Pharmacologic-guided trial of sequential methotrexate and thioguanine in children with advanced malignancies Journal Article


Authors: Tan, C. T. C.; Wollner, N.; Trippett, T.; Goker, E.; Tong, W. P. Y.; Kheradpour, A.; Meyers, P. A.; Van Syckle, K. M.; Guarino, L.; Elisseyeff, Y.; Bertino, J. R. Jr
Article Title: Pharmacologic-guided trial of sequential methotrexate and thioguanine in children with advanced malignancies
Abstract: 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.
Keywords: adolescent; adult; child; clinical article; clinical trial; doxorubicin; advanced cancer; area under the curve; drug potentiation; solid tumor; methotrexate; dacarbazine; computer assisted tomography; blood toxicity; gastrointestinal symptom; creatinine; hemoglobin; tumor biopsy; rash; alkaline phosphatase; aspartate aminotransferase; bilirubin; acute leukemia; lymphoma; bleomycin; thorax radiography; blood cell count; drug blood level; high performance liquid chromatography; vinblastine sulfate; folinate calcium; cotrimoxazole; tioguanine; intravenous drug administration; leukemia remission; autologous bone marrow transplantation; bone marrow depression; gallium; aminoglycoside antibiotic agent; amphotericin; human; priority journal; article; phosphoribosyl pyrophosphate
Journal Title: Journal of Clinical Oncology
Volume: 12
Issue: 9
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 1994-09-01
Start Page: 1955
End Page: 1962
Language: English
DOI: 10.1200/jco.1994.12.9.1955
PROVIDER: scopus
PUBMED: 7521908
DOI/URL:
Notes: Article -- Source: Scopus
Altmetric Score
MSK Authors
  1. William Ping-Yiu Tong
    129 Tong
  2. Joseph Bertino
    269 Bertino
  3. Paul Meyers
    247 Meyers
  4. Charlotte T C Tan
    16 Tan