Clinical use of thymidine as a rescue agent from methotrexate toxicity

Abstract

Thymidine has been available for clinical research as a rescue agent since 1978 under sponsorship of the Division of Cancer Treatment, National Cancer Institute. Renal insufficiency following administration of high dose methotrexate results in prolonged exposure to toxic concentrations of drug. Thymidine has been used in conjunction with leucovorin and alkaline hydration to protect patients with acute renal dysfunction from life-threatening methotrexate toxicity. The outcome of eight cases in which thymidine was released under the special exception mechanism to treat patients who developed acute renal failure following methotrexate are reported. The clinical trials using thymidine in combination with methotrexate in patients with normal renal function are also reviewed.

Understanding and Managing Methotrexate Nephrotoxicity

“…Unlike LV, Thd does not compete with MTX for transport into the cell but is directly converted to thymidine monophosphate by the salvage enzyme thymidine kinase, thereby circumventing blockade of the de novo pathway by MTX ( Fig. 3) [58]. Repletion of deoxythymidine monophosphate (dTMP) and consequently of thymidine triphosphate pools allows restoration of DNA synthesis.…”

“…infusion in order to maintain effective plasma concentrations [59]. Thd has been used in 16 patients with MTX-induced renal dysfunction as a rescue agent in combination with LV [14,58]. Severe toxicity was observed in only three patients, in whom Thd was initiated 5, 12, and 13 days after the start of MTX infusion.…”

Hepatic Failure and Lactic Acidosis Due to Fialuridine (FIAU), an Investigational Nucleoside Analogue for Chronic Hepatitis B

“…All seven patients were treated with intravenous infusions of thymidine (8 g per kilogram per day) in an attempt to reverse the effects of fialuridine, which is a thymidine-based nucleoside analogue, 21 and with oral uridine (24 g per day) to replenish intracellular pyrimidine stores. 22 Neither thymidine nor uridine produced obvious clinical improvement.…”

High‐dose methotrexate‐induced nephrotoxicity in patients with osteosarcoma

“…14 However, reports of significant morbidity and mortality secondary to HDMTX-induced renal dysfunction have continued to appear in the literature. 11,[15][16][17][18][19] Because there is no centralized reporting mechanism for MTX nephrotoxicity, to our knowledge the current incidence of HDMTX-induced renal dysfunction is unknown.…”