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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.