Enhancement of Fluorouracil Uptake in Human Colorectal and Gastric Cancers by Interferon or by High-Dose Methotrexate: An In Vivo Human Study Using Noninvasive 19F-Magnetic Resonance Spectroscopy

Abstract

PURPOSE: To study whether two modulators, high-dose methotrexate (MTX) and interferon alfa-2a (IFNα-2a) will alter the intratumoral pharmacokinetics of fluorouracil (5-FU). PATIENTS AND METHODS: Five patients, two with gastric cancer and three with colorectal cancer, who had metastatic tumor nodules in their livers were studied dynamically in vivo after 5-FU injection. In a magnetic resonance imaging unit, noninvasive 19F-magnetic resonance spectroscopy (MRS) was used to detect 19F signals from 5-FU and its metabolites. RESULTS: The intratumoral half-life (t1/2) of 5-FU in these tumors ranged from 18.8 minutes to 42.3 minutes. Four of the five patients exhibited increases in the t1/2 of 5-FU after intravenous (IV) administration of MTX or IFNα-2a. In the two patients with gastric cancer who received IV high-dose MTX followed by IV 5-FU, increases were seen in either the total t1/2 of 5-FU (41.8%) or in the t1/2 of the α phase (150%). In the three patients with colorectal cancer who received IV IFNα-2a followed by IV 5-FU, the two patients with partial responses had increases in the t1/2 of 5-FU of 41% and 30.2%, whereas the nonresponder had a nonsignificant increase (5.6%) in the t1/2 of 5-FU. CONCLUSIONS: These results document that the in vivo modulation of the tumoral pharmacokinetics of 5-FU can be measured noninvasively by 19F-MRS and suggest that such information correlates with subsequent clinical outcomes. The findings also indicate that IFNα-2a and high-dose MTX can increase the intratumoral 5-FU in some patients. Such information, obtained prospectively in vivo, may assist in better individual cancer patient management and in developing novel drug combinations.