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Journal of Clinical Oncology : Official... Jan 1996
Comparative Study
Topics: Aminopterin; Antineoplastic Agents; Drug Administration Schedule; Head and Neck Neoplasms; Humans; Methotrexate; Mouth Mucosa; Palliative Care; Stomatitis
PubMed: 8558215
DOI: 10.1200/JCO.1996.14.1.322 -
Arthritis Research & Therapy Aug 2011High expression of folate receptors is characteristic for the effector cell population of synovial macrophages in synovial inflammation. A new drug conjugate, EC0746,...
High expression of folate receptors is characteristic for the effector cell population of synovial macrophages in synovial inflammation. A new drug conjugate, EC0746, targets the folate inhibitor aminopterin to folate receptors. In vitro studies show that this conjugate acts antiproliferatively and inhibits cytokine production by macrophage cell lines. Moreover, it shows strong anti-arthritic effects in the rat model of adjuvant-induced arthritis in vivo. Toxicity of aminopterin was reduced 40-fold by using equimolar doses of the drug conjugate. In conclusion, this new treatment approach has the potential to further improve the most successful principle of folate inhibition in the treatment of arthritis.
Topics: Aminopterin; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Female; Folic Acid; Folic Acid Antagonists
PubMed: 21861856
DOI: 10.1186/ar3392 -
Cancer Chemotherapy and Pharmacology 1984A group of folate analogs of the 10-deaza-aminopterin series, which were designed on the basis of the results of an intensive biochemical and pharmacokinetic program,... (Comparative Study)
Comparative Study
New folate analogs of the 10-deaza-aminopterin series. Further evidence for markedly increased antitumor efficacy compared with methotrexate in ascitic and solid murine tumor models.
A group of folate analogs of the 10-deaza-aminopterin series, which were designed on the basis of the results of an intensive biochemical and pharmacokinetic program, have been examined in therapy experiments utilizing a group of murine tumor models. These new analogs were found to be markedly superior to methotrexate against four of five ascites tumors (L1210 leukemia, Sarcoma 180, Ehrlich carcinoma and Tapper carcinosarcoma) and against four of five solid tumors (S180, Tapper carcinosarcoma, E0771 mammary adenocarcinoma, Lewis lung carcinoma, and T241 sarcoma). Analogs alkylated (methyl or ethyl) at the 10 position of 10-deaza-aminopterin were found to be the most effective of the group. These analogs achieved log10 reduction in tumor burden several-fold greater in magnitude than methotrexate against L1210 and S180 ascites tumors and there were also long-term survivors. 10-Deaza-aminopterin itself gave a result intermediate between those obtained with the 10-alkyl derivatives and methotrexate. Against the solid forms of the Tapper tumor some partial regressions were obtained with methotrexate and 10-deaza-aminopterin, but a far greater number, extending over a longer period were obtained with the 10-ethyl derivative of 10-deaza-aminopterin. Against the E0771 tumor, 10-deaza-aminopterin was 2-fold and the ethyl derivative of 10-deaza-aminopterin was greater than 5-fold more effective than methotrexate in retarding tumor growth. Evidence for partial regressions and marked effects against metastatic disease were also obtained in the case of the 10-alkyl derivative. Similar results were also obtained with the T241 sarcoma. For Lewis lung carcinoma the relative potency was about the same but overall antitumor effects were more modest.
Topics: Aminopterin; Animals; Drug Evaluation, Preclinical; Female; Methotrexate; Mice; Neoplasms, Experimental; Structure-Activity Relationship
PubMed: 6690070
DOI: No ID Found -
Biochemical Pharmacology May 1966
Comparative Study
Topics: Aminopterin; Animals; Chromatography; Enzymes; Female; Guinea Pigs; Liver; Male; Methotrexate; Mice; Oxidoreductases; Rabbits; Rats; Spectrophotometry
PubMed: 5961434
DOI: 10.1016/0006-2952(66)90022-0 -
Clinical Dysmorphology Jan 2009Exposure to folic acid antagonists during the first trimester of pregnancy may lead to fetal death or to a recognized pattern of malformations in liveborn infants. Few...
Exposure to folic acid antagonists during the first trimester of pregnancy may lead to fetal death or to a recognized pattern of malformations in liveborn infants. Few reports of affected adult individuals have been observed. In this report, the clinical findings of a likely affected 45-year-old woman are described and compared with reported cases. New ectodermal abnormalities are also described.
Topics: Abortion, Induced; Aminopterin; Female; Humans; Karyotyping; Methotrexate; Middle Aged; Syndrome
PubMed: 19011571
DOI: 10.1097/MCD.0b013e32831552c4 -
Journal of Medicinal Chemistry Dec 2004Heretofore unknown analogues of aminopterin (AMT) and methotrexate (MTX) in which free rotation of the amide bond between the phenyl ring and amino acid side chain is...
Heretofore unknown analogues of aminopterin (AMT) and methotrexate (MTX) in which free rotation of the amide bond between the phenyl ring and amino acid side chain is prevented by a CH(2) bridge were synthesized and tested for in vitro antifolate activity. The K(i) of the AMT analogue (9) against human dihydrofolate reductase (DHFR) was 34 pM, whereas that of the MTX analogue (10) was 2100 pM. Both compounds were less potent than the parent drugs. However, although the difference between AMT and MTX was <2-fold, the difference between 9 and 10 was 62-fold, suggesting that the effect of N(10)-methyl substitution is amplified in the bridged compounds. The K(i) values of 9 and 10 as inhibitors of [(3)H]MTX influx into CCRF-CEM human leukemia cells via the reduced folate carrier (RFC) were 0.28 and 1.1 muM, respectively. The corresponding K(i) and K(t) values determined earlier for AMT and MTX were 5.4 and 4.7 muM, respectively. Thus, in contrast to its unfavorable effect on DHFR binding, the CH(2) bridge increased RFC binding. In a 72 h growth assay with CCRF-CEM cells, the IC(50) values of 9 and 10 were 5.1 and 140 nM, respectively, a 27-fold difference that was qualitatively consistent with the observed combination of weaker DHFR binding and stronger RFC binding. Although rotationally restricted inhibitors of other enzymes of folate pathway enzymes have been described previously, 9 and 10 are the first reported examples of DHFR inhibitors of this type.
Topics: Aminopterin; Enzyme Inhibitors; Folic Acid Antagonists; Humans; Magnetic Resonance Spectroscopy; Methotrexate; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase
PubMed: 15615544
DOI: 10.1021/jm040122s -
Expert Opinion on Drug Metabolism &... Sep 2011Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of T-cell neoplasms. Most patients with PTCL have a poor outcome with conventional therapies and are not... (Review)
Review
INTRODUCTION
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of T-cell neoplasms. Most patients with PTCL have a poor outcome with conventional therapies and are not cured without stem-cell transplantation. Pralatrexate, a novel antifolate chemotherapeutic agent, was rationally designed to impede folate metabolism by inhibiting dihydrofolate reductase (DHFR) and to be more efficiently internalized into tumor cells. Pralatrexate is the first drug that is FDA approved for patients with relapsed and refractory PTCL.
AREAS COVERED
Pralatrexate has been used as a single agent and in combination with other agents in clinical trials for non-Hodgkin's lymphoma and Hodgkin's disease as well as in solid tumors. This review will cover the development of pralatrexate, the pharmacokinetics of pralatrexate, preclinical findings with pralatrexate and clinical studies of pralatrexate in hematologic malignancies.
EXPERT OPINION
Pralatrexate has significant activity in vitro, and in early Phase I/II trials, responses were noted in patients with aggressive T-cell lymphomas. The Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma trial demonstrated the activity of pralatrexate across a spectrum of heavily pretreated patients with different aggressive T-cell lymphoma subtypes, and studies in cutaneous T-cell lymphoma have shown efficacy at different doses and schedules. The most frequent adverse events in these trials were mucositis, reversible thrombocytopenia and fatigue.
Topics: Aminopterin; Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Folic Acid Antagonists; Humans; Lymphoma, T-Cell
PubMed: 21726160
DOI: 10.1517/17425255.2011.595404 -
Anti-cancer Drugs Jul 2002The antifolate aminopterin (AMPT) was developed before methotrexate (MTX), but was not clinically established or generally used due its increased toxicity compared to...
The antifolate aminopterin (AMPT) was developed before methotrexate (MTX), but was not clinically established or generally used due its increased toxicity compared to MTX. Recently, we reported on the increased metabolism of albumin conjugates such as methotrexate-albumin (MTX-SA) in malignant tumors and the feasibility of using albumin as a carrier for drug targeting. Consequently, AMPT was covalently bound to serum albumin (AMPT-SA) at a 1:1 molar ratio. Biodistribution, tolerability and efficacy of this novel conjugate were studied in Walker-256 (W-256) carcinoma-bearing rats. As compared to native albumin, the same biodistribution and plasma clearance were found for AMPT-SA, which achieved 20.1% tumor uptake (estimated uptake per g tumor 6.4%) within 24 h after i.v. administration in rats. In a randomized study, AMPT-SA, repeatedly i.v. injected, was compared with low-molecular-weight AMPT. Depending on the molar concentration, the maximum tolerated dose (MTD) of AMPT covalently bound to SA was twice that of unbound AMPT (three repeated injections of 1.0 mg AMPT-SA/kg body weight versus three repeated injections of 0.5 mg AMPT/kg body weight; p=0.0006). Efficacy was studied at the level of the MTD and MTD/2, and demonstrated that AMPT-SA was significantly more active. At the MTD/2 in W-256 carcinoma-bearing rats, AMPT-SA achieved a 100% volume reduction and an optimal volume reduction during treatment/control (T/C) of 8.3% compared to a 53% volume reduction of AMPT and a T/C of 16.5% (p=0.032). Tumor relapses were reduced and occurred later in the AMPT-SA group (two tumor recurrences for AMPT-SA versus seven for AMPT; p=0.05). In this comparative study, the AMPT-SA conjugate showed high antitumor activity in vivo and a favorable toxicity compared to low-molecular-weight AMPT. These effects are attributed to the albumin carrier which seems to be an effective tool for selective tumor drug targeting.
Topics: Aminopterin; Animals; Antimetabolites, Antineoplastic; Carcinoma 256, Walker; Chelating Agents; Drug Delivery Systems; Female; Folic Acid Antagonists; Neoplasm Transplantation; Pentetic Acid; Radionuclide Imaging; Rats; Rats, Sprague-Dawley; Serum Albumin; Tissue Distribution; Tumor Cells, Cultured
PubMed: 12172507
DOI: 10.1097/00001813-200207000-00008 -
Cancer Chemotherapy Reports Feb 1962
Topics: Aminopterin; Child; Humans; Infant; Leukemia; Meningeal Neoplasms; Meninges; Meningitis
PubMed: 14492194
DOI: No ID Found -
Cancer Nov 1952
Topics: Aminopterin; Folic Acid Antagonists; Methotrexate; Neoplasms
PubMed: 12998027
DOI: 10.1002/1097-0142(195211)5:6<1201::aid-cncr2820050617>3.0.co;2-1