HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Phase II trial of oral aminopterin for adults and children with refractory acute leukemia.

AbstractPURPOSE:
To determine the antileukemic activity of weekly oral aminopterin in patients with refractory acute leukemia; to describe the pharmacodynamic properties of aminopterin; and to contrast the intracellular metabolism of aminopterin and methotrexate by patients' blasts in vitro.
EXPERIMENTAL DESIGN:
Forty-six patients were enrolled in three strata: children with acute lymphoblastic leukemia (ALL), adults with ALL, and patients with acute myeloid leukemia (AML). Aminopterin was given weekly, in two doses of 2 mg/m(2), 12 hours apart. Limited sampling pharmacokinetic analysis was done during the first week of therapy. Accumulation of [(3)H]aminopterin and [(3)H]methotrexate by leukemic blasts was studied in vitro.
RESULTS:
Six of 22 children with ALL (27%; 95% confidence interval, 8-47%) had clinically significant responses. None of those with AML and only two of 11 adults with ALL had responses meeting protocol definitions, although peripheral blast counts tended to decrease with therapy in all groups. Mucosal toxicity was minimal, even with limited use of leucovorin rescue. Complete bioavailability of aminopterin was confirmed, with a mean area under the curve of 0.52 +/- 0.03 micromol hour/L after oral dosing. No relationship between aminopterin pharmacokinetics and response was seen. In vitro, aminopterin showed more consistent metabolism by leukemic blasts to polyglutamates than methotrexate. Lineage-specific differences in the pattern of intracellular antifolylpolyglutamates were observed.
CONCLUSIONS:
Weekly oral aminopterin has significant activity among children with refractory ALL. With greater cellular accumulation and metabolism, more reliable bioavailability than methotrexate, and tolerable toxicity at this dose and schedule, aminopterin deserves further study as a potent alternative to methotrexate.
AuthorsPeter D Cole, Richard A Drachtman, Angela K Smith, Sarah Cate, Richard A Larson, Douglas S Hawkins, John Holcenberg, Kara Kelly, Barton A Kamen
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 22 Pg. 8089-96 (Nov 15 2005) ISSN: 1078-0432 [Print] United States
PMID16299240 (Publication Type: Clinical Trial, Phase II, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Folic Acid Antagonists
  • Aminopterin
Topics
  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Aminopterin (blood, pharmacokinetics, therapeutic use)
  • Area Under Curve
  • Child
  • Child, Preschool
  • Drug Resistance, Neoplasm
  • Female
  • Folic Acid Antagonists (pharmacokinetics, therapeutic use)
  • Hematopoietic Stem Cells (metabolism)
  • Humans
  • Leukemia, Myeloid, Acute (drug therapy, ethnology)
  • Male
  • Middle Aged
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, ethnology)
  • Treatment Outcome

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: