Modulation of 5-fluorouracil in mice using uridine diphosphoglucose

Uridine diphosphoglucose (UDPG) is a precursor of uridine that can be used as a rescuing agent from 5-fluorouracil (5FU) toxicity, Four doses of UDPG (2000 mg/kg i.p. or p.o. at 2, 6, 24, and 30 h after 5FU bolus) allowed the escalation of a weekly bolus of 5FU from 100 mg/kg (5FU(100)) to 150 mg/kg (5FU(150)) in healthy and tumor-bearing BALB/c, C57/BI, and CD8F(1) (BALB/c x DBA/B) mice. 5FU(150) without rescuing agents is not tolerated by the animals. When followed by UDPG, on the contrary, it is possible to increase the dose of 5FU even when it is modulated by leucovorin, Toxicity was the same for 5FU(100) and 5FU(150) + UDPG, and the nadir values (expressed as a percentage of pretreatment values) were 83 and 85% for weight, 45 and 45% for hematocrit, and 45 and 61% for leukocytes, respectively, Platelets were not affected by treatment. A protective effect was also shown for the gastrointestinal tract, The enzymes thymidine kinase, maltase, and sucrase were measured in the intestinal mucosa at different times after 5FU treatment with or without UDPG rescue, Even if the nadir values in enzyme activities were similar in mice receiving or not receiving UDPG, the pattern of recovery showed that cell repopulation was more rapid in the group treated with UDPG. 5FU(150) + UDPG had enhanced antitumor activity against CD8F, mammary carcinoma and against the resistant tumor Colon 26 (tumor doubling time 1.9 days for controls, 8.5 days for 5FU(100), 13.7 days for 5FU(150) + UDPG, and 15.9 days for 5FU(150) + leucovorin + UDPG). We demonstrated that UDPG administered at 2, 24, and 30 h after 5FU(100) does not reduce the antitumor activity of 5FU in two sensitive tumors (Colon 38 and Colon 26-10), In conclusion, UDPG is a promising rescuing agent for 5FU; it reduces the toxic side effects and increases the therapeutic index

Chemotherapy Does Not Influence Intestinal Amino Acid Uptake in Children

Chemotherapy will frequently induce intestinal damage (mucositis). Enteral nutrition is then often withheld for fear of impaired intestinal absorption as shown in animal models. There is no clinical evidence, however, that absorption is indeed compromised during chemotherapy-induced mucositis. The aim of this study was to evaluate systemic availability of dietary amino acids (leucine) during chemotherapy-induced mucositis. We studied eight childhood cancer patients (age 1.5-16 y) on 2 d, i.e. the day before chemotherapy and 3-5 d after. Chemotherapy-induced oral mucositis and diarrhea were scored on a World Health Organization toxicity scale. Stable isotope tracers were used to measure first-pass splanchnic leucine uptake and whole-body leucine kinetics. Patients showed increased mucositis and/or diarrhea toxicity scores (p <0.0001) after chemotherapy. Systemic availability of enterally administered leucine was not significantly affected by chemotherapy (before 60%, after 90%, p = 0.46). Interestingly, five patients already showed a negative leucine balance before chemotherapy. In conclusion, most children receiving chemotherapy are already catabolic before start of a new cycle of chemotherapy. Amino acid transport as measured by leucine uptake in the intestine is not affected by chemotherapy-induced mucositi