BIOMODULATION OF FLUOROURACIL IN COLORECTAL-CANCER

5-Fluorouracil (5-FU) remains the agent of choice for the treatment of colorectal cancer. Research has focused on the biomodulation of 5-FU in order to attempt to improve the cytotoxity and therapeutic effectiv eness of this drug in the treatment of advanced colorectal cancer. Mod ulation of 5-FU by methotrexate (MTX) trimetrexate (TMTX), interferon- alpha (IFN-alpha), leucovorin (LV), or N-(phosphonacetyl)-L-asparte ac id (PALA) has produced higher response rates than those observed with 5-FU alone. Methotrexate may improve the durability of response to or survival with 5-FU, but with inferior results compared with those in t rials of 5-FU and leucovorin. Trimetrexate produces a number of respon ses, and further phase III trials are in progress to confirm the resul ts of promising phase II trials with this drug. IFN-alpha has shown th erapeutic efficiency when combined with 5-FU alone or with 5-FU and le ucovorin, but latest studies with these combinations have shown increa sed toxicity. Initial single-institution phase I trials with 5-FU and PALA reported promising responses, but the latter responses with PALA were not substantiated in randomized multicenter trials. Leucovorin en hances the cytotoxic activity of 5-FU in vitro and in vivo, and severa l clinical trials have shown improved response rates and possible tren ds in improved survival when such therapy is compared with the use of 5-FU as a single-agent. More recent randomized trials have focused the ir attention on determining the optimal dose and schedule with this co mbination for producing a better clinical response with minimal toxici ty. Schedules using infusional 5-FU appear to be the most active regim ens when 5-FU is used as a single agent, as demonstrated by recent ran domized trials. The Southwest Oncology Group (SWOG) and the Eastern Co operative Oncology Group (ECOG) have performed separate randomized tri als and have shown that the optimal regimens employ infusional 5-FU as a single agent, and that these are the least toxic regimens, perhaps more effective, and associated with a better quality of life. Future s tudies will focus on infusional regimens involving either short-term, high-dose protracted or long-term, low-dose protracted infusion of 5-F U, since these regimens have shown the most favorable toxicity spectru m and produced the longest survival times. Future research will also f ocus on the evaluation of various methods of delivery of 5-FU, includi ng oral administration of the drug in combination with compounds that can modify its catabolism.