Journal of Clinical Oncology, Vol 12, 1955-1962, Copyright © 1994 by American Society of Clinical Oncology
Pharmacologic-guided trial of sequential methotrexate and thioguanine in children with advanced malignancies
CT Tan, N Wollner, T Trippett, E Goker, WP Tong, A Kheradpour, PA Meyers, KM VanSyckle, L Guarino and Y Elisseyeff
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
PURPOSE: Based on in vitro studies that have shown synergistic effects of
sequential administration of methotrexate (MTX) and thioguanine (6- TG), we
conducted a pharmacologically guided trial of sequential MTX and 6-TG to
determine the following: (1) the maximum-tolerated dose (MTD) of 6-TG; (2)
the nature of the dose-limiting toxicity; and (3) the modulation effect of
MTX on 6-TG given by this sequence and schedule. PATIENTS AND METHODS:
Thirty-one children with advanced malignancies (acute leukemia, n = 10;
lymphoma n = 10; and solid tumors, n = 11) were treated weekly for 3 weeks
with a 2-week rest; treatment consisted of a fixed dose of MTX (30 mg/m2
over 24 hours) followed by a 2-hour infusion of 6-TG in escalating doses.
RESULTS: Measurement of plasma MTX, 6-TG, and mononuclear
5-phosphoribosyl-1- pyrophosphate (PRPP) levels indicates that the desired
biochemical modulation and serum levels were achieved. Nonhematologic
toxicities were mild and the dose-limiting toxicity was bone marrow
depression. A 300-mg/m2 dose of 6-TG with MTX is considered the MTD.
Responses were noted in patients with lymphoma. CONCLUSION: Encouraging
antitumor effects were produced with this regimen in heavily pretreated
patients with lymphoma, particularly Hodgkin's disease (HD). The durations
of responses were 17, 13+, 12, 9, and 7+ months. A phase II trial of the
MTX/6-TG combination is warranted for the treatment of relapsed lymphoma.
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