Enhancement of fluorouracil uptake in human colorectal and gastric cancers by interferon or by high-dose methotrexate: An in vivo human study using noninvasive (19)F-magnetic resonance spectroscopy.
OBJECTIVE
To study whether two modulators, high-dose methotrexate (MTX) and interferon alfa-2a (IFNalpha-2a) will alter the intratumoral pharmacokinetics of fluorouracil (5-FU).


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 (19)F-magnetic resonance spectroscopy (MRS) was used to detect (19)F signals from 5-FU and its metabolites.


RESULTS
The intratumoral half-life (t(1/2)) of 5-FU in these tumors ranged from 18.8 minutes to 42.3 minutes. Four of the five patients exhibited increases in the t(1/2) of 5-FU after intravenous (IV) administration of MTX or IFNalpha-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 t(1/2) of 5-FU (41.8%) or in the t(1/2) of the alpha phase (150%). In the three patients with colorectal cancer who received IV IFNalpha-2a followed by IV 5-FU, the two patients with partial responses had increases in the t(1/2) of 5-FU of 41% and 30.2%, whereas the nonresponder had a nonsignificant increase (5.6%) in the t(1/2) of 5-FU.


CONCLUSIONS
These results document that the in vivo modulation of the tumoral pharmacokinetics of 5-FU can be measured noninvasively by (19)F-MRS and suggest that such information correlates with subsequent clinical outcomes. The findings also indicate that IFNalpha-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.
Presant
C A
CA
Los Angeles Oncologic Institute at the St. Vincent Medical Center, CA, USA.
Wolf
W
W
Waluch
V
V
Wiseman
C L
CL
Weitz
I
I
Shani
J
J
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D017611:Fluorine Compounds; D005472:Fluorouracil / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D016898:Interferon-alpha / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*
D000964:Antimetabolites, Antineoplastic; D017611:Fluorine Compounds; D016898:Interferon-alpha; D005472:Fluorouracil; D008727:Methotrexate