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Biochimica Et Biophysica Acta Aug 1979The polar lipids of Streptococcus pneumoniae wild type and aminopterin-resistant strains were analysed. The membrane contained only two acid phospholipids,...
The polar lipids of Streptococcus pneumoniae wild type and aminopterin-resistant strains were analysed. The membrane contained only two acid phospholipids, phosphatidylglycerol and cardiolipin, and a large amount of two glycolipids, glucosyldiglyceride and galactosylglucosyldiglyceride. The unsaturated acyl chains ranged from 58 to 87% of total fatty acids, depending on the strain and on growth conditions. No relation could be established between aminopterin resistance and polar lipid or fatty acid compositions. However, in the presence of bacteriostatic concentrations of aminopterin, the wild type and the resistant mutant did not have the same behavior. The resistant strain maintained its fatty acid composition and a normal [32P]phosphate distribution among phospholipids while the wild type shifted to a higher content in unsaturated fatty acids and to a high relative cardiolipin labelling. Such a differencein [32P] distribution was not observed when bacteriostatic concentrations of chloramphenicol were used, or when growth was stopped after amino acid deprivation induced by high concentrations of isoleucine. The biochemical basis of the aminopterin resistant character of the amiA mutants are not yet well understood but the present study establishes that the mutation confers a certain insensitivity of the lipid metabolism to aminopterin.
Topics: Aminopterin; Drug Resistance, Microbial; Fatty Acids; Lipids; Phospholipids; Streptococcus pneumoniae
PubMed: 39617
DOI: 10.1016/0005-2760(79)90010-9 -
Journal of Medicinal Chemistry Apr 2018A series of novel hydrogen peroxide sensitive prodrugs of methotrexate (MTX) and aminopterin (AMT) were synthesized and evaluated for therapeutic efficacy in mice with...
A series of novel hydrogen peroxide sensitive prodrugs of methotrexate (MTX) and aminopterin (AMT) were synthesized and evaluated for therapeutic efficacy in mice with collagen induced arthritis (CIA) as a model of chronic rheumatoid arthritis (RA). The prodrug strategy selected is based on ROS-labile 4-methylphenylboronic acid promoieties linked to the drugs via a carbamate linkage or a direct C-N bond. Activation under pathophysiological concentrations of HO proved to be effective, and prodrug candidates were selected in agreement with relevant in vitro physicochemical and pharmacokinetic assays. Selected candidates showed moderate to good solubility, high chemical and enzymatic stability, and therapeutic efficacy comparable to the parent drugs in the CIA model. Importantly, the prodrugs displayed the expected safer toxicity profile and increased therapeutic window compared to MTX and AMT while maintaining a comparable therapeutic efficacy, which is highly encouraging for future use in RA patients.
Topics: Aminopterin; Animals; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Boronic Acids; Collagen Type II; Humans; Hydrogen Peroxide; MCF-7 Cells; Male; Methotrexate; Mice, Inbred DBA; Microsomes, Liver; Prodrugs; Solubility
PubMed: 29605999
DOI: 10.1021/acs.jmedchem.7b01775 -
Skin Dec 1962
Topics: Aminopterin; Methotrexate; Psoriasis
PubMed: 13973589
DOI: No ID Found -
Current Opinion in Oncology May 2012To discuss the clinical development of new formulations of old cytotoxic agents and highlight the value of adopting this strategy. (Review)
Review
PURPOSE OF REVIEW
To discuss the clinical development of new formulations of old cytotoxic agents and highlight the value of adopting this strategy.
RECENT FINDINGS
Several drugs are currently in clinical development with high potential in improving clinical outcomes compared with their older counterparts. We emphasize on the results of four of these agents, each belonging to a known group of cytotoxics namely amrubicin, EndoTAG-1, pralatrexate and NKTR-102. Each has shown promising results that have the potential in addressing some limitations that have been observed with the 'earlier generation' agents.
SUMMARY
Improvement in drug development strategies and the appreciation of the mechanisms of action and resistance of the cytotoxic agents currently available in the clinic open the door for developing agents that have the potential of improving clinical outcomes with better safety profiles. It is important to adopt innovative clinical trials designs integrating molecular markers in early clinical development in order to identify the subgroups of patients who would derive the maximal benefit of these novel agents.
Topics: Aminopterin; Anthracyclines; Antineoplastic Agents; Camptothecin; Chemistry, Pharmaceutical; Folic Acid Antagonists; Humans; Irinotecan; Neoplasms; Paclitaxel; Topoisomerase I Inhibitors
PubMed: 22343388
DOI: 10.1097/CCO.0b013e328351fb29 -
Clinical Lymphoma & Myeloma Dec 2008Peripheral T-cell lymphomas are a heterogenous mix of histology, as well as clinical presentation, and outcome and remain a challenging group of diseases to treat.... (Review)
Review
Peripheral T-cell lymphomas are a heterogenous mix of histology, as well as clinical presentation, and outcome and remain a challenging group of diseases to treat. Because of difficulty and variability in diagnosis, improvements in diagnostic technology, and changing classification systems over time, the interpretation of studies is complicated. In addition, the response to current treatments and long-term outcome is generally poor. This review outlines these problems and discusses the current status of treatment strategies, including the disappointing results with standard anthracycline-based therapy as well as experience with modifications to CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone); increasing dose intensity; antimetabolites; and T-cell-targeted therapies. We conclude with a description of a new agent, pralatrexate, including the preclinical and early clinical experience as well as a description of a large phase II prospective trial. Because of the relative rarity of this group of diseases, large-scale prospective clinical trials are difficult to implement. New treatment strategies are needed if we hope to improve patient outcomes.
Topics: Aminopterin; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Drug Delivery Systems; Humans; Lymphoma, T-Cell, Peripheral; Prednisone; Vincristine
PubMed: 19073525
DOI: 10.3816/CLM.2008.s.014 -
Experimental Parasitology Oct 2009The antifolate anticancer drug methotrexate (MTX) has potent activity against Plasmodium falciparum in vitro. Experience of its use in the treatment of rheumatoid...
The antifolate anticancer drug methotrexate (MTX) has potent activity against Plasmodium falciparum in vitro. Experience of its use in the treatment of rheumatoid arthritis indicates that it could be safe and efficacious for treating malaria. We sought to establish a murine malaria model to study the mechanism of action and resistance of MTX and its analogue aminopterin (AMP). We used Plasmodium berghei, Plasmodium yoelii yoelii, Plasmodium chabaudi and Plasmodium vinckei. None of these species were susceptible to either drug. We have also tested the efficacy of pyrimethamine in combination with folic acid in P. berghei, and data indicate that folic acid does not influence pyrimethamine efficacy, which suggests that P. berghei may not transport folate. Since MTX and AMP utilise folate receptor/transport to gain access to cells, their lack of efficacy against the four tested murine malaria species may be the result of inefficiency of drug transport.
Topics: Administration, Oral; Aminopterin; Animals; Biological Availability; Enzyme Inhibitors; Female; Folic Acid; Folic Acid Antagonists; Malaria; Methotrexate; Mice; Plasmodium; Plasmodium berghei; Plasmodium chabaudi; Plasmodium yoelii; Pyrimethamine
PubMed: 19527714
DOI: 10.1016/j.exppara.2009.06.007 -
The Biochemical Journal Nov 1958
Topics: Adenine; Aminopterin; Enterobacter aerogenes; Glutamates; Humans
PubMed: 13596365
DOI: No ID Found -
Expert Opinion on Pharmacotherapy Mar 2013Pralatrexate is a novel antifolate agent that belongs to the class of 10-deazaaminopterins. Its clinical efficacy as a single agent in relapsed or refractory peripheral... (Review)
Review
INTRODUCTION
Pralatrexate is a novel antifolate agent that belongs to the class of 10-deazaaminopterins. Its clinical efficacy as a single agent in relapsed or refractory peripheral T-cell lymphoma (PTCL) has been established in randomized trials. Treatment with this agent is generally safe.
AREAS COVERED
This paper discusses the pharmacokinetics and efficacy of pralatrexate in T-cell lymphoma in clinical trials. In addition, the authors highlight pralatrexate-associated adverse effects and safety concerns.
EXPERT OPINION
Although established as a second-line therapy, pralatrexate offers a clinical benefit to less than one-third of patients with PTCL. In addition, toxicity of this agent can be significant, especially mucositis, immunosuppression and thrombocytopenia. Currently, the potential synergy between pralatrexate and other agents in T-cell lymphoma is being explored in a number of studies. These results will hopefully prove the validity of this approach, leading to improved quantity of life in these patients, with an acceptable comfort index.
Topics: Aminopterin; Animals; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Disease-Free Survival; Drug Screening Assays, Antitumor; Folic Acid Antagonists; Humans; Lymphoma, T-Cell
PubMed: 23409799
DOI: 10.1517/14656566.2013.770474 -
Perspectives in Biology and Medicine 1983
Review
Topics: Aminopterin; Animals; Ascorbic Acid; Folic Acid; Humans; Methotrexate
PubMed: 6359053
DOI: 10.1353/pbm.1983.0006 -
Cancer Chemotherapy and Pharmacology 1984Structural modification of the N10 position of 4-amino folates affects mediated membrane transport in mammalian cells but has little or no effect on target enzyme...
Structural modification of the N10 position of 4-amino folates affects mediated membrane transport in mammalian cells but has little or no effect on target enzyme (dihydrofolate reductase) inhibition. Some of these modifications have been associated with differential effects on transport in various cell types in a manner which favored greater accumulation and persistence of drug in responsive tumor cells than in normal proliferative tissue. With the aid of identifying new structures with greater potential for differential mediated accumulation, we have studied three new 10-alkyl analogs of 10-deaza-aminopterin. Two of these analogs showed therapeutic efficacy substantially greater than 10-deaza-aminopterin, an analog with antitumor properties superior to methotrexate. These analogs, the 10-methyl, 10-ethyl, and 10,10-dimethyl derivatives, were equivalent to the parent compound, 10-deaza-aminopterin, and aminopterin, and slightly more potent than methotrexate, as inhibitors of L1210 cell dihydrofolate reductase. The three new analogs, 10-deaza-aminopterin, and aminopterin exhibited similar transport properties in L1210, Ehrlich, and S180 cells. Efflux and influx Vmax were similar to those of methotrexate, but influx Km was 4- to 14-fold lower than for methotrexate. That is, substitution at N10, but not at C10, reduced influx potential in these tumor cells. These differences in transport properties among this group of analogs which determine net accumulation were reflected in the individual values for growth-inhibitory potency. In contrast to that seen in tumor cells, alkylation at both N10 and C10 reduced influx potential (increased Km) in isolated intestinal epithelial cells from mouse small intestine. Influx was in the order aminopterin greater than 10-deaza-aminopterin with further reduction in each series showing a magnitude in proportion to the size of the 10 substituent. Otherwise, influx Vmax and efflux were similar for the group. Accumulation of polyglutamates in small intestine was greater following aminopterin administration than following administration of other analogs (10-ethyl, 10-deaza-aminopterin less than methotrexate less than 10-deaza-aminopterin). Polyglutamate accumulation for all the analogs was greater in tumor cells, but accumulation of each varied between the two tumors (L1210 and S180) examined. Differences among the analogs were not as great in L1210 as in S180 cells, and their metabolism was not in the same relative order.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Aminopterin; Animals; Cells, Cultured; Epithelium; Female; Folic Acid Antagonists; Intestine, Small; Kinetics; Mice; Structure-Activity Relationship
PubMed: 6690069
DOI: 10.1007/BF00255903