High-dose edatrexate with oral leucovorin rescue: a phase I and clinical pharmacological study in adults with advanced cancer.

Our objective was to determine the maximum tolerated dose and toxicity of i.v. edatrexate with p.o. leucovorin. Thirty-one adults with advanced solid tumors received edatrexate as a 2-h infusion, once a week for 3 weeks, recycled every 28 days. p.o. leucovorin (10 mg/m2, every 6 h for 10 doses) began 24 h later. All had urinary alkalinization and p.o. hydration. Nine dosage levels ranging from 120 to 3750 mg/m2 were explored. Fatigue, epistaxis, nausea/emesis, mucositis, rash, myalgias, leukopenia, thrombocytopenia, and transient elevations of serum aspartate transferase were observed. Leukoencephalopathy with clinical manifestations occurred in two patients (one had prior cranial irradiation). Pharmacokinetic studies carried out at the 120- and 1080-mg/m2 dose levels revealed no significant difference in the elimination half-life at the two dose levels studied and no significant intrapatient variability between day 1 and day 8 edatrexate administration. Serum edatrexate levels measured using a dihydrofolate reductase inhibition assay correlated with those by high-performance liquid chromatography. Three major and two minor antitumor responses occurred. The maximum tolerated dose was 3750 mg/m2, with grade 3 or 4 leukopenia (one patient), stomatitis (one patient), and leukoencephalopathy (one patient). Because of the occurrence of leukoencephalopathy, further study of high-dose edatrexate with leucovorin rescue is not recommended.

Antifolate analogs: mechanism of action, analytical methodology, and clinical efficacy.

Antifolates have demonstrated effective antineoplastic activity in the treatment of disorders of cell proliferation, e.g., acute lymphocytic leukemia, breast cancer, and mycosis fungoides. The enzymatic pathways involved in DNA biosynthesis, specifically dihydrofolate reductase and thymidylate synthetase, are the biochemical targets of antifolates. Methotrexate (MTX) and its analogs, 10-ethyl-10-deazaaminopterin (edatrexate), and trimetrexate (TMT) are paradigms for cytotoxicity at the biochemical level. Understanding the cellular pharmacology of MTX and other antifolates has provided a strong rationale for the use of high-dose MTX with leucovorin (LV) rescue. The combination of MTX and LV prevents severe toxicity without diminishing the antitumor activity of the drugs. The efficacy of antifolate drugs is related to the extent of intracellular polyglutamation in normal and cancer cells. Since toxicity in patients is difficult to predict, monitoring drug concentrations is critical. 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. Chemical and physical properties, mechanism of chemotherapeutic activity, and analytical methodology for measurement of serum concentrations of antifolates will be discussed.

Acute high-dose methotrexate neurotoxicity in the rat.

Intravenous high-dose methotrexate chemotherapy may produce acute, subacute, or chronic neurotoxicity in patients with cancer. Acute encephalopathies following high-dose methotrexate treatment are recognized with increasing frequency. This study describes a model of acute high-dose methotrexate neurotoxicity in the rat characterized by a profound dose-dependent depression of cerebral glucose metabolism in association with behavioral and electroencephalographic abnormalities. Alterations in the amino acid profile, similar to those described in cancer patients after high-dose methotrexate treatment, were observed in the absence of biochemical evidence of systemic organ toxicity. This model facilitates the study of the biochemical mechanisms of antifolate neurotoxicity in humans and permits the evaluation of potential therapeutic interventions.