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Annals of the New York Academy of... Nov 1971
Review
Topics: Administration, Oral; Aminopterin; Animals; Enterococcus faecalis; Folic Acid Antagonists; Injections, Intraperitoneal; Lethal Dose 50; Leukemia L1210; Methotrexate; Mice; Mice, Inbred Strains; Quinazolines
PubMed: 5002440
DOI: No ID Found -
Medizinische Klinik Aug 1958
Topics: Aminopterin; Contraceptive Agents; Contraceptives, Oral; Female; Humans
PubMed: 13577400
DOI: No ID Found -
Expert Opinion on Pharmacotherapy Jul 2010Pralatrexate (PDX; 10-propargyl 10-deazaaminopterin), is an exciting new chemotherapeutic agent that is approved for the treatment of relapsed and refractory peripheral... (Review)
Review
IMPORTANCE OF THE FIELD
Pralatrexate (PDX; 10-propargyl 10-deazaaminopterin), is an exciting new chemotherapeutic agent that is approved for the treatment of relapsed and refractory peripheral T-cell lymphomas (PTCL). This is the only approved therapy for patients with PTCL.
AREAS COVERED IN THIS REVIEW
This review describes the clinical development of PDX from its synthesis to its FDA approval. It details the biochemical basis of the differences between PDX and other antifolates that form the basis of the superiority of its activity. This is followed by a description of the preclinical data that led to early-phase clinical trials in lung cancer and lymphoma and, finally, the definitive trial that led to its approval in PTCL. The review also describes how PDX is being combined with other agents in both the preclinical and clinical arenas.
WHAT THE READER WILL GAIN
These trials have been instrumental in defining a safe dose as well as the safety profile of the agent. FDA approval for the use of PDX in PTCL has been granted based on the results of the pivotal Phase II trial of this agent in relapsed and refractory PTCL patients.
TAKE HOME MESSAGE
PDX is a unique antifolate that has been rationally designed to have a high affinity for the reduced folate receptor (RFC-1) and the enzyme folylpolyglutamy synthetase. It is active in T-cell lymphomas and non-small-cell lung cancer. It is now being studied in combination with other chemotherapeutic and targeted agents for the treatment of hematological malignancies.
Topics: Aminopterin; Animals; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Evaluation, Preclinical; Folic Acid Antagonists; Humans; Lung Neoplasms; Lymphoma; Neoplasms
PubMed: 20509772
DOI: 10.1517/14656566.2010.489552 -
Cancer Research Mar 1990The biological activities of novel analogues of methotrexate (MTX) and aminopterin (AMT) in which the gamma-carboxyl was replaced by a 1H-tetrazol-5-yl ring, an...
The biological activities of novel analogues of methotrexate (MTX) and aminopterin (AMT) in which the gamma-carboxyl was replaced by a 1H-tetrazol-5-yl ring, an isosteric group with acidic properties similar to a carboxyl group, were investigated. The tetrazolyl analogues of MTX and AMT were more potent inhibitors of the growth of CCRF-CEM and K562 human leukemia cell lines during continuous (120 h) and 24-h pulse exposure than were the respective parent drugs; only when the exposure time was reduced to 6 h were the parent drugs more potent. These inhibitory effects on growth correlated with the onset of and recovery from inhibition of de novo thymidylate biosynthesis. Growth inhibition by the analogues was protectable by leucovorin. MTX-resistant CCRF-CEM sublines with decreased transport or increased dihydrofolate reductase (DHFR) levels were cross-resistant to the analogues. The analogues were as potent as their parent drugs in inhibiting DHFR activity in vitro and at displacing [3H]MTX from intracellular DHFR. Each analogue was more effective than its parent drug at inhibiting uptake of [3H]MTX into CCRF-CEM cells. The tetrazole analogue of AMT was a linear competitive inhibitor (Kis = 50 microM) of CCRF-CEM folylpolyglutamate synthetase, while the tetrazole analogue of MTX, unlike all other inhibitors, was linear noncompetitive (Kis = 51 microM, Kii = 321 microM). The data suggest that, compared with MTX or AMT, the tetrazole substituent, in place of the gamma-carboxyl group, allows more efficient transport into cells via the reduced folate/MTX carrier and the resulting greater uptake of the analogues leads to inhibition of DNA synthesis and cell death at lower extracellular concentrations during long exposures. The mechanism of cell death could involve inhibition at folypolyglutamate synthetase, but DHFR is the primary target. The low potency of the analogues during short exposure is presumably related to the inability to form the poly-gamma-glutamyl metabolites required for intracellular retention.
Topics: Aminopterin; Animals; Biological Transport; Cell Division; Folic Acid Antagonists; Humans; Leucovorin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Liver; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rats; Structure-Activity Relationship; Tumor Cells, Cultured; gamma-Glutamyl Hydrolase
PubMed: 2306727
DOI: No ID Found -
American Journal of Obstetrics and... Aug 1962
Topics: Abortion, Induced; Abortion, Spontaneous; Aminopterin; Congenital Abnormalities; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Pregnancy
PubMed: 13890101
DOI: 10.1016/0002-9378(62)90132-1 -
Cancer Treatment Reports Jul 1978A new folate analog, 10-deaza-aminopterin, was substantially more active than methotrexate, following sc administration in mice, against three of five ascites tumors and... (Comparative Study)
Comparative Study
A new folate analog, 10-deaza-aminopterin, was substantially more active than methotrexate, following sc administration in mice, against three of five ascites tumors and two of three solid tumors. For ascites tumors, maximum increases in lifespan (using 6--12 mg/kg q2d X 5) with 10-deaza-aminopterin versus methotrexate were + 171.2%/+ 149.8% against L1210 leukemia, +118.4%/+109.1% against P815 plasmacytoma, +64%/+20.9% against Ehrlich ascites carcinoma, +84.2%/+44.8% against Taper liver tumor, and greater than +159.6%/+64.0% against Sarcoma 180 with longterm survivors after 10-deaza-aminopterin. In a smaller number of experiments comparing LD10 dosages (given q2d X 5) of aminopterin, methotrexate, and 10-deaza-aminopterin, aminopterin was the least effective and 10-deaza-aminopterin was the most effective against the L1210 leukemia, Sarcoma 180, and Ehrlich ascites tumors. Following oral administration (3--6 mg/kg q2d X 5), a twofold greater increase in survival time was obtained against the L1210 leukemia with 10-deazaaminopterin (+122.8%) versus methotrexate (+57%). At a dosage of 6 mg/kg q1d X 5 against solid tumors, the relative tumor volumes (treated/control X 100%) were 12%/41% for Sarcoma 180, 16%/31% for Taper liver tumor, and 20%/30% for Ehrlich ascites carcinoma. Overall, the data suggest a broader spectrum of effective antitumor action in mice and a potential for the expanded clinical utility of this category of agent.
Topics: Aminopterin; Animals; Carcinoma, Ehrlich Tumor; Drug Evaluation, Preclinical; Female; Folic Acid; Leukemia L1210; Liver Neoplasms; Male; Methotrexate; Mice; Neoplasms, Experimental; Plasmacytoma; Sarcoma 180
PubMed: 688246
DOI: No ID Found -
Biochimica Et Biophysica Acta 1967
Topics: Aminopterin; Animals; Antineoplastic Agents; Biological Transport; Cell Membrane; Enzyme Induction; Folic Acid; Folic Acid Antagonists; Ouabain; Rats; Sarcoma, Yoshida; Snakes; Tetrahydrofolate Dehydrogenase; Venoms
PubMed: 6065687
DOI: 10.1016/0005-2736(67)90063-6 -
The Biochemical Journal Nov 1958
Topics: Alanine; Aminopterin; Enterobacter aerogenes; Valine
PubMed: 13596364
DOI: 10.1042/bj0700472 -
Archives of Biochemistry and Biophysics Mar 1963
Topics: Aminopterin; Leukocytes; Liver; Methotrexate; Oxidoreductases; Tritium
PubMed: 13992822
DOI: 10.1016/0003-9861(63)90122-x -
Archives of Biochemistry and Biophysics Aug 1977
Topics: Aminopterin; Animals; Cell Line; Computers; Deoxyuridine; Dialysis; Enzyme Activation; Folic Acid Antagonists; Kinetics; Leukemia L1210; Mathematics; Methotrexate; Protein Binding; Tetrahydrofolate Dehydrogenase
PubMed: 561567
DOI: 10.1016/0003-9861(77)90545-8