Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Edatrexate (10-ethyl, 10-deaza-aminopterin; 10-EdAM) is one of a group of compounds developed by substitutions at the N10-position of 4-aminofolate. In phase I and II trials, activity has been seen against non-small-cell lung cancer, breast cancer, non-Hodgkin's lymphoma, and cancer of the head and neck. In preclinical studies, a synergistic effect has been reported when edatrexate is combined with other antineoplastic drugs, and enhanced activity has been seen in two combination-chemotherapy phase II studies in patients with non-small-cell lung cancer. In in vivo preclinical studies, edatrexate has demonstrated antitumor activity against mouse solid and ascites tumors as well as human tumor xenografts. The activity is superior to that of methotrexate and the other antifolates tested. The improved therapeutic index of edatrexate appears to be related to its increased entry into, and polyglutamylation within, tumor cells, and its relative exclusion and rapid elimination from sensitive host tissues, compared to methotrexate. Edatrexate is metabolized in the liver and then excreted mainly in the bile. In clinical trials in cancer patients, the dose-limiting and most frequent toxicity is mucositis. Other side effects are generally mild and include myelosuppression, nausea, vomiting, elevations in SGOT, and macular rash. The responses seen in clinical trials along with preclinical data suggest that edatrexate may be a valuable agent in the treatment of cancer. Studies currently underway include the evaluation of edatrexate in small-cell lung cancer and edatrexate in combination with leucovorin, new vinca alkaloids, and cisplatin.
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PMID:Edatrexate, an antifolate with antitumor activity: a review. 842 95

Edatrexate (EDX) (10-ethyl-10-deazaaminopterin or 10-EDAM) is an analogue of methotrexate with improved pre-clinical antitumor activity, more selective cellular uptake, and with more extensive formation of intracellular polyglutamate metabolites. A phase I trial in advanced cancer using EDX was initiated to determine the toxicities associated with the use of a biweekly schedule of intravenous EDX, and to carry out a dose escalation to define the maximum tolerated dose employing this schedule. Thirty-four patients were enrolled in this phase I trial. Thirty-three patients were treated in cohorts of at least three patients (except at one dose level, 210 mg m-2, where there were only two patients). Dose escalations of EDX were administered starting with 100 mg m-2, and progressing through 120, 140, 160, 180, 210, 240, and 270 mg m-2. Edatrexate was administered by intravenous infusion over 20 min, and cryotherapy using ice chips was given prophylactically for 5 min before, during, and 15 min after each EDX treatment. The dose-limiting toxicity could not be reached in this study because it had to be closed on account of competing protocols using EDX in combination regimens. Of note though, was that the delivered dose intensity at the 160 mg m-2 week-1, was higher than the previously used or recommended phase II doses. Anemia was mild and white blood corpuscle toxicity was mostly of grade 1 or 2. One patient had grade 4 neutropenia and one had grade 3 thrombocytopenia. Of the non-hematological toxicities, nausea, vomiting, and diarrhea were mild and tolerable. Mucositis, which was the dose-limiting toxicity in previous studies, was seen in 30% of the patients, but was predominantly a grade 1 toxicity. This could have been due to either the different schedule of EDX used in this study or the use of cryotherapy. Substantial antitumor effects were noted, with two near-complete complete responses at the 120 and 160 mg m-2 levels. Additionally, six partial responses and one minor response were observed, and stable disease was observed in seven patients. Despite achieving antitumor activity at different dose levels, a clear-cut dose response was not evident at the levels tested. We feel that the biweekly EDX schedule is a tolerable regimen, which allows a higher dose intensity than weekly administration, and that EDX is an active agent for the treatment of patients with metastatic cancer.
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PMID:Phase I trial of edatrexate in advanced breast and other cancers. 1209 54

Purpose. To define the maximally tolerated dose (MTD) of ifosfamide when given with G-CSF on an every other week schedule, and to define the MTD of edatrexate that can be given every two weeks with an intense schedule of ifosfamide.Patients and Methods. Forty-one patients with metastatic or unresectable, locally advanced sarcoma participated in this 2-step phase I trial.The starting dose of ifosfamide was 10 gm/m(2) given by continuous intravenous infusion over 4 days every 2 weeks.When the MTD was defined, edatrexate, beginning at a dose of 40 mg/m(2) intravenously every 2 weeks was added in subsequent cohorts of patients.Results. Myelosuppression was the most prominent toxicity. Fatigue, nausea, and vomiting were observed in the majority of patients. Ifosfamide 12 gm/m(2) given every 2 weeks approached or exceeded the MTD. Edatrexate 100 mg/m(2) could be given safety as an intravenous bolus with ifosfamide 10 gm/m(2) every 2 weeks. Therapeutic responses were observed in patients with measurable disease.Conclusions. This study demonstrates the feasibility of administering a dose-intense schedule of ifosfamide alone or ifosfamide with edatrexate that might be applied in the adjuvant or neo-adjuvant setting.
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PMID:Evaluation of dose-intense Ifosfamide, with and without edatrexate, in adults with sarcoma. 1852 Dec 74