Orotate phosphoribosyltransferase is overexpressed in malignant pleural mesothelioma

Mechanism of TS inhibitors (5-FU and Pemetrexed)

The first mechanism of action is to inhibit DNA synthesis. In vivo, 5-FU is converted to its active form, 5-fluoro-20 -deoxyuridine-50 -monophosphate (FdUMP). Then, with reduced folic acid as a coenzyme, it strongly binds with TS, which catalyzes the synthesis of thymidine necessary for DNA synthesis, forming a tripartite complex. This reduces the activity of TS, thereby inhibiting DNA synthesis. However, when TS is highly expressed in tumor tissues, DNA synthesis occurs due to the residual excess TS, and the antitumor effect of 5-FU is attenuated. TS expression in the tumor tissues of various solid cancers has been investigated and has been found to be lower in lung cancer than in other cancers. In view of the above, though 5-FU should be effective against most lung cancers based on its expression patterns, its efficacy is actually poor. A proposed reason for this is that, although 5-FU is activated in vivo, it is rapidly broken down by DPD, a 5-FU-degrading enzyme. Furthermore, in cancer types with high intratumoral levels of DPD activity, 5-FU is rapidly degraded and its efficacy is decreased. DPD activity has been reported to be at least two-fold higher in lung carcinoma than in gastric and colon cancers. Therefore, when 5-FU is used to treat carcinoma types with high DPD activity levels, inhibition of DPD is considered to be essential, and this realization led to the development of S-1, which contains gimeracil (CDHP; 5-chloro-2,4-dihydroxy- pyridine). We also found high DPD expression in mesothelioma tissues, but theologically, S-1, which contains CHDP, a DPD inhibitor, may have an anticancer effect in tumors with high DPD expression. The second mechanism of action of 5-FU is the inhibition of RNA function, which is mediated by the conversion of OPRT to fluorouridine monophosphate (FUMP) by a phosphorylating enzyme. Investigation of OPRT expression in lung cancer has shown that it is at least two-fold higher in squamous cell carcinoma than in adenocarcinoma. It can be surmised that S-1 exerts an antitumor effect on squamous cell carcinoma, mainly by inhibiting RNA function. In the present study, we found high OPRT expression in MPM tumor tissues. Therefore, we presumed that MPM would have the potential to respond more to S- 1 treatment. In contrast, although pemetrexed inhibits multiple enzymes involved in pyrimidine and purine synthesis, its major target enzyme is TS (Fig.). After cellular uptake, pemetrexed is converted into more effective polyglutamated forms by folylpoly-g -glutamate synthetase (FPGS). There is no pathway related to OPRT in its mode of action. Overall, like in squamous lung cancer and thymic carcinoma,10 when combined with TS inhibition, cancer tissue that has​ high OPRT protein expression have the potential to