Synergistic effects of docetaxel and S‐1 by modulating the expression of metabolic enzymes of 5‐fluorouracil in human gastric cancer cell lines

Abstract

We have recently demonstrated in a Phase I/II study that combination chemotherapy with docetaxel (TXT) and S-1 is active against metastatic gastric carcinomas. To elucidate the mechanisms underlying the synergistic effects of these drugs, both the growth inhibitory effects and the expression profiles of enzymes involved in fluorouracil (5-FU) metabolism were examined in vitro and in vivo. TXT alone and in combination with 5-FU inhibited the growth of each of the 5 gastric cancer cell lines that we examined , in a time-and dosedependent manner. Moreover, striking synergistic effects were observed in TMK-1 cells in vitro with IC 50 values of between 4.73 and 0.61 nM 5-FU. Furthermore, in TMK-1 xenografts, 5-FU/ TXT cotreatments exhibited synergistic antitumor effects. The combination of S-1 and TXT, however, exhibited greater growthinhibitory effects than the 5-FU/TXT cotreatments. The mechanisms underlying these synergistic effects of S-1 and TXT were examined by expression and activity analyses of the 5-FU metabolic enzymes. The expression of thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) were decreased 50 and 73% of control levels, respectively, and that of orotate phosphorybosyl transferase (OPRT) was increased by 3.9-fold at the protein level. These findings suggested that biochemical modulation of the 2 drugs had occurred, which was further confirmed by the results of the activity assays. These data strongly indicate that a combination chemotherapy of TXT and S-1 is effective against gastric carcinomas and is therefore a good candidate as a standard chemotherapeutic strategy in treating these tumors. ' 2006 Wiley-Liss, Inc.Key words: gastric cancer; TMK-1; docetaxel; 5-fluorouracil; S-1; TS, thymidylate synthase; DPD, dihydropyrimidine dehydrogenase; OPRT, orotate phosphorybosyl transferase; combination effectIn spite of recent advances in the development of both diagnostic and therapeutic tools, gastric cancer is still a major cause of death throughout the world. Moreover, because many patients are still diagnosed at only the late stages of this disease, recurrent tumors are often detected even after curative surgery. In such patients, chemotherapy is one of the main treatment strategies that is employed, as it has been shown to improve prognoses. 1-3 However, a standard regimen of the treatment of metastatic gastric cancer has not been yet established in Japan.5-Fluorouracil (5-FU) is widely used an anticancer agent and is currently considered to be a key drug in clinical chemotherapeutic treatments for gastrointestinal cancers, such as esophageal, 4 gastric 5 and colorectal. 6 In addition, 5-FU has been also used to treat both breast 7 and cervical 8 cancers. 5-FU is catabolized to 2-fluorob-alanin by the first and rate-limiting enzyme of its metabolic pathway, dihydropyrimidine dehydrogenase (DPD). The functional effects of 5-FU are thought to occur through its active metabolite, 5-fluorodeoxyuridine diphosphate (FdUMP) 9,10 which, together with the coenzyme 5,10-methylenethtrahydr...

Preliminary trial of adjuvant surgery for advanced gastric cancer

“…Wada et al reported that docetaxel and S-1 combination therapy showed synergistic effects by modulating the expression of the metabolic enzymes of 5-fluorouracil, including thymidylate synthase, dihydropyrimidine dehydrogenase and orotate phosphoribosyl transferase in human gastric cell lines (24). In a phase II study of docetaxel and S-1 combination therapy, the median time to tumor progression was 7.3 months (95% CI, 4.3-10.0 months) (15).…”

2300 A multicenter randomized phase II study of docetaxel vs. docetaxel plus cisplatin vs. docetaxel plus S-1 as second-line chemotherapy in metastatic gastric cancer patients who had progressed after cisplatin plus either S-1 or capecitabine

“…Based on the preclinical synergism between docetaxel and either S-1 or cisplatin [11][12][13][14][15], it was hypothesized that a combination of docetaxel and either S-1 or cisplatin as a secondline treatment might have better efficacy than docetaxel alone, even after the failure of first-line cisplatin plus either S-1 or capecitabine. On the other hand, compared to doc- In contrast, the addition of S-1 to docetaxel showed a better PFS (median, 2.7 months vs. 1.3 months; p=0.034) than docetaxel alone without substantial impairment in the QoL or increasing toxicity except for all grades of nausea.…”

“…In particular, based on its different mechanism of action from those of fluoropyrimidine and platinum and the lack of cross-resistance with these agents, docetaxel is used frequently as a secondline regimen after the failure of fluoropyrimidine-and/or platinum-based first-line therapy. Furthermore, docetaxel shows synergistic antitumor activity with fluoropyrimidines, particularly S-1, by modulating the expression of enzymes involved in the 5-FU metabolism, including thymidylate synthase, dihydropyrimidine dehydrogenase, and orotate phosphoribosyltransferase [11,12]. Docetaxel has also shown synergistic activity with cisplatin in gastric cancer, which was attributed partially to the suppression of the cisplatininduced multidrug resistance-associated protein-1 by docetaxel [13], resulting in the accumulation of intracellular platinum-glutathione complexes.…”

Prediction of clinical outcome of S-1-based chemotherapy for gastric cancer patients

“…The combination of S-1 and docetaxel exhibited greater growth-inhibitory effects in human tumor xenograft models than treatment with S-1 alone or docetaxel alone [32]. This synergistic antitumor effect was greater for the combination of S-1 and docetaxel than for a combination of 5-FU and docetaxel.…”