TY - JOUR
T1 - Carboxypeptidase-G2, thymidine, and leucovorin rescue in cancer patients with methotrexate-induced renal dysfunction
AU - Widemann, Brigitte C.
AU - Balis, Frank M.
AU - Murphy, Robert F.
AU - Sorensen, J. Mel
AU - Montello, Michael J.
AU - O'Brien, Michelle
AU - Adamson, Peter C.
PY - 1997/5
Y1 - 1997/5
N2 - 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.
AB - 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.
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U2 - 10.1200/JCO.1997.15.5.2125
DO - 10.1200/JCO.1997.15.5.2125
M3 - Article
C2 - 9164227
AN - SCOPUS:0030611877
SN - 0732-183X
VL - 15
SP - 2125
EP - 2134
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 5
ER -