[Metastatic colorectal cancer: new therapeutics]

NEED FOR NEW CHEMOTHERAPEUTIC AGENTS: The use of 5-FU in combination with leucoverin (LV) in the treatment of advanced colorectal cancer has consistently provided antitumoral response. The antitumoral activity of the 5-FU/LV combination is associated with inhibition of thymidylate synthetase, an essential enzyme in pyrimidine de novo biosynthesis of thymidilates as precursors of DNA synthesis. However, dose-limiting toxicities and the limited impact on survival point to the need to develop new drugs and approaches to improve therapeutic efficacy and survival.

In advanced colorecal cancer, clinical results have confirmed the therapeutic efficacy of direct and indirect thymidylate synthetase inhibitors. Promising new agents: 5-FU prodrugs and inhibitors of dihydropyrimidine dehydrogenase (DPD) are promising chemotherapeutic agents with good oral bioavailability which can be combined with other drugs (leucoverin) with acceptable toxicity. Oxaliplatin and topoisomerase inhibitors such as irinotecan (CPT-11) have demonstrated activity in previously treated and newly diagnosed patients.

The best combination between DNA interaction drugs based on potentiation of DNA damage induced by thymidylate synthetase inhibitors and inhibition of DNA repair by DNA interactions remains to be evaluated.