Modulation of fluoropyrimidines: role of dose and schedule of leucovorin administration.
The biochemical modulation of 5-fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd) by leucovorin (LV) has resulted in a significant improvement of the antitumor activity in a variety of malignancies. Although this combination is frequently used, the optimal dose and schedule of LV remains to be determined. In vitro studies with human colon carcinoma (HCT-8) and renal carcinoma (SE) cells show that the increase of intracellular folate pools by LV is dose and time dependent and varies significantly between cell lines. While HCT-8 cells showed optimal modulation of FdUrd cytotoxicity with 1 mumol/L [6S]LV for 5 hours, SE cells required 10 mumol/L [6S]LV for 5 days. Clinical data indicate that low doses of [6R,S]LV (20 mg/m2) might be equivalent to higher doses (200 to 500 mg/m2) when 5-FU is given on 5 consecutive days, whereas doses of 200 mg/m2 might be necessary when 5-FU chemotherapy is given once weekly. Unless biochemical assays to assess a patient's individual needs of LV become available, the use of higher (200 to 500 mg/m2) doses might offer the best chance to effectively modulate 5-FU clinically.
Zhang
Z G
ZG
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263.
Harstrick
A
A
Rustum
Y M
YM
D002986:Clinical Trials as Topic; D004334:Drug Administration Schedule; D005467:Floxuridine / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage*; D013763:Tetrahydrofolates / Q000737:chemistry / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D013763:Tetrahydrofolates; D005467:Floxuridine; C013123:5,10-methylenetetrahydrofolic acid; D002955:Leucovorin