Pemetrexed is an antimetabolic agent and is well-known as a potent inhibitor of thymidylate synthase (TS). It also inhibits dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyl transferase (GARFT). We reported an intriguing case in which a non-small cell lung cancer patient who was refractory to pretreatment with S-1, a strong TS inhibitor, showed good response to pemetrexed treatment.
Pemetrexed and S-1 are antitumor agents frequently used in patients with non-small cell lung cancer (NSCLC). The result of a phase III trial indicated the usefulness of pemetrexed as chemotherapy for patients with previously treated NSCLC [
A 54-year-old woman presented with cough and sputum. Previously she had been diagnosed as having adenocarcinoma of the lung (cT4N3M0 stage IIIB) and received first-line chemotherapy with S-l (100 mg/body, d1-14) and cisplatin (80 mg/m2, d1) on a three-week schedule [
About a month later she enrolled in a clinical trial in which second-line chemotherapy was started with pemetrexed 500 mg/m2 [
The patient was followed by other chemotherapies and died approximately 21 months after the first administration of pemetrexed.
Single-agent chemotherapy with pemetrexed has been studied in previously treated patients in a Japanese phase II trial [
This case was one of the 108 patients who were evaluable for efficacy in the 500 mg/m2 group of the phase II trial. She received seven cycles of pemetrexed treatment with severe adverse events. Even though this patient showed no response to previous treatment with S-1 plus cisplatin combination therapy, a remarkable response (76.2% tumor reduction and progression-free survival of 5.2 months) was seen following treatment with pemetrexed. We feel that this notable difference in efficacy may have been due to differences in the mechanism of action between pemetrexed and S-1.
Both pemetrexed and S-1 are categorized as antimetabolic agents and strongly inhibit TS. However, these
CT scan of the chest: right upper lobe (target lesion), lym- phangitis carcinomatosa, and left hilar lymph nodes (above non-target lesions). (a) Before pemetrexed chemotherapy; (b) After four cycles ofpemetrexed chemotherapy, showing partial response in the target lesion
agents interact with two different TS substrate binding sites: one for deoxyuridine monophosphate (dUMP) and the other for the folate (5,10-methylenetetrahydrofolate polyglutamate). S-1 has three components: 5-Fluorou- racil (5-FU) prodrug tegafur; 5-chloro-2, 4-dihydroxypyridine; and potassium oxonate. The 5-FU component is phosphorylated to 5-fluoro-2’-deoxyuridine 5’-monophosphate (FdUMP), which reacts with reduced folate cofactors to form a ternary complex with TS via interaction with dUMP binding site, thereby inhibiting pyrimidine synthesis. In contrast, pemetrexed, which is rapidly metabolized to active polyglutamate derivatives within cells, has a structure similar to that of folate. Pemetrexed inhibits pyrimidine synthesis by binding to TS instead of folate. Consequently, the interaction with TS is substantially different from that of S-1.
In addition, pemetrexed was shown to have a high inhibitory effect on dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyl transferase (GARFT) as well as TS in a previous preclinical research. It was reported that the Ki value of pemetrexed pentaglutamates was 1.3 nM for TS inhibition, which may be comparable or superior to the reported Ki value of 6.4 nM for 5-FU. Furthermore, pemetrexed pentaglutamates have also shown strong inhibition of DHFR and GARFT. The in vitro study has obtained Ki values of 7.2 nM and 65 nM, respectively, for each of these enzymes [
These differences in the mode of action may explain the clinical efficacy seen in this case. The response in this patient suggests that pemetrexed has a unique mode of action and is a potent multi-target antifolate agent in NSCLC.