Potent combination therapy for human breast tumors with high doses of 5-fluorouracil: remission and lack of host toxicity

Metabolites modulate the functional state of human uridine phosphorylase I

“…Changes in the levels of these metabolites, like in cancer cells, may significantly modulate the function of hUP1. A “uridine rescue” strategy was recently developed for increasing the efficacy of 5‐FU in chemotherapy 19,20,44–46 . By increasing the concentration of uridine in plasma, it was found that experimental animals could tolerance higher doses of 5‐FU.…”

“…A "uridine rescue" strategy was recently developed for increasing the efficacy of 5-FU in chemotherapy. 19,20,[44][45][46] By increasing the concentration of uridine in plasma, it was found that experimental animals could tolerance higher doses of 5-FU. Moreover, this high-dose chemotherapy actually enhanced the efficiency of killing cancer cells, but not normal cells.…”

Design of Novel Potent Inhibitors of Human Uridine Phosphorylase-1: Synthesis, Inhibition Studies, Thermodynamics, and in Vitro Influence on 5-Fluorouracil Cytotoxicity

“…Uridine (Urd) is a natural pyrimidine nucleoside that is involved, directly or indirectly, in many cellular processes including RNA and biomembrane synthesis, galactose metabolism, , modulation of reproduction, regulation of body temperature, and peripheral and central nervous systems activities. , Furthermore, Urd has been described for decades as a promising biochemical modulator of 5-fluorouracil (5-FU) metabolism. − 5-FU was synthesized in 1957 by Charles Heidelberger, and since then it has been broadly used in the clinical setting to treat solid tumors such as breast, colorectal, and head and neck cancers. , 5-FU requires metabolic activation and, as a uracil analogue, it is processed by the same enzymes involved in pyrimidine salvage pathway. , The active metabolites act through two main pathways: by forming a ternary complex with thymidylate synthase (TS) leading to inhibition of DNA synthesis and interference with DNA repair and by incorporating fluorouridine 5′-triphosphate (FUTP) into RNA. − It has been hypothesized that the therapeutic activity of 5-FU is due to DNA damage, whereas the toxic side effects are related to RNA damage by FUTP incorporation. − In this context, there has been interest in the use of Urd as a biochemical modulator to counteract the host toxicity caused by chemotherapy with fluoropyrimidines, as 5-FU, thereby enabling the increase in doses of these drugs. High levels of Urd leads to an increase in UTP levels, which will compete with FUTP for RNA incorporation. ,, However, sustainable high plasma concentration is required for Urd to exert a protective effect against 5-FU toxicity.…”