Abstract:
:DON (6-diazo-5-oxo-L-norleucine), a glutamine antagonist, has been subjected to limited clinical trials since 1957. Use of the drug in adults has been curtailed due to sparse reports of effectiveness as well as its dose-limiting toxicities, i.e., severe nausea, vomiting and mucositis. In earlier studies, children given DON orally in combination with 6-mercaptopurine had significant prolongation of remission of acute leukemias during maintenance therapy. As DON is acid-labile and relatively unstable in solution, oral administration does not appear to be ideal for DON. In the trial described in this report, i.v. DON therapy was studied, using i.v. chlorpromazine to control vomiting, in 20 children, 17 of whom were evaluable following treatment at DON dose levels ranging from 150 mg/m2 to 520 mg/m2. Nausea and vomiting, the dose-limiting toxicity for adults, was controlled with chlorpromazine. Mucositis, which has also been observed in adults, did not occur in the children given DON i.v. A maximum tolerated dose was not defined; however, the projected maximum tolerated dose appears to be in excess of 450 mg/m2. DON was measured in plasma using a rapid-sampling HPLC procedure. The total body clearance, plasma t1/2, and area under the plasma concentration curve (AUC) were calculated using a noncompartmental method. The drug is rapidly cleared from plasma (t 1/2 = 3 h), and its volume of distribution is approximately twice that of total body water in children. These pharmacokinetic data, differ from that of adults reported by others. Specifically, the plasma t 1/2 for children is longer: total body clearance (Cl), and volume of distribution at steady state (Vss) are greater. In addition, no dose dependency of t 1/2, Cl or Vss was observed in this study, and the DON pharmacokinetics were linear and predictable. Five of nine children with acute leukemia showed improvement, though insufficient for classification as partial response, and five of eight children with solid tumors also showed improvement. Further trials using DON in combination with thiopurines or other agents appear indicated.
journal_name
Cancer Chemother Pharmacoljournal_title
Cancer chemotherapy and pharmacologyauthors
Sullivan MP,Nelson JA,Feldman S,Van Nguyen Bdoi
10.1007/BF00262746subject
Has Abstractpub_date
1988-01-01 00:00:00pages
78-84issue
1eissn
0344-5704issn
1432-0843journal_volume
21pub_type
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journal_title:Cancer chemotherapy and pharmacology
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journal_title:Cancer chemotherapy and pharmacology
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journal_title:Cancer chemotherapy and pharmacology
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journal_title:Cancer chemotherapy and pharmacology
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journal_title:Cancer chemotherapy and pharmacology
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journal_title:Cancer chemotherapy and pharmacology
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journal_title:Cancer chemotherapy and pharmacology
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journal_title:Cancer chemotherapy and pharmacology
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journal_title:Cancer chemotherapy and pharmacology
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更新日期:1992-01-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
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更新日期:2007-11-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/BF00685857
更新日期:1995-01-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
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