lometrexol and Lymphoma

Lometrexol [(6R)-5,10-dideaza-5,6,7,8-tetrahydrofolate] is the prototype folate antimetabolite that targets the de novo purine synthesis pathway. Early phase I trials were confounded by cumulative myelosuppression that prevented repetitive administration. Subsequent preclinical and clinical studies suggested that coadministration of folic acid might favorably modulate lometrexol toxicity without eliminating potential antitumor activity. We set out to determine if concurrent folic acid would allow administration of lometrexol on a weekly schedule, and, if so, to identify an appropriate dose combination for phase II trials. Pharmacokinetic and metabolism studies were undertaken in an attempt to improve our understanding of lometrexol pharmacodynamics.. Patients with advanced cancer received daily oral folic acid beginning 7 days before lometrexol and continuing for 7 days beyond the last lometrexol dose. Lometrexol was administered by short i.v. infusion weekly for 8 weeks. Scheduled lometrexol doses were omitted for toxicity of more than grade 2 present on the day of treatment, and dose-limiting toxicity was prospectively defined in terms of frequency of dose omission as well as the occurrence of severe toxic events. Plasma and whole blood total lometrexol contents (lometrexol plus lometrexol polyglutamates) were measured in samples taken just prior to each lometrexol dose.. A total of 18 patients were treated at five lometrexol dose levels. The maximum tolerated dose was identified by frequent dose omission due to thrombocytopenia and mucositis. The recommended phase II dose combination is lometrexol 10.4 mg/m(2) per week i.v. with folic acid 3 mg/m(2) per day orally. One patient with melanoma experienced a partial response, and three patients, two with melanoma and one with renal cell carcinoma, experienced stable disease. Lometrexol was not detectable in any predose plasma sample tested. The total red blood cell content of lometrexol increased over several weeks and then appeared to plateau.. Weekly administration of lometrexol is feasible and well-tolerated when coadministered with daily oral folic acid. The nature of the interaction between natural folates and lometrexol that renders this schedule feasible remains unclear. A definition of dose-limiting toxicity that incorporated attention to dose omissions allowed efficient identification of a recommended phase II dose that reflects the maximum feasible dose intensity for a weekly schedule. Lometrexol is a promising, anticancer agent.

Topics: Administration, Oral; Adult; Aged; Anemia; Drug Administration Schedule; Drug Evaluation; Erythrocyte Count; Female; Folic Acid; Folic Acid Antagonists; Hematinics; Humans; Infusions, Intravenous; Lymphoma; Male; Middle Aged; Neoplasms; Tetrahydrofolates

Trimetrexate (TMTX), 5,10-dideazatetrahydrofolate (DDATHF), and 10-propargyl-5,8-dideazafolate (PDDF, CB3717) are antifolates whose primary intracellular targets are dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and thymidylate synthase, respectively. Varying the medium folic acid (PteGlu) concentration over the range of 0.5 to 100 microM increasingly blocks the growth inhibitory effects of the individual antifolates in Manca human lymphoma cells, but increasingly enhances the synergistic interaction of both TMTX + DDATHF and TMTX+ PDDF combinations. Drug interactions were quantitated using the universal response surface approach, which consists of fitting a concentration-effect surface to experimental data with weighted nonlinear regression, enabling the estimation of the synergism parameter, alpha. Estimates for alpha are larger (more intense synergism) for the TMTX + DDATHF combination (alpha = 4.68 +/- 0.66 at 2 microM PteGlu; alpha = 53.6 +/- 3.7 at 40 microM PteGlu) than for the TMTX + PDDF combination (alpha = 0.690 +/- 0.25 at 2 microM PteGlu; alpha = 7.20 +/- 1.8 at 40 microM PteGlu). However, the relative increase brought about by increasing the PteGlu concentration from 2 microM to 40 microM is similar in each instance, 11- and 10-fold, respectively. These experiments suggest that the enhanced cytotoxic interaction brought about by increased PteGlu concentration with the TMTX + DDATHF combination and the TMTX + PDDF combination may share a common mechanism. The dramatic intensity of the synergism between DDATHF and TMTX at 40 microM PteGlu, along with the concept of modulation of antifolate synergism by folates, suggests future in vivo and/or clinical applications of combinations of these (or similar) compounds.

Topics: Cell Division; Dose-Response Relationship, Drug; Drug Synergism; Folic Acid; Folic Acid Antagonists; Humans; Lymphoma; Quinazolines; Tetrahydrofolates; Trimetrexate; Tumor Cells, Cultured