Enhancement of 5-fluorouracil anabolism by methotrexate and trimetrexate in two rat solid tumor models, Walker 256 carcinosarcoma and Novikoff hepatoma, as evaluated by F-19-magnetic resonance spectroscopy

Although 5-fluorouracil (5-FU) is one of the most effective single agents i n treating solid tumors, its low effectiveness as a single agent has led to development of a number of modulators intended to enhance its therapeutic effectiveness. Of these methotrexate (MTX) and trimetrexate (TMTX) have bee n shown to have synergistic anticancer activity with 5-FU. The effect of th ese two drugs on the uptake and the intratumoral metabolism of 5-FU was stu died in two rat tumor models using F-19-nuclear magnetic resonance spectros copy: an excised samples of Walker 256 carcinosarcoma and noninvasively (in vivo) in Novikoff hepatoma. In the rats bearing the Walker 256 tumor, a 4- hr pretreatment with MTX showed the maximal increase in the rate of convers ion from 5-FU to its fluorinated nucleotides/nucleosides. In the rats beari ng the Novikoff hepatoma, bath modulators increased the amounts of cyctotox ic anabolites of 5-FU, but at the doses administered the cumulative amounts of 5-FU anabolites formed after MTX were significantly higher than those f ormed after TMTX or after saline control. On the other hand, the increase i n the levels of the fluorinated nucleotides/nucleosides after TMTX peaked a t a later time. The possible significance of these findings is that timing of administration of a modulator is important because it affects both trans port and metabolism of 5-FU. The two modulators studied, both antifolates, act differently on transport and on metabolism: MTX affects both, whereas T MTX, at the level studied, appears to affect predominantly the metabolic pr ocess. In addition, significant differences exist between tumor models. The se data suggest possible mechanisms and processes that should be studied fu rther in humans, using these noninvasive pharmacokinetic imaging methods fo r monitoring 5-FU targeting and metabolism.