Thymidylate synthase inhibition, a dead end?

Abstract

While in the 197Os, chemotherapy studies in colorectal cancer seemed to be rather uninspired, the advent of biochemical modulation of 5-fluorouracil(5FU) has changed this considerably. Whereas before, most patients, particularly in Europe, did not receive chemotherapy at all for advanced colorectal cancer, now the combination of 5-FU and folinic acid (FA) has advanced to standard treatment in many institutions. What was the basis for this? In the late 198Os, several randomised studies were published showing a significant advantage of 5-FU plus FA over 5-FU alone in terms of response rate and some even in terms of survival[ 11. Was this enough evidence to show that 5-FU can be modulated by FA? By adding FA to the same dose of 5-FU in the same schedule, more responses, more toxicity and perhaps even longer survival are obtained, which would indicate that FA does modulate 5FU. However, the evidence to show that 5-FU plus FA is superior to 5-FU alone is insufficient. In almost all trials, patients in the 5-FU alone arm received inadequate treatment, which can be seen when toxicity is examined. Those trials using a higher 5FU dose in the control arm showed no advantage for the 5-FU plus FA combination[ 11. Admittedly, since the type of toxicity is different between 5-FU alone and 5-FU plus FA, it is difficult to establish an equitoxic dose. Perhaps the best of many 5-FU plus FA combinations in terms of response rate and yet the least expensive one was reported by the NCCTG-Mayo Group[Z]. It originally produced a response rate of 43% (i.e. 16 of 37 patients with measurable disease) (99% confidence interval 23-65%) and a significantly longer survival as compared to 5-FU alone (limited to patients with non-measurable disease). In a follow-up study, 36 of 102 patients (35%, 99% confidence interval 23-48%) with measurable disease responded to the same regimen[3]. The results of the 5-FU plus FA combination, whose target is thymidylate synthase (TS), has triggered the development of specific TS inhibitors. The first one on the market is likely to be Tomudex (ZD1694), and the results of a phase III study, comparing Tomudex to the Mayo type 5-FU plus FA regimen, are reported in this issue (pages). With the help of the company