Aminopterin in the Treatment of Acute Leukaemia

Dacie, J. V.; Dresner, Ellis; Mollin, D. L.; White, John

doi:10.1136/bmj.1.4668.1447

Cited by 22 publications

(9 citation statements)

References 5 publications

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“…In lymphoblasts from patients with B-lineage ALL, methotrexate polyglutamates from glu 2 through glu 5 are found in increasing frequency with increasing chain length, whereas the corresponding aminopterin polyglutamates are found in decreasing frequency (Fig. 3A).…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with earlier data with murine cells (40,41), diglutamate predominance was observed in blasts from patients with T-phenotype ALL or AML. However, we note that in blasts from patients with B-lineage ALL, longer chain polyglutamates (aminopterin-glu [3][4][5] ) were seen with a frequency similar to that of the diglutamate. The reasons for this lineage-specific difference in aminopterin polyglutamylation are not clear.…”

Section: Discussionmentioning

confidence: 99%

“…3B and C), where aminopterin-glu 2 predominates and little longer-chain aminopterin is seen (<30% of the total). It is striking that under similar conditions, the natural ligand methyl tetrahydrofolate is metabolized completely to very longchain polyglutamates, predominantly -glu [5][6][7] (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…aminopterin (1). Clinical resistance to antifolates upon relapse was also described (4,5,10,11), and much of the biochemical basis for antifolate resistance has been elucidated over the subsequent decades (34,35). We initially brought aminopterin back to the clinic, because laboratory data suggest that it may offer advantages over methotrexate for some patients with ALL.…”

Section: Discussionmentioning

confidence: 99%

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Phase II Trial of Oral Aminopterin for Adults and Children with Refractory Acute Leukemia

Cole

Drachtman

Smith³

et al. 2005

Clinical Cancer Research

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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: 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 [ 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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phase II Trial of Oral Aminopterin for Adults and Children with Refractory Acute Leukemia

Cole

Drachtman

Smith³

et al. 2005

Clinical Cancer Research

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“…Children are more responsive to treatment than are adults, and the subacute lymphoblastic leukaemias with an aleukaemic blood picture react better than do myeloblastic or leukaemic types. 6,7,9 The chief disadvantage of folic acid antagonists are their unpredictability of action, their extreme toxicity and the development of resistance to them. The amount of the drugs required varies from case to case within a wide range and serious toxic manifestations may necessitate their withdrawal before the bone marrow has been influenced.…”

Section: Folic Acid Antagonistsmentioning

confidence: 99%