Potential Cytotoxic Effect of the Drug Interaction Between 5-FU and Carcinogens: Histopathological Evidence in an In Vivo Murine Model ^†

Introduction: 5-fluorouracil (5-FU) is the standard chemotherapeutic agent for treating squamous cell carcinoma (SCC). While 5-FU is used to treat lesions induced by 7,12-Dimethylbenz(a)anthracene (DMBA) and 12-O-Tetradecanoylphorbol-13-acetate (TPA), the simultaneous use of these chemicals has not been researched. Therefore, this study aimed to describe histopathological alterations from the possible cytotoxic interaction between 5-FU and these carcinogens in a murine model. Methodology: SCC lesions were induced in BALB/c mice (n = 6) with a single dose of DMBA and two total applications of TPA. Simultaneously, the animals received daily treatment with 5-FU (10 mg/kg, topically on the dorsum) for 5 days. Animals were then euthanized, and skin, intestine, kidney, lung, and liver samples were collected for histopathological analysis. Results: During treatment, clinical signs such as prostration, piloerection and diarrhea were observed, suggesting possible adverse reaction to 5-FU. Analysis revealed cellular alterations in the epidermis and dermis of the mice, including hyperplasia with leukocytic infiltrate. Furthermore, other organs were affected, revealing pulmonary edema, renal venous thrombosis, and Kupffer cell proliferation in the liver. Gastric hemorrhage and necrosis, as well as inflammatory infiltrate in the intestinal villi, were also noted. Conclusion: The daily 10 mg/kg dosage of 5-FU induced significant cytotoxicity, a finding that contradicts the reported safe dose (<25 mg/kg) for this murine strain. It was hypothesized that this unexpected toxicity may result from a drug interaction between 5-FU and the carcinogenic agents used.