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PubMed1986

In vitro fertilization and development of ova obtained from female mice treated with aminopterin and mitomycin C.

We examined the effects of mitomycin C and aminopterin on ovulation in vivo and, fertilization, subsequent cleavage and implantation in slc-ICR female mice using methods of fertilization and culture in vitro. Chemicals were injected into mice at the MI (meiosis I) stage or 3 hours before the MI stage in order to examine their toxicity. Mitomycin C did not affect ovulation, but decreased the rate of fertilization. A high dose of mitomycin C (4 mg/kg) inhibited fertilization and the development of ova to the 2-cell stage. Aminopterin affected neither ovulation nor fertilization. At either the MII (meiosis II) stage or 3 hours before the MII stage, high doses (4 and 2 mg/kg) of mitomycin C arrested cleavage and implantation. The cleavage was blocked frequently between the 3-4 cell stage and the 5-8 cell stage. Aminopterin affected neither cleavage nor implantation.

Aminopterin↗
PubMed1985

New folate analogs of the 10-deaza-aminopterin series: markedly increased antitumor activity of the 10-ethyl analog compared to the parent compound and methotrexate against some human tumor xenografts in nude mice.

In an extension of our prior studies in murine tumor models, we examined two new folate analogs in the 10-deaza-aminopterin series for antitumor activity against a group of human tumor xenografts in nude mice. In all three xenograft models studied, MX-1 mammary carcinoma, LX-1 lung carcinoma, and CX-1 colon carcinoma, 10-deaza-aminopterin was minimally active, while methotrexate was inactive. In contrast, against the MX-1 and LX-1 tumors, 10-ethyl, 10-deaza-aminopterin at or near the LD10 dose (2-4.5 mg/kg) given once per day X 5 produced frank regressions. Activity of this analog against the CX-1 tumor was less, but retardation of tumor growth was observed with some minor regressions.

Aminopterin↗
PubMed1977

Initiation of protein synthesis in bacillus subtilis in the presence of trimethoprim or aminopterin.

Initiation of protein synthesis has been studied in the presence of the tetrahydrofolic acid analogues trimethoprim or aminopterin in Bacillus subtilis. This bacterium can grow in the presence of the inhibitors, when the medium is supplemented with the low molecular weight products of tetrahydrofolate-dependent pathways. In an attempt to show whether formylation of initiator tRNA is a prerequisite for the iniation of protein synthesis in procaryotic cells, the amount of N-formylmethionine in tRNA and in protein has been determined. The level of formylation of methionyl-tRNA was found to be 70% in control cells and approximately 2% in inhibitor-treated cells. The content of formyl groups in protein has also been found to be drastically reduced. Trimethoprim or aminopterin did not alter the amount of tRNAMet nor the degree of aminoacylation of tRNAMet in vivo. These results indicate that in B. subtilis inititation of protein synthesis is possible without prior formylation of initiator tRNA.

Aminopterin↗
PubMed1987

An improved selection procedure for the rescue of hybridomas. A comparative study of methotrexate versus aminopterin.

Several of aminopterin's drawbacks such as photosensitivity and high toxicity prompted us to compare the ability of methotrexate to select for hybridomas. Assessing the effect of both drugs on X63/Ag 8.653 myeloma cells and hybrid cells secreting monoclonal antibodies by tritiated thymidine incorporation and percentage of viable cells, we have shown that methotrexate could be used in place of aminopterin for the rescue of hybrid cells in selective medium. In addition, methotrexate hybrids develop more rapidly and can therefore be processed earlier. The stability and low toxicity of methotrexate also favor its use in the selection of hybridomas.

Aminopterin↗
PubMed1989

Chromosomes of older humans are more prone to aminopterine-induced breakage.

We have adopted a simplified version of the "cell hybrid cotransfer method" to test the hypothesis that human lymphocytes derived from elderly individuals have a higher chromosome instability. 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). Both series of hybrid clones were analyzed with respect to the retention of the enzyme glucose-6-phosphate dehydrogenase and the surface antigen MIC2 identified by monoclonal antibody 12E7, two human X chromosome-linked markers located at opposite ends of the X chromosome. Cell hybrid clones with an X chromosome from a young control retained both markers in about 70% of the cells. In contrast, cell hybrid clones with an X chromosome from an old donor retained the MIC2 marker in only 30% of their cells. Slot-blot hybridization studies have established that the observed loss of the MIC2 marker is due to loss of the coding gene, not to suppression of its expression. Similar hybridization studies with molecular probes specific for other regions of the X chromosome suggest preferential chromosomal breakage sites. T lymphocytes from old donors were also found to have an LD50 for aminopterine significantly lower than the concentration of this drug in the HAT medium used to grow the hybrids, suggesting that the higher level of gene loss observed in the X chromosomes from old donors may be directly related to their increased sensitivity to the clastogenic effect of aminopterine. We speculate that the higher rate of chromosomal breakage and of marker loss observed along the "old-age" X chromosomes could be the result of "molecular scars" accumulated with aging at sites of constitutive chromosomal fragility.

Adult↗
PubMed1983

[Study of the effect of 2 inhibitors of nucleotide synthesis, aminopterin and fluorodeoxyuridine, on wild type strains and vestigial mutants in Drosophila melanogaster].

Two inhibitors of nucleotide metabolism, aminopterin and FUdR, were tested on a wild type strain, on two mutant strains: vg and vgnp, and on a vg strain with the wild type genetic background. Without inhibitors, a lengthening of the developing time was observed for the mutant strains compared to the wild type. With aminopterin, larval mortality and lengthening of developing time are significantly higher in the wild type than in the mutant strains. Mutant strains seemed to be resistant to low concentrations of FUdR. The hypothesis of a perturbed pyrimidine metabolism in the mutants seems to be confirmed.

Aminopterin↗
PubMed1976

Metabolism of dihydroaminopterin and the influence of aminopterin and related derivatives on the metabolism of (-)-5-formyl-tetrahydrofolic acid in Pediococcus cerevisiae.

[3H]Dihydroaminopterin, but not [3H]methotrexate or [3H]aminopterin, was rapidly taken up by resting cell of Pediococcus cerevisiae and inhibited the uptake of (-)-5-formyl-tetrahydrofolic acid to more than 90% at a concentration of 25 muM. On the other hand 5-formyl-tetrahydrofolic acid inhibited the uptake of dihydroaminopterin to a similar extent. Dihydroaminopterin was metabolized by Pediococcus cerevisiae, but not by Lactobacillus casei, to a compound tentatively identified as dihydroaminopterin diglutamate. Methotrexate or aminopterin at a concentration of 25 muM did not inhibit the uptake of 5-formyl-tetrahydrofolic acid in Pediococcus cervisiae, but inhibited the conversion of this compound to polyglutamate forms almost completely at a level of 2.5 mu M.

Aminopterin↗
PubMed1990

Time dependent inhibition of xanthine oxidase in irradiated solutions of folic acid, aminopterin and methotrexate.

The xanthine oxidase catalyzed oxidation of hypoxanthine was followed by monitoring the formation of uric acid at 290 nm. Inhibition of xanthine oxidase occurs in aqueous solutions of folic acid methotrexate and aminopterin. These compounds are known to dissociate upon exposure to ultraviolet light resulting in the formation of their respective 6-formylpteridine derivatives. The relative rates of dissociation were monitored spectrophotometrically by determining the absorbance of their 2,4-dinitrophenylhydrazine derivatives at 500 nm. When aqueous solutions of folic acid, aminopterin and methotrexate were exposed to uv light, a direct correlation was observed between the concentrations of the 6-formylpteridine derivatives existing in solution and the ability of these solutions to inhibit xanthine oxidase. The relative potency of the respective photolysis products were estimated.

Aminopterin↗
PubMed1990

Toxic dermatitis induced by 10-ethyl-10-deaza-aminopterin (10-EdAM), a novel antifolate.

A new methotrexate analog, 10-ethyl-10-deaza-aminopterin (10-EdAM), was found to induce a particular form of skin toxicity different than the skin rash reported to result from methotrexate. At histologic examination, it was found to be a toxic dermatitis that clinically most often first appears on the lower legs but can occur anywhere in the body, especially if treatment is continued. Nine cases are reported. A specific risk factor could not yet be identified. Discontinuation of 10-EdAM administration leads to complete healing; concomitant corticosteroid treatment also induces healing.

Aged↗
PubMed1993

Pharmacokinetics of 10-ethyl-10-deaza-aminopterin, edatrexate, given weekly for non-small-cell lung cancer.

We studied the pharmacokinetics of 10-ethyl-10-deaza-aminopterin (10-EdAM), edatrexate and its 7-hydroxy metabolite during a phase II trial of treatment in advanced non-small-cell lung cancer. A dose of 80 mg/m2 was given weekly, with dose reduction being undertaken for mucositis or haematological toxicity. A triphasic pattern of plasma elimination was seen, the mean half-lives being 0.10 +/- 0.07, 0.8 +/- 0.3 and 7 +/- 7 h, respectively. The mean plasma clearance was 25 +/- 14 l/h, with 18% +/- 11% of the dose appearing unchanged in the urine. The serum concentration at 1 h accurately predicted the area under the curve (AUC) with r2 = 0.976. There was considerable variation of the clearance both within and between patients but there was no evidence of a dependence on time or dose. The 1-h concentration of the drug was shown to be related to the incidence of toxicity requiring dose reduction. The change in WBC due to the initial dose was shown to be related to both the AUC of the drug and that of its 7-OH metabolite.

Aminopterin↗
PubMed1994

Reduction in the toxicity of aminopterin--monoclonal-antibody conjugates by leucovorin.

Although aminopterin(AMN)-antibody drug conjugates have been demonstrated to have a greatly increased antitumor efficacy compared to the free drug, their use is limited by an increase in systemic toxicity manifested by weight loss and bone marrow suppression. Using a murine thymoma model (E3) in inbred mice, the toxicity of a sublethal dose of free AMN could be prevented by the administration of leucovorin 24 h following drug treatment, whilst maintaining the antitumour effect of the drug. The same rescue protocol completely abrogated the antitumour efficacy of AMN-antibody, although toxicity was also diminished. However, the later administration of leucovorin 48-72 h following a sublethal dose of AMN-antibody conjugates resulted in a maintenance of the anti-tumour efficacy of the immunoconjugates and a reduction in toxicity, with a mean percentage change in mouse weight not significantly different from that of the controls. These studies demonstrate that reversal of toxicity caused by AMN-antibody conjugates can be achieved by leucovorin while maintaining a powerful antitumour effect provided that the dose of leucovorin is administered 48-72 h after the conjugate.

Aminopterin↗
PubMed1986

Methotrexate analogues-27. Dual inhibition of dihydrofolate reductase and folylpolyglutamate synthetase by methotrexate and aminopterin analogues with a gamma-phosphonate group in the side chain.

gamma-Phosphonate analogues of methotrexate (MTX) and aminopterin (AMT) were synthesized from 4-amino-4-deoxy-N10-methylpteroic acid and 4-amino-4-deoxy-N10-formylpteroic acid, respectively, by reaction with methyl D,L-2-amino-4-phosphonobutyrate followed by gentle alkaline hydrolysis. The products were compared with the corresponding D,L-homocysteic acid derivatives as inhibitors of dihydrofolate reductase and folylpolyglutamate synthetase, and as inhibitors of cell growth in culture. The gamma-phosphonates were somewhat less active than either the gamma-sulfonates or the parent drugs as inhibitors of murine dihydrofolate reductase. The MTX gamma-sulfonate and gamma-phosphonate analogues were equally inhibitory toward mouse liver folylpolyglutamate synthetase (Ki = 190 microM), but in the AMT series the gamma-phosphonate (Ki = 8.4 microM) was more potent than the gamma-sulfonate (Ki = 45 microM). The AMT analogues were consistently more inhibitory than the MTX analogues against cultured L1210 murine leukemia cells, but neither the gamma-phosphonates nor the gamma-sulfonates were as potent as their respective parent drugs. The gamma-phosphonate analogue of MTX was three times more potent than MTX against the MTX-resistant mutant line L1210/R81, but the AMT gamma-phosphonate was less potent than AMT; however, these differences were small in comparison with the level of resistance to all these compounds in the L1210/R81 line. The results suggest that N10-methyl and N10-unsubstituted compounds altered at the gamma-position do not necessarily follow identical structure-activity patterns in every test system.

Aminopterin↗
PubMed1976

Critical periods of the mitotic cycle: influence of aminopterin and thymidine on production of chromosomal aberrations by radiation in Crepis capillaris.

The influence of aminopterin (AP), tritiated thymidine ([3H] TdR) and "cold" thymidine (TdR) on production of chromosomal aberrations in meristematic cells of Crepis capillaris irradiated in different stages of the mitotic cycle with 300 rad of 63Co gamma-rays was studied. All the chemical treatments increased most of all the frequency of aberrations induced during two "critical periods" localized before the stage of DNA synthesis (fixation 9 h after irradiation) and before that of mitosis (4 h). Treatments with TdR and [3H]TdR increased most of all the frequency of chromatid aberrations when irradiation was performed in G1, and the frequency of gaps when irradiated in G2. Treatment with AP increased the yield of different types of aberration more uniformly. The modifying effect of the chemicals tested appeared to be independent of replicative synthesis. The "critical periods" are suggested to be the stages when regular "proof reading" and correction of spontaneous errors takes place [9,13]. In addition to this regular mechanism, radiation induces an "emergency" mechanism of repair. AP inhibits the mechanism of regular repair; in addition TdR and [3H] TdR suppress the lateral spread of primary injuries across the chromosome.

Aminopterin↗
PubMed1984

Recovery of V79 cell clones with different phenotypes in aminopterin- or azaserine-containing media used for the selection of HGPRT revertants.

Three 6-thioguanine (6TG)-resistant mutants were mutagen-treated and selected for clones capable of growing in 2 selective media: HAT medium, containing aminopterin (AP) and HAS medium, containing L-azaserine (AS). Both 6TG-sensitive, wild-type clones and 6TG-resistant mutants were found among colonies growing in HAT medium, while only 6TG-sensitive clones grew in HAS medium. Time for expression was required by 6TG-resistant but not by 6TG-sensitive clones, that were fully expressed immediately after treatment. All HAT-resistant, 6TG-resistant clones which were analyzed proved to be resistant to AP. These data were interpreted as follows: in HAT medium, both HGPRT+ revertants and double mutants (HGPRT-, AP-resistant) were selected, while only HGPRT+ revertants were selected in HAS medium. Not all 6TG-resistant mutants were able to produce both classes of HAT-resistant clones.

Aminopterin↗
PubMed1988

Substrate specificity of mammalian folylpoly-gamma-glutamate synthetase for 5,8-dideazafolates and 5,8-dideaza analogues of aminopterin.

The substrate specificity of pig liver folylpolyglutamate synthetase (tetrahydrofolate:L-glutamate gamma-ligase (ADP-forming), EC 6.3.2.17) for classical 5,8-dideaza analogues of folic acid, isofolic acid aminopterin and isoaminopterin has been investigated. 5,8-Dideazafolate and 5,8-dideazaaminopterin are very effective substrates with activities approaching those of the best reduced folate substrates. The analogous isofolate analogues are less effective substrates, but still better than folic acid. The 5-chloro substituent is the only modification that consistently increases the on rate, with 5-chloro-5,8-dideazaaminopterin being the most effective substrate found, thus far, for the enzyme. Methylation at positions 9 or 10 generally decreases binding, while 5-methylation increases the binding of 4-oxoquinazolines, but decreases the binding of their 4-amino counterparts. The presence of a formyl group at N9 or N10 has the opposite effect, decreasing the binding of 4-oxo analogues while increasing the rate for 4-amino derivatives. Increases in on rate with methyl, formyl or 4-amino substitutions are only significant when the parent compound is a poor substrate, suggesting that these groups do not interact directly with the enzyme but cause conformational changes in the structure of the substrate that influence binding to the enzyme.

Adenosine Triphosphate↗
PubMed2003

Further studies on the interaction of nonpolyglutamatable aminopterin analogs with dihydrofolate reductase and the reduced folate carrier as determinants of in vitro antitumor activity.

Thirteen structural analogs of the potent nonpolyglutamatable dihydrofolate reductase inhibitor N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, the para-aminobenzoyl moiety, or the 9,10-bridge were evaluated for the ability to inhibit human recombinant dihydrofolate reductase (DHFR), to utilize the reduced folate carrier (RFC) for influx, and to inhibit the growth of CCRF-CEM human leukemia cells in culture. In spectrophotometric assays of the kinetics of the reduction of dihydrofolate by DHFR in the presence of NADPH, these compounds had K(i) values ranging from 0.2 to 1.3pM, and thus were not greatly different in potency from the parent drug PT523. By comparison, the K(i) values of aminopterin (AMT), methotrexate (MTX), and 10-ethyl-10-deazaaminopterin (EDX) were 3.7, 4.8, and 11pM. In assays of competitive inhibition of [3H]MTX influx into CCRF-CEM cells, the K(i) values ranged from 0.21 to 7.3 micro M, as compared with 0.71, 5.4, and 1.1 micro M for PT523, AMT, and EDX. The K(t) for MTX was also re-analyzed and found to be 4.7 micro M, in better agreement with the literature than our previously reported value of 7.1 micro M. The IC(50) values of these compounds as inhibitors of the growth of CCRF-CEM cells after 72hr of drug exposure ranged from 0.53 to 55nM, and were qualitatively consistent with the other results.

Amino Acids↗
PubMed1977

The effect of aminopterin-induced folic acid deficiency on spermatogenesis.

Folic acid deficiency was produced by injecting aminopterin into adult male albino rats, resulting in inhibition of spermatogenesis. Bone marrow smears were studied to serve as an index of folic acid deficiency; however, changes in spermatogenesis were noticed earlier than the bone marrow changes. Meiotic division was affected more than mitotic division. The nuclei of spermatogenic cells showed degenerative changes. Chromosomal abnormalities, chiefly sticky chromosomes, were noticed in squashed preparations of seminiferous tubules.

Aminopterin↗
PubMed2001

Synthesis and antifolate evaluation of the aminopterin analogue with a bicyclo.

N-[4-[[2,4-diamino-6-pteridinyl)methyl]amino]bicyclo[2.2.2]octane-1-carbonyl]-L-glutamic acid (1) was synthesized and tested for antifolate activity. N-(4-Aminobicyclo[2.2.2]octane-1-carbonyl-L-glutamic acid dimethyl ester (6), the side chain precursor to subject compound 1, was synthesized readily via reported bicyclo[2.2.2]octane-1,4-dicarboxylic acid monoethyl ester (2). The side chain precursor 6 was alkylated by 6-(bromomethyl)-2,4-pteridinediamine (7). Subsequent ester hydrolysis then afforded 1. Antifolate and antitumor evaluation of 1 verses L1210 dihydrofolate reductase (DHFR) and three tumor cell lines (L1210, S180, and HL60) showed it to be ineffective. Although compound 1 was very similar to aminopterin structurally, the bicyclo[2.2.2]octane ring system in place of the phenyl ring in the p-aminobenzoate moiety effectively negates the stoichiometric binding displayed by many classical DHFR inhibitors bearing appropriate aromatic ring systems in the side chain.

Aminopterin↗