Disease relevance of EDATREXATE

• Toxicity, elimination, and metabolism of 10-ethyl-10-deazaaminopterin in rats and dogs [1].
• Phase II study of weekly edatrexate as first-line chemotherapy for metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group study [2].
• Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: a European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study [3].
• PURPOSE: To compared the response rates and the toxicity of the new antifolate edatrexate (EDX) with that of methotrexate (MTX) in a randomized trial in patients with metastatic or recurrent squamous cell cancer of the head and neck (SCC) and to compare the durations of response and survival [3].
• The antifolate edatrexate has shown moderate activity against cancers of the head and neck and non-small cell lung cancer, as has cisplatin [4].

High impact information on EDATREXATE

• A modest bystander effect was observed with edatrexate treatment in culture and in vivo [5].
• Schedule-dependent edatrexate toxicity [6].
• The antifolates used were either inhibitors of dihydrofolate reductase, including methotrexate (MTX) and 10-ethyl-10-deazaaminopterin (10-EdAM), or two folate-based inhibitors of thymidylate synthase, N10-propargyl-5,8-dideazafolic acid (CB3717) and 2-deamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI-198,583) [7].
• In these cells we observed the up regulation of a membrane-associated folate-binding protein with high affinities for folic acid and reduced folates, but poor affinities for the folate antagonists MTX and 10-ethyl-10-deazaaminopterin [8].
• Lower levels of FPGS activity in cell-free extract from these variants using EDX as substrate were characterized by the same relative decrease in value for Vmax with no change in apparent Km [9].

Chemical compound and disease context of EDATREXATE

• In vitro studies documented 25-30-fold and 3-fold, respectively, greater cytotoxic potency of PDX compared with methotrexate and another 10-deazaaminopterin, edatrexate, against VAMT-1 and JMN cell lines derived from human mesothelioma [10].
• Phase I trial of edatrexate plus carboplatin in advanced solid tumors: amelioration of dose-limiting mucositis by ice chip cryotherapy [11].
• Phase II study of carboplatin and edatrexate (10-EdAM) with leucovorin rescue for patients with recurrent squamous cell carcinoma of the head and neck [12].
• Antifolates, specifically MTX and edatrexate, are among a growing class of chemotherapeutic agents that require assiduous and rapid monitoring to help prevent severe systemic toxicity [13].
• The authors treated 32 patients with Stage IIIB or IV non-small cell lung cancer (NSCLC) with an outpatient regimen of edatrexate (10-ethyl-10-deaza-aminopterin) (10-EdAM) on days 1 and 8, cyclophosphamide on day 1, and cisplatin on day 1, repeated every 3 weeks with dose modification [14].

Biological context of EDATREXATE

• On schedule B, the maximum tolerated dose of biweekly edatrexate was 80 mg/m2, with leukopenia and mucositis as dose limiting [4].
• Steric limitations thwarted plans to prepare the naphthalene analogue of 10-ethyl-10-deazaaminopterin; attempted alkylations of 2-(4-carboxy-1-naphthyl)butyric acid dimethyl ester with 1a failed as did attempted further alkylation (by EtBr) of the product derived from 1a and 2 [15].
• The inhibitory concentration producing 50% absorbance (IC50 for edatrexate with 1 h exposure was 1.4 microM [16].
• Pharmacokinetics of 10-ethyl-10-deaza-aminopterin, edatrexate, given weekly for non-small-cell lung cancer [17].
• The objective of this study was to determine the effect of vehicles and penetration enhancers on the percutaneous absorption of MTX and its analog edatrexate (EDAM), and develop transdermal (TD) delivery systems of the drugs for the treatment of RA [18].

Anatomical context of EDATREXATE

• Growth inhibition tests against three tumor cell lines (L1210, S180, and HL60) showed 9a to be 4-6-fold more inhibitory than methotrexate but not as inhibitory as 10-ethyl-10-deazaaminopterin; 9b and 9c were no more inhibitory than MTX [15].
• Phase II trial of edatrexate in relapsed or refractory germ cell tumors: a Southwest Oncology Group study (SWOG 9124) [19].
• We conducted a phase II evaluation of edatrexate in 17 previously untreated patients with advanced adenocarcinoma of the pancreas; 14 patients had at least one month of therapy [20].
• We have examined the cytotoxic activities of edatrexate (EDX) and methotrexate (MTX) and their reversal by leucovorin in nine human cancer cell lines and in human bone marrow CFU-GM cells [21].
• Cytotoxicity studies combining edatrexate (EDX) and cisplatin (Cis-Pt) were carried out in HL-60 cells in vitro as a retrospective analysis of the same combination in animal models and as a prospective study of this combination for future clinical trials [22].

Associations of EDATREXATE with other chemical compounds

• Against the JMN tumor xenografted in nude mice, whereas methotrexate and, more so, edatrexate, were potently growth inhibitory, only PDX brought about substantial regression [10].
• The novel antifolates include a polyglutamatable [edatrexate (EDX)] and a lipophilic (trimetrexate) inhibitor of dihydrofolate reductase and two polyglutamatable inhibitors (ZD1694 and GW1843U89) and one lipophilic inhibitor (AG337) of thymidylate synthase (TS) [23].
• They include the taxanes (taxol and taxotere), camptothecin analogues (CPT-11 and topotecan), antimetabolites (edatrexate and gemcitabine) and the vinca alkaloid, navelbine [24].
• Although both treatments resulted in a reduced IC50 vs. carboplatin alone, the reduction was much greater when edatrexate was added first (12.59 vs. 2.59 times) [25].
• No prior chemotherapy had been used in 17 patients; 10 patients had had prior doxorubicin-based therapy; and 1 patient had had intraperitoneal therapy with edatrexate [26].

Gene context of EDATREXATE

• Phase II trial of edatrexate in patients with advanced hepatocellular carcinoma [27].
• Although CEM/MTX cells were highly resistant (162- to 300-fold) to assorted antifolate substrates for the classical transporter, including methotrexate, aminopterin, 10-ethyl-10-deazaaminopterin, ICI D1694, and 1843U89, they were only 3.6-fold resistant to (6R)-5,10-dideaza-5,6,7,8-tetrahydrofolate (DDATHF) [28].
• Due to the potential broad spectrum of activity of edatrexate plus CDDP, further studies are warranted to determine the mechanism responsible for the synergism and to investigate this combination in a variety of tumor models [16].
• In contrast, PDX was even more active (75-85% complete regressions and 25-30% cures) than EDX against the MX-1 and LX-1 tumors and highly active (30% complete regressions and 20% cures) against the A549 tumor [29].
• With no objective evidence for antitumor activity as assessed by post-therapy PSA changes in any of the patients treated, edatrexate seems a poor candidate for future study [30].

Analytical, diagnostic and therapeutic context of EDATREXATE

• Serum edatrexate levels measured using a dihydrofolate reductase inhibition assay correlated with those by high-performance liquid chromatography [31].
• In a phase II trial, 12 patients with metastatic colorectal cancer and no prior chemotherapy were treated with Edatrexate 80 mg/m2/week for an initial period of 8 weeks [32].
• 3) An edatrexate dose of 110 mg/m2 with ice chip cryotherapy is recommended for Phase II trials of this combination [11].
• BACKGROUND: The methotrexate analogue edatrexate (10-ethyl-10-deaza-aminopterin, or 10-EDAM) has demonstrated greater activity than methotrexate has against murine tumors and human tumor xenografts [27].
• A phase II study with edatrexate produced a response rate of 32% but subsequent trials using combination chemotherapy including this agent have been disappointing [24].

References