Abstract | PURPOSE: 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: 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.
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Authors | Peter D Cole, Richard A Drachtman, Angela K Smith, Sarah Cate, Richard A Larson, Douglas S Hawkins, John Holcenberg, Kara Kelly, Barton A Kamen |
Journal | Clinical 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 |
PMID | 16299240
(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.)
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Chemical References |
- Folic Acid Antagonists
- Aminopterin
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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
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