PREVENTION OF METHOTREXATE TOXICITY BY THYMIDINE INFUSIONS IN HUMANS

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  • 1 January 1977
    • journal article
    • research article
    • Vol. 37  (6) , 1857-1863
Abstract
Continuous i.v. thymidine (TdR) was given to 12 patients with metastatic cancer in an attempt to prevent methotrexate (MTX) toxicity. MTX was infused in 27 courses with progressive dose increase from 80 mg/m2 for 24 h to 6 g/m2 for 72 h. TdR at 8 g/m2 per day was infused concurrently and continued 24-48 h beyond MTX infusion. The median pretreatment serum TdR level was 0.19 .mu.M. With TdR infusion, the median level was 1.5 .mu.M. Serum TdR fell with a half-time of 8-10 min after a pulse dose or cessation of infusion. Spinal fluid TdR equaled serum TdR levels after 2 h of infusion. Less than 2% of administered TdR appeared in urine. MTX serum levels were proportional to dose infused, ranging from 80-100 .mu.M with 2 g/m2 per day. The half-time for MTX clearance from serum was 4-8 h. Spinal fluid MTX reached equilibrium at 3-12% of serum levels by 4 h. Bone marrow dysfunction during MTX infusion was prepvented by TdR as determined by labeling indices and cytofluorographic analyses. Toxicity was not seen in patients with normal MTX clearance using 48 h infusions of MTX where TdR was continued for an additional 48 h after the MTX infusion ended. Three of 6 courses of MTX at 6 g/m2 over 72 h led to toxicity. Toxicity was reversible in 2 patients, 1 of whom was retreated with a similar dose duration of MTX without toxicity when TdR was continued beyond the end of the MTX infusion for 48 h instead of the usual 24 h. The 3rd patient with toxicity died of progressive disease and thrombocytopenia 19 days after treatment. No TdR-related toxicity or unusual MTX toxicity was detected. Antitumor effects were noted in 4 patients. TdR offers significant protection against MTX toxicity and deserves further clinical study.

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