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PubMed1978

Antitumor properties of a new folate analog, 10-deaza-aminopterin, in mice.

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.

Aminopterin↗
PubMed1977

Selective inhibition of reproduction in aminopterin-treated nematodes.

Aminopterin was applied to the free-living nematode Caenorhabditis briggsae and subsequent growth was recorded. Nematode populations, containing all developmental stages and selected juvenile stages, were exposed to the drug in both growth-promoting and non-promoting media. It is suggested that aminopterin creates a specific requirement for thymine in thymine-free medium. In otherwise growth-promoting medium, aminopterin-induced thymine deficiency will lead to progressively unbalanced growth and maturation and hence to sterility even after removal of the drug. The omission of essential amino acids from the medium during thymine starvation prevents larval growth and results in better reproduction and faster proliferation in aminopterin-free medium. The 4 juvenile stages exhibit a different response to thymine starvation created by aminopterin.

Aminopterin↗
PubMed1984

Inhibition of dihydrofolate reductase from bacterial and vertebrate sources by folate, aminopterin, methotrexate and their 5-deaza analogues.

The inhibition of dihydrofolate reductases from Escherichia coli and chicken liver by folate, methotrexate, aminopterin and their 5-deaza analogues was investigated to examine the importance of the N-5 nitrogen in slow-binding inhibition. Methotrexate, aminopterin and their 5-deaza analogues acted as slow, tight-binding inhibitors of both enzymes. Inhibition by methotrexate and 5-deazamethotrexate conformed to a mechanism in which there is an initial rapid formation of an enzyme-NADPH-inhibitor complex followed by a slow isomerization of this complex (Mechanism B). Aminopterin exhibited the same type of inhibition with the enzyme from E. coli. With the chicken-liver enzyme, however, the inhibition by aminopterin conformed to another type of slow-binding mechanism which involves only the slow interaction of the inhibitor with the enzyme to form an enzyme-NADPH-inhibitor complex (Mechanism A). The inhibition of both enzymes by 5-deazaaminopterin was also described by Mechanism A. Folate behaved as a classical, steady-state inhibitor of both enzymes, whereas 5-deazafolate exhibited slow-binding inhibition (Mechanism B) with the enzyme from E. coli and classical, steady-state inhibition with the enzyme from chicken liver. The substitution of a carbon for a nitrogen at the 5-position of methotrexate and aminopterin did not affect the tightness of binding of these compounds. By contrast, 5-deazafolate was bound about 4000 times more tightly than folate to the enzyme from E. coli and about 30 times more tightly than folate to the chicken-liver enzyme. Reasons for the differences in the binding of folate and 5-deazafolate are discussed.

Aminopterin↗
PubMedDate not supplied

Distinct effects of aminopterin on stimulation of T and B lymphocytes with mitogen.

Aminopterin, a folate antagonist, added to cultures of mouse spleen cells stimulated with T-cell mitogens markedly inhibited, in a dose-dependent manner, [3H]thymidine incorporation into the cells. Contrary to this inhibitory effect aminopterin added at the same concentrations to cell cultures stimulated with B-cell mitogens significantly increased [3H]thymidine incorporation. The inhibitory effect of aminopterin on T-cell activation was completely reversed by adding hypoxanthine to the cultures. Analysis of the mechanism of aminopterin action showed direct, mutually opposite, effects of this drug on T- and B-cell populations. The results thus not only demonstrate that polyclonally activated T and B lymphocytes differ in their sensitivity to the toxic action of aminopterin, but simultaneously support early findings suggesting differences in nucleic acid metabolic pathways between T- and B-cell populations.

Aminopterin↗
PubMed1986

Phase II trial of 10 deaza-aminopterin in patients with bladder cancer.

Deaza-aminopterin is a folate analog which is transported more rapidly than methotrexate into cells and appears to be more active than methotrexate against human and animal tumor in vitro. Fifteen patients with advanced urothelial tract cancer were given deaza-aminopterin 30-37.5 mg/m2 IV QW. In responding patients drug was given QOW after 4-6 consecutive doses. Doses were escalated or de-escalated by 7.5 mg/m2 depending on toxicity. Twelve patients had received prior chemotherapy which included methotrexate in nine. Three patients achieved a partial remission lasting 1, 3, and 3 months respectively: all responders had previously failed methotrexate after an initial response to a methotrexate containing regimen. None of the six patients who were methotrexate naive responded to deaza-aminopterin; 3 subsequently received methotrexate without response. Mild mucositis was universal and in 5 was severe. Six patients had an increase in liver transaminases probably secondary to anti-folate hepatotoxicity. Other toxicities included diarrhea, nausea, skin rash and fever. Further studies are needed to define the precise efficacy of deaza-aminopterin in patients with urothelial tract cancers.

Aged↗
PubMed1989

Vestigial mutants of Drosophila melanogaster live better in the presence of aminopterin: increased level of dihydrofolate reductase in a mutant.

Vestigial (vg) mutants of Drosophila melanogaster are characterized by atrophied wings. In this paper we show that: (1) aminopterin an inhibitor of dihydrofolate reductase (DHFR) and fluorodeoxyuridine (FUdR), an inhibitor of thymidylate synthetase induce nicks in the wings of wild-type flies and phenocopies of the vg mutant phenotype when vg/+ and vgB/+ flies are reared on these substances (vgB is a deficiency of the vg locus). Only thymidine and thymidylate can rescue the flies from the effect of aminopterin. We propose that the vg phenotype is due to a decrease in the dTMP pool in the wings. (2) Mutant vg strains yield more offspring on medium containing aminopterin than on normal medium. The resistance of vg larvae to the inhibitor seems specific to the gene. This is the first case of aminopterin resistance in living eucaryotes. In contrast sensitivity of the vg larvae to FUdR is observed. (3) An increase in the activity and amount of DHFR is observed in mutant strains as compared with the wild-type flies. Our data suggest that the vg+ gene is a regulatory gene acting on the DHFR gene or a structural gene involved in the same metabolic pathway.

Aminopterin↗
PubMed1987

The photodecomposition of aminopterin.

Aminopterin is used in cell fusion experiments to select for hybrid cells by killing unfused cells which are deficient in enzymes for nucleotide salvage pathways. Aqueous aminopterin solutions exposed to fluorescent room light (wavelength greater than 300 nm) were found to lose cytotoxicity. Inactivation was accompanied by changes in the ultraviolet absorption spectra of the solutions. The ultraviolet spectrum of an irradiated aminopterin solution is used to provide a quantitative measure of its cytotoxicity. Aminopterin appears to be photolytically cleaved at the C9-N10 methylene-anilino bond in a reaction analogous to that known for the photolysis of folic acid irradiated at 365 nm (Lowry et al., 1949).

Aminopterin↗
PubMed1981

Carbon-13 nuclear magnetic resonance study of protonation of methotrexate and aminopterin bound to dihydrofolate reductase.

Methotrexate, aminopterin, and folate have been synthesized with 90% enrichment of C-2 with 13C. 13C nuclear magnetic resonance has been used to examine the state of protonation of the pteridine ring of these compounds under various conditions and gives much more clear-cut results than most other methods. For the free compounds the following pK values were obtained: methotrexate, 5.73 +/- 0.02 (N-1); aminopterin, 5.70 +/- 0.03 (N-1); folic acid, 2.40 (N-1) and 8.25 +/- 0.05 (N-3, O-4 amide group). The state of protonation of these compounds when complexed to dihydrofolate reductase (isoenzyme 2 from Streptococcus faecium) was also studied over the pH range 6--10. The resonance from bound methotrexate showed a constant chemical shift over the whole pH range studied, and it is inferred that in the complex the pteridine ring remains protonated to at least pH 10. The same result was obtained for the binary complex of aminopterin with the reductase and for either methotrexate or aminopterin in ternary complex with reductase and NADPH4. The latter is an inhibitor of the reductase competitive with NADPH. However, folate bound to the reductase in either the binary or the ternary complex shows the same protonation behavior as in the free state. The data indicate that the association constant for binding of methotrexate is increased enough when protonation of N-1 occurs to account for the enhanced binding of methotrexate as compared with folate.

Aminopterin↗
PubMed1992

vestigial suppressor genes and resistance to aminopterin in Drosophila melanogaster.

We have shown that the vestigial (vg) mutant of D. melanogaster has a perturbed nucleotide metabolism compared to various wild-type strains. The mutant is particularly spontaneously resistant to aminopterin. The resistance seems to correlate with an increase in dihydrofolate reductase (DHFR) activity and quantity. The DHRF is a target enzyme of aminopterin. Our results suggest that the vg+ gene could be a regulatory gene acting on the DHFR gene. The wing mutant phenotype being due to a decrease in the thymidylate pool (dTMP) (Silber et al., 1989). In order to understand better the action of the mutant gene on nucleotide metabolism, we have induced suppressor genes of the mutant phenotype by mutagenesis with ethyl methanesulfonate (EMS) and bromouridine (BUR). The suppressor strains obtained display a phenotype intermediate between wild-type and vg phenotype. The action of three independent suppressor genes on eight parameters of nucleotide metabolism is reported here [three enzyme activities, resistance to aminopterin and to fluorodeoxyuridine (FUdR), auxotrophy test and the ability to use exogenous thymidine and uridine]. In comparison to the original vg strain, major changes for the parameters tested are observed. The most striking effects are obtained with the vgBUR27 strain, which is highly sensitive to aminopterin and to fluorodeoxyuridine and didplas the highest thymidine kinase (TK) and DHFR activities within the strains tested. The potential actions of suppressor genes on the vg mutant are discussed.

Aminopterin↗
PubMed1977

[Effect of aminopterin on pre-implantation rat embryos cultivated outside the body].

The rat embryos at the stage of 8 blastomeres were explanted in the Biggers' medium with 20% of blood serum from the rats obtained different doses of aminopterin. The marked delay of cleavage rate, morphological anomalies of blastocysts, selective damaging effect of aminopterin upon the inner cells mass (embryoblast) and high resistance of trophectoderm cells against this drug were observed. The role of dihydrololate reductase at the preimplantation developmental stages, the resistance against aminopterin of the early rat embryos within the maternal organism and high sensitivity to this drug of the embryos in vitro are discussed. A conclusion is drawn on the presence of the barrier function of oviducts with respect to aminopterin.

Aminopterin↗
PubMed1966

Thymidylate synthesis and aminopterin resistance in Bacillus subtilis.

Wilson, Melba Carr (Brown University, Providence, R.I.), James L. Farmer, and Frank Rothman. Thymidylate synthesis and aminopterin resistance in Bacillus subtilis. J. Bacteriol. 92:186-196. 1966.-The thymine-requirement of Bacillus subtilis 168 thy results from mutation in two unlinked genes (i.e., genetic loci) designated thyA and thyB. The thyB gene is located between the met and ile markers. Both thyA(+)thyB and thyA thyB(+) strains are phenotypically thy(+). ThyA(+)thyB strains resemble the wild type in their sensitivity to aminopterin, poor incorporation of exogenous thymine into deoxyribonucleic acid (DNA), and high level of thymidylate synthetase activity in crude extracts. ThyA thyB(+) strains are resistant to aminopterin in the presence of thymine, incorporate exogenous thymine into DNA, and have no detectable thymidylate synthetase activity. Experiments designed to elucidate the role of the thyB gene indicate that it specifies an alternate pathway of thymidylate synthesis, similar to thymidylate synthetase but requiring a cofactor other than tetrahydrofolate. The mechanism of selection of thymine-requiring mutants by aminopterin is revealed by these results.

Bacillus subtilis↗
PubMed1963

THE EFFECT OF 6-MERCAPTOPURINE AND AMINOPTERIN ON EXPERIMENTAL IMMUNE THYROIDITIS IN GUINEA PIGS.

The influence of 6-mercaptopurine and aminopterin was studied on immune response and immune thyroiditis in guinea pigs immunized with thyroid extract. 1. Both compounds depressed delayed hypersensitivity to thyroglobulin and immune thyroiditis. 2. Antibody formation to thyroglobulin was strongly depressed by aminopterin but not significantly influenced by 6-mercaptopurine. 3. Immune response and thyroiditis were suppressed as long as the compounds were administered; after discontinuation of treatment, immune response and thyroiditis appeared in the same time intervals as observed in control animals after initiation of immunization. 4. Treatment with 6-mercaptopurine and aminopterin 10 days after immunization lead to suppression of delayed hypersensitivity and thyroiditis. 5. Treatment with 6-mercaptopurine of animals after onset of thyroiditis lead to suppression of delayed hypersensitivity and disappearance or diminution of round cell infiltration in the thyroid. 6. The results are discussed in terms of the pathogenesis of experimental immune thyroiditis, the mode of action of these antimetabolites on this experimental immune disease, and in view of the potential value of these compounds in human diseases.

Aminopterin↗
PubMed1976

Teratogenicity studies with methotrexate, aminopterin, and acetylsalicylic acid in domestic cats.

Pregnancy was timed in cats following induced ovulation. Methotrexate, (0.5 mg/kg), aminopterin, (0.1 mg/kg), and acetylsalicylic acid, (25 or 50 mg/kg) were administered orally in gelatin capsules in single daily doses on different days of gestation, methotrexate (MTX) on days 11-14, 14-17, or 17-20, aminopterin on day 12, 14, or 16, and acetylsalicylic acid (ASA) on days 10-15 or 15-20. Maternal toxicity was produced only by MTX. MTX given on days 11-14 and 14-17 produced high frequencies of malformations including umbilical hernia. Aminopterin caused no conclusive teratogenic response. An overall increased frequency of anomalies occurred after 50 mg/kg ASA but no single anomaly predominated.

Abnormalities, Drug-Induced↗
PubMed1985

Dihydrofolate reductase activity and resistance to aminopterin in various species of Drosophila.

The aim of our work was to compare the mechanisms of resistance to aminopterin, inhibitor of the dihydrofolate reductase enzyme, between different Drosophila species and those described for cultured cells. Moreover we compared the systematic species divisions based on morphological traits and those based on a molecular approach. For this purpose, the effect of aminopterin on viability and wing phenotype was studied in different Drosophila species. Dihydrofolate reductase was measured in adult flies. We found an important dihydrofolate reductase activity in the melanogaster sub-group compared to the other species studies. Wing effect was observed only in this sub-group. The effects of aminopterin on the wing phenotype were very similar to the phenotype of rudimentary mutants. Both deplete the pyrimidine pool and it has been shown by the studies of the structural genes of the nucleotide pyrimidine pathway that the wing tissue is very sensitive to every pertubation of this metabolism. The D. ananassae species was found to be fully resistant at the concentrations of the inhibitor tested. No or very little dihydrofolate reductase activity was detected. The binding of the enzyme to the inhibitor was comparable to that found in the Oregon strain of D. melanogaster. The purine and pyrimidine salvage pathways were investigated and the D. ananassae species displayed an important thymidine kinase activity. The D. ananassae flies were sensitive on Sang medium compared to the Oregon flies but were able to use exogenous bases or nucleosides more efficiently.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopterin↗
PubMed1991

Rapid isolation of monoclonal hybridoma cultures by a 'fusion-cloning' method: the requirement for aminopterin.

Hybridomas were generated by fusing the Balb/c SP2/0 myeloma-like cell line with either: (i) splenocytes from Balb/c mice immunized with foot-and-mouth disease virus (FMDV), rinderpest virus (RPV), peste des petits ruminants virus (PPRV), African swine fever virus (ASFV) or pig thymocytes; or (ii) lymph node cells from cattle immunized with FMDV. If the fusion mixtures were plated in cloning medium of methyl cellulose and HAT medium, small hybridoma colonies developed which rarely survived. Fusion mixtures were then plated in liquid HT medium on to 3T3/A31 feeder layers in 75 cm2 flasks, incubated at 37 degrees C for 24 h before adding aminopterin, and incubated for a further 2 to 4 days before cloning in methyl cellulose/HT medium. Without the aminopterin in the cloning medium, colonies of hybridomas, which could be cultured, developed from the majority of fusions. These colonies were isolated in HT medium over feeder layers and given two subcultures in HAT medium as a precaution against any reversion to aminopterin sensitivity during the cloning. No evidence of such reversions were seen, and recloning results suggested that the initial cloning was highly efficient at generating monoclonal cultures.

Aminopterin↗
PubMed1968

Pyruvate metabolism by aminopterin-inhibited Aerobacter aerogenes.

1. The synthesis and utilization of both alanine (by reductive amination, oxidative deamination and transamination) and valine (by transamination only) in Aerobacter aerogenes are unaffected by aminopterin. These amino acids, which accumulate in aminopterin-treated cultures of this organism, are therefore considered to be formed as secondary products from the excess of pyruvate that also accumulates. 2. Oxidative metabolism of pyruvate and the synthesis of acetylmethylcarbinol by A. aerogenes cells are unaltered by growth in the presence of aminopterin. 3. Cells from static and anaerobic cultures that have been treated with the folic acid antagonist in the early exponential phase have a decreased ability to cleave pyruvate to acetate and formate, and to effect the exchange of formate with the carboxyl group of pyruvate. 4. 3-Methyl-2-oxobutanoate, the keto acid precursor of valine, cannot replace pyruvate as substrate in either the phosphoroclastic or the exchange reaction.

Alanine↗
PubMed1996

Import of a DHFR hybrid protein into glycosomes in vivo is not inhibited by the folate-analogue aminopterin.

Dihydrofolate reductase fusion proteins have been widely used to study conformational properties of polypeptides translocated across membranes. We have studied the import of dihydrofolate reductase fusion proteins into glycosomes and mitochondria of Trypanosoma brucei. As signal sequences we used the last 22 carboxy-terminal amino acids of glycosomal phosphoglycerate kinase for glycosomes, and the cleavable presequences of yeast cytochrome b2 or cytochrome oxidase subunit IV for mitochondria. Upon addition of aminopterin, a folate analogue that stabilizes the dihydrofolate reductase moiety, import of the fusion protein targeted to glycosomes was not inhibited, although the results of protease protection assays showed that the fusion protein could bind the drug. Under the same conditions, import of a DHFR fusion protein targeted to mitochondria was inhibited by aminopterin. When DHFR fusion proteins targeted simultaneously to both glycosomes and mitochondria were expressed, import into mitochondria was inhibited by aminopterin, whereas uptake of the same proteins into glycosomes was either unaffected or slightly increased. These findings suggest that the glycosomes possess either a strong unfolding activity or an unusually large or flexible translocation channel.

Aminopterin↗