Disease relevance of aminopterin

• Reduced forms of aminopterin and methotrexate in L1210 lymphoma [1].
• The mutants were aminopterin-sensitive and possessed no measurable hypoxanthine phosphoribosyltransferase activity; their behavior was indistinguishable from that of keratinocytes cultured from individuals with Lesch-Nyhan syndrome [2].
• These rabbits developed plasmacytomas, and we obtained several plasmacytoma cell lines from which we isolated hypoxanthine/aminopterin/thymidine-sensitive clones [3].
• These differences accounted, to some extent, for the reduced toxicity of the 5-alkyl-5-deazaaminopterin analogues compared to aminopterin and the increased toxicity of 5-methyl-5-deazamethotrexate compared to methotrexate [4].
• However, in Sarcoma 180 cells, only aminopterin polyglutamates reached a similar maximum percentage of accumulation, while lower relative polyglutamate levels were achieved with the other analogues [5].

Psychiatry related information on aminopterin

• We report on a boy with a combination of manifestations reminiscent of aminopterin embryopathy: brachyturricephaly with craniosynostosis, poorly mineralised vault, upslanted palpebral fissures, malar hypoplasia, high-arched palate, micrognathia, thick, abnormal auricles, ASD, minor hand anomalies, growth and mental retardation [6].
• Regarding human data, intrauterine deaths were observed to occur in association with 1) maternal homeostatic changes due to phenylketonuria and diabetes and 2) maternal toxicity resulting from alcohol abuse, use of aminopterin, and, possibly, trimethadione [7].

High impact information on aminopterin

• Human T cell hybrids were generated by fusing lectin-activated normal and leukemic human T cells with an aminopterin-sensitive human T cell line [8].
• Selection of hybrids formed from one of these cell lines was performed by using aminopterine-containing culture medium as this cell line was deficient in hypoxanthine-guanine-phosphoribosyl transferase (HGPRT) [9].
• Import of a DHFR hybrid protein into glycosomes in vivo is not inhibited by the folate-analogue aminopterin [10].
• Under the same conditions, import of a DHFR fusion protein targeted to mitochondria was inhibited by aminopterin [10].
• Peripheral blood lymphocytes from "old" male individuals and "young" controls were fused with a Chinese hamster cell line (CHO-YH21), yielding 10 HAT-resistant rodent-human clones from the old propositi and 22 from the young controls (HAT = hypoxanthine/aminopterin/thymidine) [11].

Chemical compound and disease context of aminopterin

• In L1210 and Sarcoma 180 cells, the relative rates of polyglutamylation were in the order aminopterin greater than 10-ethyl-10-deazaaminopterin greater than methotrexate greater than 10-deazaaminopterin [5].
• In drug-induced hepatitis caused by a heterogenous group of drugs consisting of ajmaline, aminopterine, isaxonine, isoniazid, perhexiline, phenylbutazone and troleandromycine, antiorganelle antibodies were absent or rare [12].
• The effects of pH upon the C-2 resonances of the 5 histidine residues of Escherichia coli MB 1428 dihydrofolate reductase in binary complexes with methotrexate, aminopterin, folate, methopterin, and trimethoprim were studied by 300-MHz 1H nmr spectroscopy [13].
• The amount of exogenous dThd required to rescue phage DNA synthesis in FUdR-inhibited cultures was 20-fold higher than the concentration required to rescue cellular replication, whereas the same low concentrations of dThd sufficed to rescue viral and bacterial DNA syntheses in aminopterin-inhibited cultures [14].
• Synthesis of 5-chloro-5,8-dideaza analogues of folic acid and aminopterin targeted for colon adenocarcinoma [15].

Biological context of aminopterin

• Analyses of karyotypes, HLA phenotypes, and other surface phenotypes, such as T-cell-specific antigens or receptors for sheep erythrocytes and the patterns of mitogen responsiveness confirmed that the hypoxanthine/aminopterin/thymidine-resistant cell lines were human T-T hybridomas [16].
• Chromosomes of older humans are more prone to aminopterine-induced breakage [11].
• After transfection with vector-Ecogpt DNAs, surviving cells producing XGPRT can be selectively grown with xanthine as the sole precursor for guanine nucleotide formation in a medium containing inhibitors (aminopterin and mycophenolic acid) that block de novo purine nucleotide synthesis [17].
• We have therefore examined the ability of normal and CF cells to survive exposure to ethacrynic acid, another inhibitor of ion transport, and to survive colchicine and aminopterin, resistance to which has been associated with membrane alterations in other cells [18].
• Plasmid pSV2gpt-CaPO4 coprecipitates induced aminopterin resistance with equal efficiency in the 6-thioguanine-resistant, aminopterin-sensitive, repair-proficient parental line AA8-4(tg-1) and in UV-135(tg-2) [19].

Anatomical context of aminopterin

• The resulting hybrid cells, which were selected in hypoxanthine/aminopterin/thymidine medium, retained almost all of the mouse chromosomes and various numbers of rat chromosomes, and showed many chromosomal rearrangements [20].
• Exposure of the cells to ethacrynic acid, colchicine, or aminopterin did not reveal any differences in survival between normal and CF fibroblasts [18].
• We have investigated DNA-mediated transfer of aminopterin resistance conferred by plasmid and UV resistance conferred by genomic DNA to the Chinese hamster ovary (CHO) cell line UV-135, a UV-sensitive mutant defective in nucleotide excision repair [19].
• Persistence of aminopterin was similar to that seen in small intestine [21].
• For FPGS derived from proliferative intestinal epithelium, aminopterin was also the preferred substrate, but the value for Vmax (derived with crude cell-free extract) was 6-fold lower than for tumor cell FPGS [22].

Associations of aminopterin with other chemical compounds

• The hybrid cells were selected in medium with 100 microM hypoxanthine/1 microM aminopterin/12 microM thymidine to eliminate the neuroblastoma cells and with cis-hydroxyproline to retard fibroblast growth [23].
• In other studies, it was found that the diglutamate of aminopterin (aminopterin +G1) was a relatively poor substrate for FPGS derived from all three sources compared with methotrexate diglutamate, both in respect to values for Km and Vmax that were measured in each case [22].
• Hybrids were selected in medium supplemented with hypoxanthine: aminopterin: thymidine and 5 mM ouabain [24].
• The relationship between HSP27 overexpression and increased resistance to cytotoxic agents was also evaluated in three independent pooled cell populations stably transformed with both the human HSP27 and the xanthine-guanine phosphoribosyltransferase gene and selected on the basis of resistance to mycophenolic acid and aminopterin [25].
• Mitogen-stimulated human peripheral blood T cells were treated with aminopterin to inhibit purine synthesis de novo and to make the cells dependent on an exogenous purine source [26].

Gene context of aminopterin

• They grow in medium containing hypoxanthine, aminopterin, and thymidine plus IFN and are killed by 6-thioguanine plus IFN [27].
• Moreover, a decrease in VG or addition of aminopterin, a specific DHFR inhibitor, shift the dorso-ventral boundary cells of the disc to a cell death sensitive state that is correlated with reaper induction and DIAP1 downregulation [28].
• Decreased polyglutamylation was attributable to folylpolyglutamate synthetase (FPGS) activity in R30dm extracts which was 1, 2, and less than or equal to 10% of CCRF-CEM extracts with the substrates MTX, aminopterin, and naturally occurring folates, respectively [29].
• Substitutions at the 2-position (e.g., 2-CH3) improved the RFC substrate affinity for methotrexate and aminopterin [30].
• Inhibition of murine thymidylate synthase and human dihydrofolate reductase by 5,8-dideaza analogues of folic acid and aminopterin [31].

Analytical, diagnostic and therapeutic context of aminopterin

• The native enzyme has a molecular weight of about 44,500, as determined by sedimentation velocity and gel filtration, and a subunit molecular weight of about 23,000, as determined by aminopterin titration and denaturing gel electrophoresis [32].
• Human PRL (hPRL)-secreting adenoma cells obtained at hypophysectomy were fused with a mutant mouse fibroblast line (LMTK-) which is aminopterin sensitive due to a deficiency in the enzyme thymidine kinase [33].
• Cell culture toxicity reversal studies and enzyme inhibition tests showed that 1 was cytotoxic but not by the mechanism of the dihydrofolate reductase inhibitor aminopterin [34].
• This construct permits cell growth in hypoxanthine/aminopterin/thymidine media and confers 6-thioguanine sensitivity upon mouse Hprt- embryonic stem cells, allowing either positive or negative selection in gene-targeting experiments [35].
• This ionic excitation occurred in no cells at less than 5 days after treatment with aminopterin but at 5 days or more after treatment, 20% of cells responded to low calcium while 52% responded to low calcium and zero potassium [36].

References