Does leucovorin alter the intratumoral pharmacokinetics of 5-fluorouracil (5-FU)? A Southwest Oncology Group study.
OBJECTIVE
We previously documented that there was an association between the intra-tumoral pharmacokinetics (TPK) of 5-FU and response to therapy with 5-FU and leucovorin (p < .0001). Since we have shown that other modulators of 5-FU, such as methotrexate, interferon and neutrexin alter its TPK, it was of interest to determine if the modulating effect of leucovorin would also alter the tumoral PK of 5-FU. In order to determine the effect of leucovorin on intratumoral 5-FU pharmacokinetics, 23 patients (21 evaluable) underwent 19F magnetic resonance spectroscopy (19F-MRS) twice. The first 19F-MRS was following 5-FU 600 mg/m2 alone, and the second 19F-MRS was following by leucovorin 500 mg/m2 and then 5-FU 600 mg/m2.


RESULTS
A comparison of the intratumoral 5-FU pharmacokinetics indicated that there was no general effect of leucovorin on the intratumoral half-life of 5-FU. In only two of these 21 patients was the half-life of 5-FU altered, and in both cases it was decreased by more than 20%. Partial responses to 5-FU plus leucovorin therapy were seen only in patients with a long intratumoral half-life (trapping) of 5-FU (3 PR in 11 patients with T1/2 > or = 20 minutes, compared to 0 PR in 11 patients with T1/2 < 20 minutes). There was a statistically significant correlation between tumor response and the intratumoral T1/2 of 5-FU, consistent with our prior results in a larger number of patients. However, there was no statistically significant correlation of time-to-progression or survival with classification of the patients into trappers or non-trappers, probably due to the small sample size in this current study.


CONCLUSIONS
The data reported here are compatible with the hypothesis that leucovorin enhancement of 5-fluorouracil antitumor responses is not mediated by the levels of 5-FU in tumors, but rather, is due to the modulation by leucovorin of cellular metabolic processes that follow the uptake of free 5-FU into the tumor cell. The MRS technique may be useful in selected instances for elucidating the possible metabolic interactions of drugs in vivo.
Presant
Cary A
CA
Los Angeles Oncologic Institute, St. Vincent Medical Center, CA, USA.
Jacobson
Joth
J
Wolf
Walter
W
Waluch
Victor
V
Weitz
Ilene C
IC
Macdonald
John S
JS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D024221:Antineoplastic Protocols; D016009:Chi-Square Distribution; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D002955:Leucovorin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D015206:Southwestern United States; D015996:Survival Rate
D002955:Leucovorin; D005472:Fluorouracil