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


CONCLUSIONS
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.
Widemann
B C
BC
Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1928, USA. widemanb@pbmac.nci.nih.gov
Balis
F M
FM
Murphy
R F
RF
Sorensen
J M
JM
Montello
M J
MJ
O'Brien
M
M
Adamson
P C
PC
D000293:Adolescent; D000328:Adult; D000931:Antidotes / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D002268:Carboxypeptidases / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D002955:Leucovorin / Q000627:therapeutic use*; D008228:Lymphoma, Non-Hodgkin / Q000097:blood / Q000188:drug therapy; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy; D012509:Sarcoma / Q000097:blood / Q000188:drug therapy; D013936:Thymidine / Q000009:adverse effects / Q000627:therapeutic use*
D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D002268:Carboxypeptidases; D002955:Leucovorin; D013936:Thymidine; D008727:Methotrexate