Carboxypeptidase-G2, thymidine, and leucovorin rescue in cancer patients with methotrexate-induced renal dysfunction

J Clin Oncol. 1997 May;15(5):2125-34. doi: 10.1200/JCO.1997.15.5.2125.


Purpose: Methotrexate nephrotoxicity can lead to delayed methotrexate elimination and the development of life-threatening toxicity, which may not be preventable with the standard rescue agent leucovorin. In preclinical studies, we previously demonstrated that carboxypetidase-G2 (CPDG2) rapidly hydrolyzes methotrexate to nontoxic metabolites. A protocol for the compassionate use of CPDG2 in patients who develop nephrotoxicity while receiving high-dose methotrexate was therefore developed. The pharmacologic and clinical outcome of CPDG2 rescue administered with thymidine and leucovorin in 20 patients is presented here.

Methods: Patients with high-dose methotrexate-induced renal dysfunction received one to three doses of CPDG2, 50 U/kg body weight intravenously (i.v.), thymidine 8 g/m2/d by continuous i.v. infusion, and standard pharmacokinetically guided leucovorin rescue. Plasma concentrations of methotrexate and its inactive metabolite 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) were measured before and after CPDG2 using high-pressure liquid chromatography (HPLC). Tolerance of CPDG2 and thymidine, development of methotrexate toxicities, and recovery of renal function were monitored.

Results: Twenty patients who received high-dose methotrexate for osteosarcoma (n = 11), lymphoid cancers (n = 8), and gastric cancer (n = 1) developed nephrotoxicity (median serum creatinine, 3.2 mg/dL) and elevated plasma methotrexate concentrations (median, 201 mumol/L at hour 46). CPDG2 and thymidine rescue was well tolerated and resulted in a rapid 95.6% to 99.6% reduction in the plasma methotrexate concentration. Methotrexate-related toxicity was mild to moderate. Serum creatinine returned to normal values at a median of 22 days.

Conclusion: CPDG2, thymidine, and leucovorin rescue was highly effective in 20 patients at high risk for developing life-threatening methotrexate toxicity after the onset of methotrexate-induced nephrotoxicity and delayed methotrexate excretion.

Publication types

  • Multicenter Study

MeSH terms

  • Adolescent
  • Adult
  • Antidotes / therapeutic use*
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / adverse effects*
  • Antimetabolites, Antineoplastic / blood
  • Carboxypeptidases / adverse effects
  • Carboxypeptidases / therapeutic use*
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Infant
  • Kidney / drug effects*
  • Kidney / metabolism
  • Kidney Diseases / chemically induced*
  • Kidney Diseases / metabolism
  • Kidney Diseases / prevention & control
  • Leucovorin / therapeutic use*
  • Lymphoma, Non-Hodgkin / blood
  • Lymphoma, Non-Hodgkin / drug therapy
  • Male
  • Methotrexate / administration & dosage
  • Methotrexate / adverse effects*
  • Methotrexate / blood
  • Middle Aged
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / blood
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Sarcoma / blood
  • Sarcoma / drug therapy
  • Thymidine / adverse effects
  • Thymidine / therapeutic use*


  • Antidotes
  • Antimetabolites, Antineoplastic
  • Carboxypeptidases
  • Leucovorin
  • Thymidine
  • Methotrexate