TY - JOUR
T1 - WR-2721 (amifostine) infusion in patients with Ewing's sarcoma receiving ifosfamide and cyclophosphamide with mesna
T2 - Drug and thiol levels in plasma and blood cells, a Pediatric Oncology Group study
AU - Souid, Abdul Kader
AU - Fahey, Robert C.
AU - Dubowy, Ronald L.
AU - Newton, Gerald L.
AU - Bernstein, Mark L.
N1 - Funding Information:
Acknowledgements The authors are in debt to Dr. Annelies E.C. Korst for careful review of the manuscript. The study was supported in part by grants from the National Cancer Institute (CA-28439, CA-33587, CA-30969, CA-35982), a grant from U.S. Bioscience to the Pediatric Oncology Group, and a generous gift from Alfred T. Murphy.
PY - 1999
Y1 - 1999
N2 - Purpose: Previous WR-2721 human pharmacokinetic studies were limited to plasma levels in patients receiving platinum-based compounds, and none includes the effects of WR-2721 on endogenous thiols. In the present study (Pediatric Oncology Group study no. 9457), we measured the levels of WR-2721, its active metabolites, as well as cysteine and glutathione in whole blood, plasma, and blood cells in patients receiving high-dose alkylating agents with mesna. Methods: WR-2721 was administered (15 min intravenous infusion of 825 mg/m2 per dose x2) to five patients with metastatic Ewing's sarcoma receiving ifosfamide and cyclophosphamide with mesna. Intracellular and extracellular blood thiols were labeled with monobromobimane (mBBr) at the time of collection, and the low molecular weight (LMW) thiols were subsequently separated by HPLC and detected by fluorescence. Results: The active metabolite of the drug, WR-1065, peaked at 100 μM in plasma and blood cells at the end of WR-2721 infusion and decayed with a rapid initial half- life. Detectable levels of WR-1065 and its LMW disulfides were present in plasma and blood cells at ~1 h after the WR-2721 infusion. By the end of the first WR-2721 infusion (prior to mesna infusion), the mean cysteine level more than doubled and the mean Cys-SS-LMW (cystine and the mixed LMW disulfides) level decreased by ~50% in both plasma and blood cells. In four of five patients, reduced glutathione levels in blood cells increased by the end of the first WR-2721 infusions, the average increment being ~36%. Conclusions: (1) WR-1065 is rapidly formed from WR-2721 and equilibrates between plasma and blood cells; (2) WR-1065 decays in plasma and blood cells with similar rapid initial half-lives of ~16 min; (3) WR-2721 treatment increases cysteine in plasma and blood cells, an effect similar to that of mesna; (4) WR-2721 treatment appears to increase glutathione levels in blood cells; (5) Mesna does not have a substantial effect on the fate of WR-2721 in patients.
AB - Purpose: Previous WR-2721 human pharmacokinetic studies were limited to plasma levels in patients receiving platinum-based compounds, and none includes the effects of WR-2721 on endogenous thiols. In the present study (Pediatric Oncology Group study no. 9457), we measured the levels of WR-2721, its active metabolites, as well as cysteine and glutathione in whole blood, plasma, and blood cells in patients receiving high-dose alkylating agents with mesna. Methods: WR-2721 was administered (15 min intravenous infusion of 825 mg/m2 per dose x2) to five patients with metastatic Ewing's sarcoma receiving ifosfamide and cyclophosphamide with mesna. Intracellular and extracellular blood thiols were labeled with monobromobimane (mBBr) at the time of collection, and the low molecular weight (LMW) thiols were subsequently separated by HPLC and detected by fluorescence. Results: The active metabolite of the drug, WR-1065, peaked at 100 μM in plasma and blood cells at the end of WR-2721 infusion and decayed with a rapid initial half- life. Detectable levels of WR-1065 and its LMW disulfides were present in plasma and blood cells at ~1 h after the WR-2721 infusion. By the end of the first WR-2721 infusion (prior to mesna infusion), the mean cysteine level more than doubled and the mean Cys-SS-LMW (cystine and the mixed LMW disulfides) level decreased by ~50% in both plasma and blood cells. In four of five patients, reduced glutathione levels in blood cells increased by the end of the first WR-2721 infusions, the average increment being ~36%. Conclusions: (1) WR-1065 is rapidly formed from WR-2721 and equilibrates between plasma and blood cells; (2) WR-1065 decays in plasma and blood cells with similar rapid initial half-lives of ~16 min; (3) WR-2721 treatment increases cysteine in plasma and blood cells, an effect similar to that of mesna; (4) WR-2721 treatment appears to increase glutathione levels in blood cells; (5) Mesna does not have a substantial effect on the fate of WR-2721 in patients.
KW - Chemoprotection
KW - Monobromobimane
KW - Pediatric oncology
KW - Thiols
KW - WR-2721
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U2 - 10.1007/s002800051124
DO - 10.1007/s002800051124
M3 - Article
C2 - 10550571
AN - SCOPUS:0032751755
SN - 0344-5704
VL - 44
SP - 498
EP - 504
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 6
ER -