Rescue after Intermediate and High-Dose Methotrexate: Background, Rationale, and Current Practice

Pharmacologic rescue methods used in combination with intermediate and high-dose methotrexate therapy are reviewed, with special emphasis on rescue with nucleosides and folinic acid. The mechanism of action, pharmacokinetics, and clinical applications of the rescue agents are described in detail in view of the literature and also of the own findings of the authors. In spite of the promising results of the in vitro studies and in vivo experiments in animal models, the clinical value of thymidine as a rescue agent remains to be determined. Currently, the only indication to use thymidine instead offolinic acid following high-dose methotrexate is to prevent toxicity related to extremely high methotrexate levels in patients with delayed elimination of methotrexate. In spite of the widespread application offolinic acid rescue, the exact mechanism of its action is not fully understood. The rescue dose and schedule in the majority of clinical protocols is empirical, and the start of the rescue administration is t...