New thymidylate synthase inhibitors
Raltitrexed is a quinazoline analogue antifolate that gains entry
to cells via the reduced folate carrier and is polyglutamated to a
potent, long acting, specific inhibitor of thymidylate synthase. Its
regimen—a short intravenous infusion every three weeks—has
similar efficacy to that of fluorouracil plus folinic acid and is
clearly more convenient, although potentially more toxic.

Oral fluorouracil prodrugs and modulators
Fluoropyrimidine analogues have been developed with reliable
oral bioavailability. In addition, oral inhibitors of fluorouracil
catabolism can facilitate oral dosing. Preliminary data show
similar effectiveness and lower toxicity compared with
fluorouracil. Given the convenience and potential cost savings,
oral therapy may soon find a place in routine practice.

Irinotecan and oxaliplatin
Irinotecan is a camptothecin analogue that acts through the
inhibition of a DNA unwinding enzyme, topoisomerase I,
resulting in replication arrest with breaks in single strand DNA.
It is useful in advanced colorectal cancer, even after resistance
to fluorouracil has developed, and is associated with a survival
benefit (about three months) compared with best supportive
care. This drug can be associated with severe late onset
diarrhoea, which must be treated immediately. Selection of
patients, therefore, plays an important part in the safe use of
this agent.

Oxaliplatin is a new platinum derivative analogue that
crosslinks DNA and induces apoptotic cell death. It shows
synergism with fluorouracil. The dominant toxic effect is
cumulative neurotoxicity.

Fluorouracil plus either irinotecan or oxaliplatin is superior to
fluorouracil alone as a first line treatment for advanced colorectal
cancer, with improvement in progression-free survival and, in the
case of irinotecan, overall survival. Questions about the optimum
sequence and combination of these agents remain and are the
subject of ongoing clinical trials.