Oral dipyridamole and methotrexate in human solid tumors: a toxicity trial.
Dipyridamole (DP) blocks nucleoside salvage by inhibiting uptake at the cell membrane. At the usual oral doses DP has no cytotoxic activity, but when combined with an antimetabolite, it results in synergistic cell kill in vitro. In this study, 45 patients with advanced solid tumors were treated with oral DP and i.v. or i.m. methotrexate (MTX) to define the toxicity of this combination. The DP dose was 75 mg b.i.d. in the first 16 patients, 150 mg b.i.d. in the next 2, and 75 mg q.i.d. in the remaining 27 patients. MTX was given weekly at an initial dose of 10-30 mg/m2 and increased weekly by 5-10 mg/m2 to the maximum tolerable dose (MTD) or a maximum of 60 mg/m2; thereafter that dose was given every other week. DP levels ranged from 2.76 to 11.46 microM, with a mean of 5.67 microM in four patients taking 75 mg q.i.d. The combination of oral DP and MTX was generally well tolerated and did not appear to result in any more myelotoxicity or mucositis than that expected for MTX alone. One patient experienced severe headaches related to DP, ten patients experienced grade 3 or 4 neutropenia and/or thrombocytopenia, and four patients had grade 3 mucositis. Although this trial was not designed as a phase II study, one partial remission was observed in a patient with metastatic pleomorphic adenoma of the parotid gland and seven patients showed significant improvement.
Higano
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CS
Department of Medicine, University of Washington School of Medicine, Seattle.
Livingston
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RB
D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004176:Dipyridamole / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D009369:Neoplasms / Q000188:drug therapy*; D013997:Time Factors
D004176:Dipyridamole; D008727:Methotrexate