Drug resistance in colorectal cancer: General aspects

The initial conventional chemotherapy of colorectal cancer (CRC) always consists of a fluoropyrimidine, either the parent drug 5-fluorouracil (5FU), the prodrug capecitabine, or the triple combination S-1, in which Ftorafur serves as a prodrug for 5FU. Initially, 5FU was combined with leucovorin, which potentiates the inhibition of the target thymidylate synthase (TS). Since TS inhibition leads to depletion of TTP, essential for DNA synthesis, this results in an increased incorporation of dUTP into DNA, together leading to a so-called thymine-less death. In advanced CRC both low TS expression and a high inhibition are related to a longer survival of patients. Other resistance parameters include decreased intratumoral activation to its nucleotide, and increased systemic degradation by dihydropyrimidine dehydrogenase. In the commonly used combinations (FOLFIRI and FOLFOX) with the topoisomerase I inhibitor, irinotecan, and the DACH-modified platinum analog, oxaliplatin, the relation with TS became less clear. Resistance to irinotecan is mainly associated with its systemic degradation by cytochrome P450 enzymes or conjugation by the UDP-glucuronyl transferase, while resistance to oxaliplatin is associated with increased repair of oxaliplatin-DNA adducts by the repair enzyme ERCC1. With the introduction of capecitabine, the limiting activation catalyzed by carboxyl-esterase and cytidine deaminase was associated with resistance, although the last step in the activation to 5FU catalyzed by both uridine phosphorylase and thymidine phosphorylase (TP) has more often been associated with resistance. Recently, another fluoropyrimidine, TAS-102, containing trifluorothymidine, was registered as third-line treatment. For this drug, decreased cellular uptake by the equilibrative nucleoside transporter, activation by thymidine kinase 1, and decreased incorporation into DNA have been associated with resistance. Analysis of these parameters should enable to guide treatment.