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Aminopterin

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Barton A. Kamen – One of the best experts on this subject based on the ideXlab platform.

  • Phase 2B trial of Aminopterin in multiagent therapy for children with newly diagnosed acute lymphoblastic leukemia
    Cancer Chemotherapy and Pharmacology, 2008
    Co-Authors: Peter D. Cole, Richard A. Drachtman, Angela K. Smith, Margaret Masterson, John Glod, John A. Zebala, Stacey Lisi, Drew-anne Drapala, Barton A. Kamen

    Abstract:

    Purpose Aminopterin offers advantages over the related antifolate, methotrexate, including greater potency, complete bioavailability, and more consistent accumulation and metabolism by patients’ blasts. This current trial was done to document the toxicity of the Aminopterin within a multiagent therapeutic regimen for children with newly diagnosed ALL. Experimental Design Patients at high risk of relapse were non-randomly assigned to therapy including oral Aminopterin 4 mg/m^2, in two doses 12 h apart, in place of methotrexate 100 mg/m^2 in four divided doses. Results Thirty-two patients, 22 with pre-B ALL and ten with T-lineage ALL, have been treated with Aminopterin, with median follow up of 40 months. Hematologic, mucosal and hepatic toxicity has been tolerable and reversible. There have been no toxic deaths among patients in remission. During weekly AMT therapy, higher mean neutrophil counts were observed among patients who were wild type for polymorphisms in methylene tetrahydrofolate reductase and methionine synthase reductase. Conclusions Aminopterin can be safely incorporated in multiagent therapy for patients with ALL, in place of systemic methotrexate, without causing excessive toxicity. These results support a larger trial comparing the efficacy and toxicity of Aminopterin and methotrexate in therapy for patients with ALL.

  • Phase 2B trial of Aminopterin in multiagent therapy for children with newly diagnosed acute lymphoblastic leukemia
    Cancer chemotherapy and pharmacology, 2007
    Co-Authors: Peter D. Cole, Richard A. Drachtman, Angela K. Smith, Margaret Masterson, John Glod, John A. Zebala, Stacey Lisi, Drew-anne Drapala, Barton A. Kamen

    Abstract:

    Purpose
    Aminopterin offers advantages over the related antifolate, methotrexate, including greater potency, complete bioavailability, and more consistent accumulation and metabolism by patients’ blasts. This current trial was done to document the toxicity of the Aminopterin within a multiagent therapeutic regimen for children with newly diagnosed ALL.

  • Phase II Trial of Oral Aminopterin for Adults and Children with Refractory Acute Leukemia
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2005
    Co-Authors: Peter D. Cole, Richard A. Drachtman, Angela K. Smith, Sarah Cate, Richard A. Larson, Douglas S. Hawkins, John S. Holcenberg, Kara M. Kelly, Barton A. Kamen

    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 patients9 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 μmol 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.

Doo-jin Paik – One of the best experts on this subject based on the ideXlab platform.

  • Requirement of de novo protein synthesis for Aminopterin-induced apoptosis in a mouse myeloma cell line.
    Immunology Letters, 2001
    Co-Authors: Yong-hoon Chung, Jeehee Youn, Yong Choi, Doo-jin Paik

    Abstract:

    Abstract Cells synthesize nucleotides through de novo and salvage pathways that require the activities of dihydrofolate reductase (DHFR) and hypoxanthine-guanine phosphoribosyltransfease (HGPRT), respectively. Aminopterin, an inhibitor of dihydrofolate reductase, has been demonstrated to allow HGPRT − cells to be negatively selected. However, the pathway by which Aminopterin leads to cell death remains to be clarified. In this study, we characterized features of cellular responses induced by Aminopterin treatment in P3-X63-Ag8.653, a mouse HGPRT − myeloma cell line. Upon treatment with Aminopterin, the cells readily underwent an apoptotic process, as assessed by DNA fragmentation assay and electron microscopic analysis. Aminopterin-induced apoptosis was drastically reduced by addition of actinomycin D and cycloheximide, indicating that active RNA and protein synthesis is required for the apoptotic effect of Aminopterin. Interestingly, the induction of c-myc gene expression preceded the activity of DNA fragmentation in Aminopterin-treated cells. Taken together, these results suggest that cells deficient in the salvage pathway of purine biosynthesis are susceptible to Aminopterin-induced apoptosis that requires de novo synthesis of proapoptotic factors, including Myc oncoprotein.

M. Preus – One of the best experts on this subject based on the ideXlab platform.

  • An Aminopterin-like syndrome without Aminopterin (ASSAS).
    Clinical genetics, 2008
    Co-Authors: F. C. Fraser, R. A. Anderson, J. I. Mulvihill, M. Preus

    Abstract:

    In two patients that closely resembled the phenotype of the syndrome produced by Aminopterin in early pregnancy, no evidence of maternal exposure could be elicited. These, plus two similar cases from the literature, suggest the existence of an “Aminopterin-like syndrome sine Aminopterin” (ASSA) syndrome. Characteristic traits are: ossification defects of the cranium, temporal recession of hairline with upswept frontal hair pattern, ocular hypertelorism, prominent nose root, low set posteriorly rotated ears, limited elbow movement, variable digital defects, simian creases, short stature, and mild to moderate psychomotor retardation. Autoso-mal recessive inheritance is a possibility.