Modulation of 5FU

A number of agents have been combined with 5-FU in order to increase either its efficacy or therapeutic index.

Folinic acid 5-FU and folinic acid combinations are the mainstay of treatment of colon cancer. Folinic acid is given by infusion, before or concomitant with 5-FU. By increasing supply of CH2-FH4, folinic acid potentiates interaction between 5-FU and TS. Although more toxic, has higher response rate in advanced colorectal cancer with combined treatment than single-agent 5-FU.

Levamisole the anti-helminth agent, levamisole, has some activity as an immune modulator and has been used in the treatment of colon cancer. It has been combined with 5-FU in the adjuvant setting and the combination is superior to no treatment, but not to intravenous 5-FU (with or without folinic acid). The mechanism of action is uncertain.

Interferon Interferon may enhance TS inhibition. In combination with 5-FU (with or without folinic acid), it has not been shown to be superior to single-agent 5-Fu.

PALA PALA (N-phosphonacetyl-L-aspartate) inhibits de novo pyrimidine synthesis, and thus increases 5-FU anabolism and incorporation into RNA.

DPD inhibitors Inhibit the main catabolic pathway of 5-FU and may result in increased efficacy. Early clinical trials are in progress.

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