Prevention of 5-fluorouracil-induced infection with indigenous Escherichia coli in tumor-bearing mice by nonspecific immunostimulation

Abstract

We have previously reported that the lethal toxicity of 5-fluorouracil (5-FU) in specific-pathogen-free mice is due to an indigenous infection with Escherichia coli (K. Nomoto, T. Yokokura, Y. Yoshikai, et al. Can. J. Microbiol. 37:244-247, 1991). In the present study, we demonstrate that nonspecific immunostimulation augments host resistance against the lethal toxicity of 5-FU in tumor-bearing mice. Intravenous administration of a preparation of heat-killed Lactobacillus casei (LC 9018), a nonspecific immunostimulant, at a dose of 20 mg/kg to BALB/c mice augmented their resistance against the lethal toxicity of 5-FU if the preparation was injected into the mice 10-40 days before administration of 5-FU. Injection of LC 9018 into BALB/c mice bearing Meth A fibrosarcoma also enhanced their resistance against the lethality of 5-FU. Systemic infection with E. coli was induced in all of the 5-FU-treated tumor-bearing mice 10 days or more after administration of the drug at a lethal dose of 500 mg/kg, and it was accompanied by an overgrowth of the bacteria in the intestine. Treatment of tumor-bearing mice with LC 9018 resulted in decreased rates of occurrence of systemic infection with E. coli and inhibition of overgrowth of the bacteria in the intestine after administration of 5-FU. A single administration of either LC 9018 or 5-FU significantly inhibited the growth of Meth A cells in vivo, and a combined antitumor effect was shown in the mice treated with both 5-FU and LC 9018.

Prophylactic effect of lafutidine against the adverse reaction induced in rat stomach by repeated administration of 5-fluorouracil

“…Especially, 5-FU causes disturbances in the gastrointestinal microfl ora (Nomoto et al, 1992), systemic immunosuppression (von Bültzingslöwen et al, 1999) and impairment of the epithelial integrity (Hirata et al, 1999;Siber et al, 1980). Clinically, various symptoms, such as vomiting and heartburn, are recognized in patients when they take anti-tumor drugs for a long period (Polloni et al, 1986;Sartori et al, 1991).…”

CD8α-Deficient Mice Are Highly Susceptible to 5-Fluorouracil-Induced Lethality

“…A high dose of 5-FU would destroy the first line of defense, such as intestinal epithelial cells and immunocompetent cells derived from hematopoetic cells, -against intestinal microflora, leading to lethal translocation of intestinal microflora (21,26,31,41). CD8 ϩ i-IEL are located at the basolateral surfaces of i-EC, which are continuously exposed to numerous environmental antigens via the intestinal epithelium (18,24).…”

“…Although 5-FU is a widely used antineoplastic agent, the cytotoxicity of 5-FU is not limited to tumor tissue. Hematopoietic cells and normal epithelial cells of the gastrointestinal tract are susceptible to 5-FU-induced cytotoxicity, which produces severe leukopenia and intestinal toxicity, leading to lethal translocation of intestinal microflora (21,26,31,41). We have previously reported that the number of CD8 ϩ i-IEL was severely reduced after 5-FU administration and that a nonapaeide thymic hormone, facteur thymique serique (FTS), accelerated recovery in a number of CD8 ϩ i-IEL following 5-FU administration and protected mice from 5-FUinduced bacterial translocation (22).…”

Impairment by 5-Fluorouracil of the Healing of Gastric Lesions in Rats: Effect of Lafutidine, a Histamine H2 Receptor Antagonist, Mediated by Capsaicin-Sensitive Afferent Neurons

“…Notably, 5-FU causes disturbances in the gastrointestinal microflora [2], systemic immunosuppression [3], and the impairment of epithelial integrity [4,5]. Clinically, patients who take anti-tumor drugs for long periods experience side effects such as vomiting and heartburn [6,7].…”