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PubMed1992

A phase II trial of 10-ethyl-10-deaza-aminopterin, a novel antifolate, in patients with advanced and/or recurrent squamous cell carcinoma of the head and neck. The EORTC Head and Neck Cancer Cooperative Group.

Forty-seven patients with advanced and/or recurrent squamous cell carcinoma of the head and neck were treated with 10-ethyl-10-deaza-aminopterin (10-EdAM), a new analogue of methotrexate. The drug was given as a weekly i.v. bolus injection, starting at 80 mg/m2 with two dose increments of 10% if no toxicity was observed after two weeks. Only patients with tumors of the larynx, oral cavity, oropharynx and hypopharynx were included in the trial. Eighty-two percent of the patients had had prior surgery and/or radiotherapy. Forty-four patients were evaluable for response and toxicity. Five CR (12%) and five PR were obtained, yielding a response rate of 24% (CR+PR). The toxicity was similar to that usually seen with methotrexate; stomatitis and skin toxicity were rather pronounced. The data suggest that 10-EdAM has activity similar to that of methotrexate in patients with head and neck cancer.

Adult↗
PubMed2002

Efficacy and tolerability of an aminopterin-albumin conjugate in tumor-bearing rats.

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.

Aminopterin↗
PubMed2006

Methotrexate-albumin and aminopterin-albumin effectively prevent experimental acute graft-versus-host disease.

BACKGROUND: During the last several years, major progress has been made in developing targeted chemotherapy using cytotoxic drugs covalently bound to human serum albumin (HSA). We explored the activity of two antifolates methotrexate (MTX) and aminopterin (AMPT) bound to HSA in prophylaxis and treatment of experimental acute graft-versus-host disease (aGVHD). METHODS: In all, 113 female F1 hybrid BN/Lew-rats were irradiated with 8.2 Gy (n=103) or 9.9 Gy (n=10). One day after irradiation each rat received 4 x 10 bone marrow cells and 1.5 x 10 spleen T-cells from female Lew-rats. GVHD prophylaxis consisted of MTX-HSA 2 mg/kg (n=25), MTX-HSA 0.5 mg/kg (n=8), AMPT-HSA 0.65 mg/kg (n=8), MTX 0.5 mg/kg (n=17), or native HSA (n=39) given intraperitoneally (IP) on days 0, 4, 8, and 12. Treatment of aGVHD consisted of MTX-HSA 2 mg/kg (n=8) or AMPT-HSA 0.5 mg/kg (n=8) given intraperitoneally at the time of onset of aGVHD and subsequently every fourth day (a total of four doses). RESULTS: All animals receiving native HSA developed lethal aGVHD. Prophylactic treatment with MTX-HSA 2 mg/kg prevented aGVHD in 18 of 25 animals and in 6 of 8 receiving AMPT-HSA. In contrast, five out of nine rats receiving free MTX died due to aGVHD. The survival rates in the prophylactic MTX-HSA 2 mg/kg and AMPT-HSA groups were significantly higher compared to the MTX and control groups (P<0.05), while non hematologic toxicity of MTX-HSA was not detectable. AMPT-HSA at a dose of 0.65 mg/kg as well as MTX at a dose of 0.5 mg/kg were associated with temporary weight loss and lethargy. CONCLUSIONS: The albumin conjugates MTX-HSA and AMPT-HSA effectively prevent experimental aGVHD.

Acute Disease↗
PubMed1988

Phase II study of 10-ethyl-10-deaza-aminopterin in patients with stage III and IV non-small-cell lung cancer.

10-ethyl-10-deaza-aminopterin (10-EDAM) is an analog of methotrexate that differs from its compound by modification of the N10 position and demonstrates greater preclinical antitumor activity and less toxicity. In this phase II trial, 20 patients with stage III or IV non-small-cell lung cancer (NSCLC) were administered 10-EDAM at a dose of 80 mg/m2 once weekly for 5 weeks. No patient had previously received chemotherapy. Nineteen of the 20 patients were adequately treated for response assessment. Six of 19 patients (32%) experienced a major objective response (exact 95% confidence limits, 15% to 55%). The median duration of response has not been reached and will exceed 13 months. Mucositis was the most common toxicity observed. Leukopenia was seen in only 10%, and 15% had platelet nadirs less than 100,000/microL. At the dosage and schedule used, 10-EDAM is an active agent in patients with NSCLC who are previously untreated with chemotherapy with a predicted response rate greater than or equal to 15% (P = .05). Because of its level of antitumor activity and the fact that 10-EDAM causes minimal myelosuppression, it is a suitable agent for further study in combination with other chemotherapeutic agents in this disease.

Aged↗
PubMed1998

Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies.

PURPOSE: Aminopterin (AMT) is a potent folate analog that is no longer in routine clinical use. Because of laboratory data that suggests improved metabolism of AMT versus methotrexate (MTX) in lymphoblasts, we developed a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of AMT. PATIENTS AND METHODS: Twenty patients with refractory malignancies were treated. The starting dose of AMT was 2.5 mg/m2 every 12 hours for two doses weekly: the dose of AMT was decreased and leucovorin (LV) rescue was added after the DLT was observed. Pharmacokinetics were performed after both intravenous (i.v.) and oral AMT administration. RESULTS: Mucosal toxicity was dose-limiting and resulted in the need for a dose reduction (dose level 2: AMT 2 mg/m2 every 12 hours for two doses weekly) and, subsequently, the addition of scheduled LV rescue (dose level 3: AMT 2 mg/m2 every 12 hours for two doses followed by LV 5 mg/m2 orally every 12 hours for two doses, starting 24 hours after the second dose of AMT). The mean areas under the curve (AUC) for the i.v. (n = 14) and oral (n = 13) doses were 1.20 +/- 0.09 (SE) and 1.05 +/- 0.14 micromol x h/L respectively. The half-life was 3.64 +/- 0.28 hours and the oral bioavailability in 12 matched subjects was 83.5% +/- 8.3%. One patient with endometrial adenocarcinoma achieved a complete response (CR) and remains on therapy at 11+ months. Seven patients had stable disease (SD) for 8 weeks or greater, which included one patient with a metastatic nerve sheath tumor who was stable for 9 months. CONCLUSION: We conclude that AMT has good oral bioavailability and that, when given on a q12 hour x two weekly schedule, the MTD is 2 mg/m2 with delayed LV rescue.

Administration, Oral↗
PubMed1999

PT523 and other aminopterin analogs with a hemiphthaloyl-L-ornithine side chain: exceptionally tight-binding inhibitors of dihydrofolate reductase which are transported by the reduced folate carrier but cannot form polyglutamates.

Nonpolyglutamatable antifolates are potentially of therapeutic interest for the treatment of tumors that are inherently refractory, or have become resistant, to classical antifolates as a result of decreased expression of the enzyme folylpolyglutamate synthetase. An interesting class of water-soluble nonpolyglutamatable analogs of aminopterin (AMT) have been developed, which are much more cytotoxic because they bind more tightly to dihydrofolate reductase (DHFR) and also utilize the reduced folate carrier (RFC) pathway more efficiently for influx into the cell. This review summarizes the in vitro and in vivo preclinical data on the initial lead compound, Nalpha-(4-amino-4-deoxypteroyl)-Ndelta- hemiphthaloyl-L-ornithine (PT523). In addition, the synthesis and in vitro biochemical and biological properties of several types of second-generation analogs are discussed. Analogs modified in the B-ring of the pteridine moiety have been found to be of particular interest because their affinity for DHFR and their influx rate into cells via the RFC pathway are even greater than those of PT523. The hemiphthaloylornithine moiety, which is larger and more hydrophobic than the glutamate side chain of classical antifolates, appears to be chiefly responsible for the exceptionally high biological potency of PT523 and its B-ring analogs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1977

The natural history of aminopterin-induced embryopathy.

A boy whose mother ingested aminopterin to induce abortion and who has the characteristic anomalies caused by fetal exposure to this drug, has been followed for 12.75 yr. Despite short stature, his growth velocity is normal, and both normal endocrine studies and a radiologic bone age, retarded consistently between 2.25 and 3.0 yr, allow a predicted adult height of over 150 cm. Intelligence testing has shown a rise in full scale IQ on the Wechsler Intelligence Scale from 64 to 80 with performance increasing from 70 to 92. Psychologic assessment suggests potential for self-support in adult years.

Abnormalities, Drug-Induced↗
PubMed1990

Biochemical and growth inhibition studies of methotrexate and aminopterin analogues containing a tetrazole ring in place of the gamma-carboxyl group.

The biological activities of novel analogues of methotrexate (MTX) and aminopterin (AMT) in which the gamma-carboxyl was replaced by a 1H-tetrazol-5-yl ring, an isosteric group with acidic properties similar to a carboxyl group, were investigated. The tetrazolyl analogues of MTX and AMT were more potent inhibitors of the growth of CCRF-CEM and K562 human leukemia cell lines during continuous (120 h) and 24-h pulse exposure than were the respective parent drugs; only when the exposure time was reduced to 6 h were the parent drugs more potent. These inhibitory effects on growth correlated with the onset of and recovery from inhibition of de novo thymidylate biosynthesis. Growth inhibition by the analogues was protectable by leucovorin. MTX-resistant CCRF-CEM sublines with decreased transport or increased dihydrofolate reductase (DHFR) levels were cross-resistant to the analogues. The analogues were as potent as their parent drugs in inhibiting DHFR activity in vitro and at displacing [3H]MTX from intracellular DHFR. Each analogue was more effective than its parent drug at inhibiting uptake of [3H]MTX into CCRF-CEM cells. The tetrazole analogue of AMT was a linear competitive inhibitor (Kis = 50 microM) of CCRF-CEM folylpolyglutamate synthetase, while the tetrazole analogue of MTX, unlike all other inhibitors, was linear noncompetitive (Kis = 51 microM, Kii = 321 microM). The data suggest that, compared with MTX or AMT, the tetrazole substituent, in place of the gamma-carboxyl group, allows more efficient transport into cells via the reduced folate/MTX carrier and the resulting greater uptake of the analogues leads to inhibition of DNA synthesis and cell death at lower extracellular concentrations during long exposures. The mechanism of cell death could involve inhibition at folypolyglutamate synthetase, but DHFR is the primary target. The low potency of the analogues during short exposure is presumably related to the inability to form the poly-gamma-glutamyl metabolites required for intracellular retention.

Aminopterin↗
PubMed1990

Effect of tumor necrosis factor on the antitumor efficacy and toxicity of aminopterin-monoclonal antibody conjugates: parameters for optimization of therapy.

Immunoconjugates of monoclonal antibodies with drugs, isotopes, or toxins are currently being investigated for their therapeutic effect on tumors. However, all have problems of access of the immunoconjugate to the tumor, particularly with solid tumors. To address this problem, we have used aminopterin-monoclonal antibody (AMN-mAb) conjugates combines with murine tumor necrosis factor (mTNF-alpha), which is known to have specific effects on tumor vasculature. In a murine model, well-established tumors (measuring 1.0-1.4 cm in diameter) were either totally eradicated or considerably reduced in size with combined therapy--a greater effect than with either mTNF-alpha or AMN-mAb used alone. The mechanisms involved in the improved antitumor effect were investigated using in vitro assays, autoradiography, and biodistribution experiments. mTNF-alpha was found both to increase the cytotoxic activity of the conjugate in vitro and to increase in vivo tumor localization of mAb up to 5-fold. The timing of mTNF-alpha administration was crucial to effects on tumor localization; mTNF-alpha given with mAb caused the greatest increase in localization and mTNF-alpha given well before mAb decreased localization. mTNF-alpha also reduced the toxicity to mice of AMN-mAb depending on the timing of injection. These results indicate that mTNF-alpha has a useful role in potentiation of immunoconjugate therapy but shows the need for careful planning of the dose regimen.

Aminopterin↗
PubMed1987

10-Ethyl-10-deaza-aminopterin: structural design and biochemical, pharmacologic, and antitumor properties.

The new folate analog 10-ethyl-10-deaza-aminopterin (10EdAM) was equivalent to methotrexate (MTX) as an inhibitor of dihydrofolate reductase, but was more effectively transported and polyglutamylated in most tumor cells. Also, the transport and polyglutamylation of 10EdAM in tumor cells vis-a-vis normal proliferative tissue is substantially increased compared to MTX, favoring much greater accumulation of 10EdAM as cytotoxic polyglutamates in some of these tumor cells. 10EdAM was superior to MTX against 4 of 6 murine ascites tumors (L1210, S180, Ehrlich and Tapper) and far superior against 4 of 6 solid murine tumors (S180, Tapper, E0771 mammary AC, T241 fibrosarcoma). 10EdAM produced 10% to 30% complete regressions against S180, E0771 and T241 tumors. Both agents showed similar activity against P288 and 1498c leukemias and the Lewis lung tumor, but were inactive against B16 melanoma. Marked superiority of 10EdAM compared to MTX was also shown against the following human tumor xenografts: MX-1 (mammary carcinoma), LX-1 (small cell lung carcinoma) and CX-1 (colon carcinoma). 10EdAM produced 30% to 40% complete regressions against the MX-1 tumor.

Aminopterin↗
PubMed1988

Cytotoxicity, uptake, polyglutamate formation, and antileukemic effects of 8-deaza analogues of methotrexate and aminopterin in mice.

In contrast to methotrexate (MTX) and aminopterin (AMT), the 8-deaza analogues of these antifolates are not substrates for rabbit liver aldehyde oxidase. Since they are not converted to 7-hydroxy derivatives, they have been investigated with regard to their cytotoxicity for CCRF-CEM cells, transport into these cells, and conversion to polyglutamate forms. For this purpose 3H-labeled analogues were synthesized. The drug concentrations of the analogues required to inhibit cell growth by 50% are significantly lower than for the parent compounds particularly for a short exposure of cells to the drug. Vmax and Km for unidirectional influx do not differ greatly among the four drugs, but amounts of uptake over 1 h are markedly different and increase in the order MTX less than 8-deazaMTX less than AMT less than 8-deazaAMT. During 1 h of uptake a much greater proportion of the 8-deaza analogues is converted to polyglutamate forms than in the case of parent drugs. Only 52% of MTX is converted to polyglutamates, whereas in the case of the other three compounds the conversion is greater than or equal to 90%. However, MTX is relatively efficient in adding two glutamate residues, whereas the other drugs predominantly accumulate as forms with only one additional glutamate (+Glu1). During 1 h of efflux the drugs without additional glutamates decrease to low concentrations and there is also a major loss of +Glu1 form, but there is also an increase in longer chain forms, especially in the case of MTX. The net result is a still greater disparity in total intracellular levels of the four drugs after the period of efflux. MTX has much lower toxicity in mice in vivo than the other three compounds, 8-deazaAMT being the most toxic. At the maximum tolerated dose MTX produced a considerably greater increase in life span for mice bearing P388 than any of the other drugs, and a somewhat greater increase for mice bearing L1210. Thus the 8-deaza analogues do not offer a therapeutic advantage over MTX against leukemias in the mouse, primarily due to their much greater toxicity.

Aminopterin↗
PubMedDate not supplied

Activity of the folate analog 10-ethyl, 10-deaza-aminopterin (10-EdAM) against human head and neck cancer xenografts.

In a previous study we established a markedly increased antitumour activity of 10-ethyl, 10-deaza-aminopterin (10-EdAM) as compared to methotrexate (MTX) when tested in vitro in squamous cell carcinoma cell lines from the head and neck (HNSCC). In this paper we describe the antitumour activity of these drugs in vivo in athymic nude mice bearing HNSCC xenografts. Using a schedule of 125 mg/kg i.p. for both drugs, injected on day 0 and 7, 10-EdAM caused a significant response in 2 out of 5 tumour lines, whereas MTX was completely inactive. These two lines moderately sensitive to 10-EdAM were not affected when the drug was given daily times 5 at an equitoxic dose of 0.75 mg/kg, indicating that the effect of the drug may be schedule dependent.

Aminopterin↗
PubMed1987

Synthesis and biologic activity of new side-chain-altered methotrexate and aminopterin analogs with dual inhibitory action against dihydrofolate reductase and folylpolyglutamate synthetase.

Replacement of the glutamic acid (Glu) moiety in methotrexate (MTX) and aminopterin (AMT) by 2-amino-4-phosphonobutyric acid (APBA) and ornithine (Orn) has been found to give analogs that retain the ability to inhibit dihydrofolate reductase (DHFR) while also displaying high activity against folylpolyglutamate synthetase (FPGS). One of these compounds, the Orn analog of AMT, is the most potent FPGS inhibitor we have found to date. A model to account for the fact that side-chain analogs containing a basic and those containing an acidic terminal group can both competitively inhibit FPGS is proposed. According to this model, binding may involve interaction of an acidic terminal group on the inhibitor with a positively charged active-site residue to which the gamma-carboxyl of the folate-antifolate substrate normally binds. It may also involve the interaction of a basic terminal group on the inhibitor with a different active-site residue which is negatively rather than positively charged and to which the alpha-amino group of the incoming Glu cosubstrate must bind before an amide bond to the gamma-carboxyl of the folate-antifolate can form. The 2 oppositely charged active-site residues assumed to take part in this binding are probably situated near each other and at approximately the same distance from the pteridine-binding site. The ability of compounds to inhibit both DHFR and FPGS makes it possible in principle for such compounds to kill cells via a "self-potentiation" mechanism in which inhibition of tetrahydrofolate synthesis is complemented by interference with the subsequent conversion of tetrahydrofolates to their polyglutamate conjugates. Possible exploitation of this mechanism to overcome MTX resistance is considered.

Aminobutyrates↗
PubMedDate not supplied

Combination chemotherapy with a new folate analog: activity of 10-ethyl-10-deaza-aminopterin compared to methotrexate with 5-fluorouracil and alkylating agents against advanced metastatic disease in murine tumor models.

A new folate analog, 10-ethyl-10-deaza-aminopterin (10EDAM), was compared to methotrexate (MTX) in combination with 5-fluorouracil (5-FU) and/or alkylating agents against three models of advanced metastatic (E0771 mammary adenocarcinoma and T241 fibrosarcoma) or disseminated (L1210 leukemia) disease in BD2F1 mice. Of all the agents examined on a schedule of every 3 days X 3, 10EDAM and cyclophosphamide (CPA) were the most active overall against the tumor models employed. Against the E0771 tumor, antitumor potency was in the descending order of CPA, 10EDAM, cisplatin (Cis Pt), melphalan (L-PAM), MTX, and 5-FU. Similar ranking in relative potency was also derived with the T241 tumor. Against both of these models, MTX and 5-FU were only minimally active. Against the L1210 leukemia, 10EDAM was the most active agent followed in descending order by MTX, CPA, 5-FU, L-PAM, and Cis Pt. All two-drug combinations required attenuation to one-half the LD10 dosage for each. The results show that 10EDAM with CPA was the most effective combination employed in all three tumor models. Therapeutic activity was far greater than that obtained with each agent alone, with a substantial number of long-term survivors. 10EDAM was also highly active in combination with L-PAM and Cis Pt against the E0771 tumor and with Cis Pt against the L1210 leukemia. Some increase in therapeutic activity beyond that obtained with each agent alone, but to a substantially lesser extent, was documented for MTX and each of the three alkylating agents against the L1210 tumor. MTX with 5-FU was not an effective combination, but against the E0771 tumor gave therapeutic effects beyond that obtained with each agent alone when 5-FU was given 7 hours after MTX. Similar effects were seen with 10EDAM and 5-FU on these schedules, but 10EDAM alone was more effective than MTX and 5-FU given together against this tumor. A combination of either antifolate with 5-FU and CPA was ineffective against all three tumor models, in part because of the further attenuation of dosage required in this mouse strain and the minimal overall activity of 5-FU in these models. Results documented with 10EDAM and CPA and, perhaps, other alkylating agents are interpreted as indicative of therapeutic synergism between these agents. These results appear to suggest substantial potential for 10EDAM in clinically employed combination therapy currently including MTX.

Adenocarcinoma↗
PubMed1979

A Phase 1 study of high doses of aminopterin with leucovorin rescue in patients with advanced metastatic tumors.

We have conducted a Phase 1 study of aminopterin (AMT) with leucovorin (LV) in 17 patients. AMT was administered by bolus injection every 7 to 14 days in dosages from 25 to 425 mg/sq m. LV rescue was instituted at 24 hr and continued for 48 to 72 hr. At dosages above 50 mg/sq m, we observed nephrotoxicity defined as greater than or equal to a 25% increase in serum creatinine 24 hr after AMT administration, but its incidence was not strictly dose related. Urinary alkalinization and volume expansion appeared to reduce the incidence of nephrotoxicity. Nephrotoxic drug courses were associated with 24-hr plasma AMT levels [3.6 +/- 2.0 (S.D.) X 10(-6) M] which were significantly higher than nonnephrotoxic courses (1.6 +/- 1.0 x 10(-6) M) (p less than 0.05). In nonnephrotoxic courses, serum elimination pharmacokinetics appeared to be biphasic with a t1/2 alpha of 1.08 +/- 0.01 hr and t1/2 beta of 12.31 +/- 0.06 hr. Systemic toxicity (myelosuppression and mucositis) could be prevented in patients with impaired AMT clearance by the administration of LV at an increased dose rate. In several courses, systemic toxicity occurred in spite of apparently normal plasma clearance, suggesting that 24-hr plasma levels may not accurately reflect intracellular drug effects. Cytokinetic studies on bone marrow aspirates allowed determination of the rescue effect of LV and may prove useful in predicting marrow protection.

Aminopterin↗
PubMed1985

[Loss and stabilization of aminopterin resistance in murine cell lines].

Mouse L-cell lines (B-82, tk-) were obtained using the stepwise selection method, their aminopterin (AP) resistance being 10(3)-5 X 10(4) times higher than that of parental cells. This resistance increase results from dihydrofolate reductase (DHFR) gene amplification which was determined from the 15-120-fold rise of the enzyme activity and with the cytogenetical techniques. The development and loss of AP resistance have been studied and karyological analysis of the lines obtained carried out. Two types of karyological changes were found in stable DM and HSR cells which correspond to extrachromosomal and intrachromosomal forms of the amplified material organization. Localization of the DHFR gene in HSR was proved using the in situ hybridization technique. Extrachromosomal localization of the amplified genes in DM providing unstable AP resistance is dominant at the early stages of the development of resistance and for a long time. It was demonstrated that DM and HSR can exist in one cell during the prolonged period. DHFR gene copy number in such cells is regulated by a change in the DM number, whereas the HSR size and localization are highly stable. HSR covers 1.7-1.9% of the genome length and 38-40% of the marker chromosome length. The genes localized in HSR provide stable AP resistance. Evidence on some intermediate, relative stabilization of the resistance has been obtained. This stabilization is mediated by temporary integration of DHFR copies into other chromosomal sites, in addition to HSR.

Aminopterin↗