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Giornale Italiano Di Dermatologia 1954
Topics: Aminopterin; Humans; Psoriasis
PubMed: 13183357
DOI: No ID Found -
Journal of Clinical Oncology : Official... Apr 1998Aminopterin (AMT) is a potent folate analog that is no longer in routine clinical use. Because of laboratory data that suggests improved metabolism of AMT versus... (Clinical Trial)
Clinical Trial Comparative Study
PURPOSE
Aminopterin (AMT) is a potent folate analog that is no longer in routine clinical use. Because of laboratory data that suggests improved metabolism of AMT versus methotrexate (MTX) in lymphoblasts, we developed a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of AMT.
PATIENTS AND METHODS
Twenty patients with refractory malignancies were treated. The starting dose of AMT was 2.5 mg/m2 every 12 hours for two doses weekly: the dose of AMT was decreased and leucovorin (LV) rescue was added after the DLT was observed. Pharmacokinetics were performed after both intravenous (i.v.) and oral AMT administration.
RESULTS
Mucosal toxicity was dose-limiting and resulted in the need for a dose reduction (dose level 2: AMT 2 mg/m2 every 12 hours for two doses weekly) and, subsequently, the addition of scheduled LV rescue (dose level 3: AMT 2 mg/m2 every 12 hours for two doses followed by LV 5 mg/m2 orally every 12 hours for two doses, starting 24 hours after the second dose of AMT). The mean areas under the curve (AUC) for the i.v. (n = 14) and oral (n = 13) doses were 1.20 +/- 0.09 (SE) and 1.05 +/- 0.14 micromol x h/L respectively. The half-life was 3.64 +/- 0.28 hours and the oral bioavailability in 12 matched subjects was 83.5% +/- 8.3%. One patient with endometrial adenocarcinoma achieved a complete response (CR) and remains on therapy at 11+ months. Seven patients had stable disease (SD) for 8 weeks or greater, which included one patient with a metastatic nerve sheath tumor who was stable for 9 months.
CONCLUSION
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.
Topics: Administration, Oral; Adolescent; Adult; Aged; Aminopterin; Area Under Curve; Biological Availability; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Folic Acid Antagonists; Humans; Injections, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms; Treatment Outcome
PubMed: 9552052
DOI: 10.1200/JCO.1998.16.4.1458 -
Vestnik Rentgenologii I Radiologii Sep 1960
Topics: Aminopterin; Humans; Psoriasis
PubMed: 13751605
DOI: No ID Found -
Cancer Treatment Reports Feb 1978
Review
Topics: Aminopterin; Animals; Folic Acid; History, 20th Century; Humans; Leucovorin; Leukemia, Experimental; Methotrexate; Mice; Neoplasms; Time Factors
PubMed: 346222
DOI: No ID Found -
Biochemical Pharmacology Oct 1986gamma-Phosphonate analogues of methotrexate (MTX) and aminopterin (AMT) were synthesized from 4-amino-4-deoxy-N10-methylpteroic acid and...
Methotrexate analogues-27. Dual inhibition of dihydrofolate reductase and folylpolyglutamate synthetase by methotrexate and aminopterin analogues with a gamma-phosphonate group in the side chain.
gamma-Phosphonate analogues of methotrexate (MTX) and aminopterin (AMT) were synthesized from 4-amino-4-deoxy-N10-methylpteroic acid and 4-amino-4-deoxy-N10-formylpteroic acid, respectively, by reaction with methyl D,L-2-amino-4-phosphonobutyrate followed by gentle alkaline hydrolysis. The products were compared with the corresponding D,L-homocysteic acid derivatives as inhibitors of dihydrofolate reductase and folylpolyglutamate synthetase, and as inhibitors of cell growth in culture. The gamma-phosphonates were somewhat less active than either the gamma-sulfonates or the parent drugs as inhibitors of murine dihydrofolate reductase. The MTX gamma-sulfonate and gamma-phosphonate analogues were equally inhibitory toward mouse liver folylpolyglutamate synthetase (Ki = 190 microM), but in the AMT series the gamma-phosphonate (Ki = 8.4 microM) was more potent than the gamma-sulfonate (Ki = 45 microM). The AMT analogues were consistently more inhibitory than the MTX analogues against cultured L1210 murine leukemia cells, but neither the gamma-phosphonates nor the gamma-sulfonates were as potent as their respective parent drugs. The gamma-phosphonate analogue of MTX was three times more potent than MTX against the MTX-resistant mutant line L1210/R81, but the AMT gamma-phosphonate was less potent than AMT; however, these differences were small in comparison with the level of resistance to all these compounds in the L1210/R81 line. The results suggest that N10-methyl and N10-unsubstituted compounds altered at the gamma-position do not necessarily follow identical structure-activity patterns in every test system.
Topics: Aminopterin; Animals; Cell Line; Folic Acid Antagonists; Kinetics; Leukemia L1210; Methotrexate; Mice; Peptide Synthases; Structure-Activity Relationship
PubMed: 3768024
DOI: 10.1016/0006-2952(86)90431-4 -
Clinical Cancer Research : An Official... Oct 2010On September 24, 2009, the U.S. Food and Drug Administration granted accelerated approval for Folotyn (pralatrexate injection, Allos Therapeutics, Inc.) as a single... (Review)
Review
Folotyn (pralatrexate injection) for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma: U.S. Food and Drug Administration drug approval summary.
PURPOSE
On September 24, 2009, the U.S. Food and Drug Administration granted accelerated approval for Folotyn (pralatrexate injection, Allos Therapeutics, Inc.) as a single agent for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL); it is the first drug approved for this indication.
EXPERIMENTAL DESIGN
This review was based on study PDX-008, a phase II, single-arm, nonrandomized, open-label, international, multicenter trial, designed to evaluate the safety and efficacy of pralatrexate when administered concurrently with vitamin B(12) and folic acid supplementation in patients with relapsed or refractory PTCL.
RESULTS
The overall response rate was 27% in 109 evaluable patients [95% confidence interval (CI), 19-36%]. Twelve percent of 109 evaluable patients (95% CI, 7-20%)] had a response duration of ≥14 weeks. Six of these 13 patients achieved a complete response, and one patient had complete response unconfirmed. The most common grade 3 and 4 toxicities were thrombocytopenia, mucositis, and neutropenia.
CONCLUSION
This accelerated approval was based on a response rate that is reasonably likely to predict clinical benefit in this heavily pretreated patient population with this rare disease. The applicant has committed to conducting postmarketing clinical trials to assess clinical benefit. The recommended starting dose of pralatrexate in patients with relapsed or refractory PTCL is 30 mg/m(2) via intravenous push over 3 to 5 min weekly for 6 weeks followed by a one-week rest (one cycle). Intramuscular injection of 1 mg vitamin B(12) should be administered every 8 to 10 weeks along with 1.0 mg folic acid given orally once a day.
Topics: Aged; Aminopterin; Drug Approval; Female; Folic Acid Antagonists; Humans; Lymphoma, T-Cell; Male; Middle Aged; United States; United States Food and Drug Administration
PubMed: 20739433
DOI: 10.1158/1078-0432.CCR-10-1214 -
Journal of Medicinal Chemistry May 1986Analogues of the antitumor antifolate methotrexate (MTX) were synthesized in which the glutamate (Glu) moiety was replaced by ornithine (Orn), 2,4-diaminobutyric acid...
Methotrexate analogues. 26. Inhibition of dihydrofolate reductase and folylpolyglutamate synthetase activity and in vitro tumor cell growth by methotrexate and aminopterin analogues containing a basic amino acid side chain.
Analogues of the antitumor antifolate methotrexate (MTX) were synthesized in which the glutamate (Glu) moiety was replaced by ornithine (Orn), 2,4-diaminobutyric acid (Dab), or 2,3-diaminopropionic acid (Dap). An aminopterin (AMT) analogue with Orn in place of Glu was also synthesized. The MTX analogues were obtained by reaction of 4-amino-4-deoxy-N10-methylpteroic acid (mAPA) and N omega-Boc-alpha,omega-diaminoalkanoic acids in the presence of diethyl phosphorocyanidate, followed by deprotection with trifluoroacetic acid (TFA) or by reaction of p-nitrophenyl-mAPA and N omega-Boc-alpha,omega-diaminoalkanoic acids and subsequent treatment with TFA. The AMT analogue (APA-Orn) was synthesized by reaction of p-nitrophenyl 4-amino-4-deoxy-N10-formylpteroate with silylated N delta-Boc-L-ornithine in DMF at 55 degrees C for 3 days (45% yield), saponification (83%), and TFA cleavage (89%). APA-Orn was a potent inhibitor of both dihydrofolate reductase (DHFR) from L1210 mouse leukemia (IC50 = 0.072 microM) and partly purified folylpolyglutamate synthetase (FPGS) from mouse liver (Ki = 0.15 +/- 0.06 microM). The MTX analogue (mAPA-Orn) was likewise active against both enzymes, with an IC50 of 0.160 microM for DHFR and a Ki of 20.4 +/- 7.7 microM for FPGS inhibition. The other MTX analogues and the previously reported lysine derivative (mAPA-Lys) showed DHFR affinity similar to that of mAPA-Orn but lacked activity as FPGS inhibitors. The positively charged amino group appears to be detrimental to cellular uptake, as evidenced by the low cytotoxicity of these compounds (IC50 = 0.40-2.4 microM) in comparison with MTX and AMT (IC50 = 0.002 microM) against wild-type L1210 cells. On the other hand, mAPA-Orn and APA-Orn were both more potent than the corresponding Glu derivatives MTX and AMT against L1210/R81 cells, suggesting that in these MTX-resistant cells there may occur a "self-potentiation" process involving enhanced antifolate activity via interference with the polyglutamylation of reduced folates. APA-Orn is the most potent dual inhibitor of DHFR and FPGS discovered to date, but its effectiveness as a therapeutic agent may require some form of prodrug modification to neutralize the terminal amino group of the side chain.
Topics: Aminobutyrates; Aminopterin; Animals; Cell Division; Folic Acid Antagonists; Glutamates; Glutamic Acid; Kinetics; Leukemia L1210; Methotrexate; Mice; Molecular Weight; Ornithine; Peptide Synthases; beta-Alanine
PubMed: 2871191
DOI: 10.1021/jm00155a012 -
The American Journal of Pediatric... 1984Chemical, physical, and metabolic processes of methotrexate are reviewed. The effects of the drug on intracellular metabolic processes, due to the inhibitory action of... (Review)
Review
Chemical, physical, and metabolic processes of methotrexate are reviewed. The effects of the drug on intracellular metabolic processes, due to the inhibitory action of methotrexate on the enzyme dihydrofolate reductase, show that the result of this inhibition is more complex and is not limited to blockade of the reduction of folic acid alone. Although rescue methods are important in prevention of lethal effects of methotrexate, some metabolic pathways are insufficiently rescued, resulting in toxic reactions following methotrexate administration. Efficient use of pharmacokinetic models may help in reducing these unwanted actions of methotrexate in cancer chemotherapy.
Topics: Aminopterin; Chromatography, High Pressure Liquid; Humans; Hydrogen-Ion Concentration; Kinetics; Methotrexate; NADP; Protein Binding; Radioimmunoassay; Tetrahydrofolate Dehydrogenase; Urine
PubMed: 6398629
DOI: No ID Found -
The Journal of Pharmacology and... Aug 1962
Topics: Aminopterin; Oxidoreductases; Tetrahydrofolate Dehydrogenase
PubMed: 14006196
DOI: No ID Found -
Journal of Medicinal Chemistry Jan 1991Analogues of methotrexate (MTX) and aminopterin (AMT) modified at the gamma-position of the glutamate side chain were synthesized and evaluated as dihydrofolate... (Comparative Study)
Comparative Study
Analogues of methotrexate (MTX) and aminopterin (AMT) modified at the gamma-position of the glutamate side chain were synthesized and evaluated as dihydrofolate reductase (DHFR) inhibitors and tumor cell growth inhibitors. Condesations of 4-amino-4-deoxy-N10-methylpteroic acid (mAPA) with dimethyl DL-4-methyleneglutamate in the presence of diethyl phosphorocyanidate (DEPC) followed by alkaline hydrolysis yielded N-(4-amino-4-deoxy-N10-methylpteroyl)-DL-4-methyleneglutamic acid (gamma-methyleneMTX). Condensation of 4-amino-4-deoxy-N10-formylpteroic acid (fAPA) with dimethyl-DL-4-methyleneglutamate by the mixed carboxylic-carbonic anhydride method yielded N-4-amino-4-deoxypteroyl)-DL-4-methyleneglutamic acid (gamma-methyleneAMT). Also prepared via DEPC coupling was a mixture of the four possible diastereomers of N-(4-amino-4-deoxy-N10-methylpteroyl)-4-cyanoglutamic acid (gamma-cyanoMTX). The requisite intermediate gamma-tert-butyl alpha-methyl 4-cyanoglutamate, as a DL-threo/DL-erythro mixture, was prepared from methyl N alpha-Boc-O-tosyl-L-serinate by reaction with sodium tert-butyl cyanoacetate followed by mild trifluoroacetic treatment to selectively remove the Boc group. The gamma-methylene derivatives of MTX and AMT are attractive because of their potential to act as Michael acceptors within the DHFR active site. gamma-CyanoMTX may be viewed as a congener of the nonpolyglutamated MTX analogue gamma-fluoroMTX. In vitro bioassay data for the gamma-methylene and gamma-cyano compounds support the idea that the active site of DHFR, already known for its ability to tolerate modification of the gamma-carboxyl group of MTX and AMT, can likewise accommodate substitution on the gamma-carbon itself.
Topics: Aminopterin; Animals; Cyanides; Drug Screening Assays, Antitumor; Folic Acid Antagonists; Indicators and Reagents; Leukemia L1210; Magnetic Resonance Spectroscopy; Methotrexate; Mice; Molecular Structure; Optical Rotation; Spectrophotometry, Infrared; Structure-Activity Relationship
PubMed: 1992118
DOI: 10.1021/jm00105a031