Pharmacologic-guided trial of sequential methotrexate and thioguanine in children with advanced malignancies.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Tan
C T
CT
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Wollner
N
N
Trippett
T
T
Goker
E
E
Tong
W P
WP
Kheradpour
A
A
Meyers
P A
PA
VanSyckle
K M
KM
Guarino
L
L
Elisseyeff
Y
Y
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D008223:Lymphoma / Q000188:drug therapy; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D010754:Phosphoribosyl Pyrophosphate / Q000097:blood; D012074:Remission Induction; D013866:Thioguanine / Q000008:administration & dosage / Q000009:adverse effects
D010754:Phosphoribosyl Pyrophosphate; D013866:Thioguanine; D008727:Methotrexate