Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies.

Ratliff, Arleen F.; Wilson, Jennifer N.; Hum, Martina; Marling-Cason, Margaret; Rose, K.; Winick, Naomi J.; Kamen, Barton A.

doi:10.1200/jco.1998.16.4.1458

Cited by 18 publications

(12 citation statements)

References 19 publications

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“…Among all patients, the mean AUC (FSE) after oral administration was 0.52 F 0.04 Amol hour/L, which is not statistically different from that seen after administration of i.v. aminopterin at the same dose (2 mg/m 2 ) on the phase I trial (15). Pharmacokinetic analysis revealed no significant difference between the tablet (n = 16) and liquid formulations (n = 29) in AUC.…”

Section: Resultsmentioning

confidence: 99%

“…Methotrexate remains a core component of all therapeutic regimens used for patients with acute lymphoblastic leukemia (ALL) and is widely used to treat many other malignant and nonmalignant disorders (13). However, aminopterin may offer advantages over methotrexate, with greater accumulation and metabolism by leukemic blasts in vitro (14) and more complete oral bioavailability (15) than has been reported for methotrexate (16,17).…”

mentioning

confidence: 99%

“…Intravenous aminopterin and the liquid for oral administration were purified and packaged by Ilex Oncology, Inc. (San Antonio, TX), as previously described (15). During the tenure of the phase II trial, the liquid preparation, which was being analyzed every 4 to 8 weeks for purity, was found to be accumulating folic acid.…”

Section: Clinical Trialmentioning

confidence: 99%

“…To confirm oral bioavailability of aminopterin, limited sampling pharmacokinetic analysis was conducted, as previously described (15). Briefly, 2 mL of blood was collected in an EDTA tube before and 30, 60, 180, and 300 minutes after the aminopterin was administered.…”

Section: Clinical Trialmentioning

confidence: 99%

“…The maximum tolerated dose of aminopterin on our phase I trial was 2 mg/m 2 /dose q12 hours for two doses weekly (15). Mucosal toxicity was dose limiting at higher doses and ameliorated by dose reduction and/or the addition of leucovorin rescue.…”

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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%

mentioning

confidence: 99%

Section: Clinical Trialmentioning

confidence: 99%

Section: Clinical Trialmentioning

confidence: 99%

mentioning

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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Folate Antagonists

Cole,

Figueiredo,

Bertino

2017

Holland‐Frei Cancer Medicine

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Overview Folic acid antagonists (antifols) are cytotoxic drugs used as antineoplastic, antimicrobial, anti‐inflammatory, and immune‐suppressive agents. While several folate antagonists have been developed, methotrexate (4‐amino‐4‐deoxy‐10‐ N ‐methyl‐pteroylglutamic acid; MTX) is the antifol with the most extensive history and widest spectrum of use. MTX remains an essential drug in curative chemotherapy regimens used to treat patients with acute lymphoblastic leukemia, osteosarcoma, and choriocarcinoma and is an important agent in the therapy of patients with lymphoma, breast cancer, bladder cancer, and head and neck cancer. In addition, it is used for patients with nonmalignant diseases such as rheumatoid arthritis, psoriasis, autoimmune diseases, and graft versus host disease. This chapter will review the clinical use of and the metabolism of MTX and discuss structurally related folate antagonists that have been developed to overcome resistance or have alternate intracellular targets.

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Folate Antagonists

Gennarini¹,

Cole²,

Bertino³

2022

Holland‐Frei Cancer Medicine

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Overview Folic acid antagonists (antifols) are cytotoxic drugs used as antineoplastic, antimicrobial, anti‐inflammatory, and immune‐suppressive agents. While several folate antagonists have been developed, methotrexate (4‐amino‐4‐deoxy‐10‐ N ‐methyl‐pteroylglutamic acid, MTX) is the antifol with the most extensive history and widest spectrum of use. MTX remains an essential drug in curative chemotherapy regimens used to treat patients with acute lymphoblastic leukemia, osteosarcoma, and choriocarcinoma, and is an important agent in the therapy of patients with lymphoma, breast cancer, bladder cancer, and head and neck cancer. In addition, it is used for patients with nonmalignant diseases such as rheumatoid arthritis, psoriasis, autoimmune diseases, and graft‐versus‐host disease. This article will review the clinical use of and metabolism of MTX and discuss structurally related folate antagonists that have been developed to overcome resistance or have alternate intracellular targets.

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Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies.

Abstract: We conclude that AMT has good oral bioavailability and that, when given on a q12 hour x two weekly schedule, the MTD is 2 mg/m2 with delayed LV rescue.

Cited by 18 publications

References 19 publications

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

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

Folate Antagonists

Folate Antagonists

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