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

Brigitte C. Widemann, Frank M. Balis, Robert F. Murphy, J. Mel Sorensen, Michael J. Montello, Michelle O'Brien, Peter C. Adamson

Research output: Contribution to journalArticle

Abstract

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 carboxypeptidase-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 (IV), thymidine 8 g/m2/d by continuous IV 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 μmol/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.

Original languageEnglish (US)
Pages (from-to)2125-2134
Number of pages10
JournalJournal of Clinical Oncology
Volume15
Issue number5
DOIs
StatePublished - May 1997

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Widemann, B. C., Balis, F. M., Murphy, R. F., Sorensen, J. M., Montello, M. J., O'Brien, M., & Adamson, P. C. (1997). Carboxypeptidase-G2, thymidine, and leucovorin rescue in cancer patients with methotrexate-induced renal dysfunction. Journal of Clinical Oncology, 15(5), 2125-2134. https://doi.org/10.1200/JCO.1997.15.5.2125