988 ISSN (Online) | 2307-8316; ISSN (Print) | 2309-3331 Copyright © 2021 Nofal and Fayyad. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1 Zoology Department, Faculty of Sciences, Menoufa University, Egypt; 2 Pharmacology Department, Faculty of Medicine Al-Azhar University, Egypt.