IMPROVED THERAPEUTIC INDEX WITH SEQUENTIAL N-PHOSPHONACETYL-L-ASPARTATE PLUS HIGH-DOSE METHOTREXATE PLUS HIGH-DOSE 5-FLUOROURACIL AND APPROPRIATE RESCUE

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (10) , 4653-4661
Abstract
Although clinical trials of high-dose methotrexate (MTX) sequenced before 5-fluorouracil (FUra) with leucovorin (LV) rescue apparently have resulted in increased numbers of tumor responses, this increased antitumor activity often has been accompanied with toxicity. An attempt to improve therapeutic results with this drug combination by appropriate metabolic modulation in the preclinical BALB/c .times. DBA/8 F1 murine breast tumor model is described. A LV rescue schedule consisting of 300 mg/kg administered 4.5 and 19.5 h after high-dose MTX (300 mg/kg per wk for 3 wk) prevented MTX toxicity. When Fura had to be decreased, and no convincing evidence for a differential cytotoxic effect on tumor vs. normal host tissue was obtained. When a delayed uridine rescue schedule was added to protect the host from the toxic activity of FUra, the FUra dose could be increased even in the presence of high-dose MTX, and the therapeutic result was enhanced significantly, without an increase in host toxicity. It was possible to add N-phosphonacetyl-L-aspartate to this drug combination (in the appropriate sequence: N-phosphonacetyl-L-aspartate before high-dose MTX before high-dose FUra, followed by double rescue with LV and uridine) without producing increased toxicity to yield a significant increase in partial tumor regression rate. The biochemical rationale for the selection and sequence of administration of these agents is discussed.