ABSTRACT
Auxin inactivation is critical for plant growth and development. To develop plant growth regulators functioning in auxin inactivation pathway, we performed a phenotype-based chemical screen in Arabidopsis and identified a chemical, nalacin, that partially mimicked the effects of auxin. Genetic, pharmacological, and biochemical approaches demonstrated that nalacin exerts its auxin-like activities by inhibiting indole-3-acetic acid (IAA) conjugation that is mediated by Gretchen Hagen 3 (GH3) acyl acid amido synthetases. The crystal structure of Arabidopsis GH3.6 in complex with D4 (a derivative of nalacin) together with docking simulation analysis revealed the molecular basis of the inhibition of group II GH3 by nalacin. Sequence alignment analysis indicated broad bioactivities of nalacin and D4 as inhibitors of GH3s in vascular plants, which were confirmed, at least, in tomato and rice. In summary, our work identifies nalacin as a potent inhibitor of IAA conjugation mediated by group II GH3 that plays versatile roles in hormone-regulated plant development and has potential applications in both basic research and agriculture.
Subject(s)
Arabidopsis , Ligases , Arabidopsis/genetics , Indoleacetic Acids/pharmacology , Chemical Phenomena , Plant Growth Regulators/pharmacology , Genetic TestingABSTRACT
MdDOX-Co, the ectopic expression of which is considered to cause the apple columnar tree shape, belongs to the 2-oxoglutarate-dependent dioxygenase (2ODD) family. It adds a hydroxyl group to position 12 of gibberellins (GAs). However, the 2ODD enzymes related to GA biosynthesis and catabolism are phylogenetically distinct from MdDOX-Co. Thus, it is possible that substrates other than GAs exist in MdDOX-Co. To identify the previously unidentified substrate(s) of MdDOX-Co, we searched for MdDOX-Co-specific inhibitors. Chemical screening using gas chromatography-mass spectrometry was performed to investigate the effects of 2400 compounds that inhibited the catalytic reaction of MdDOX-Co, but not the catabolic reaction of GA 2-oxidase, an enzyme involved in GA catabolism. By applying two positive compounds in Arabidopsis, a chemical 3-((2-chloro-6-fluorobenzyl)thio)-5,7-dimethyl-5H-pyrazolo[3,4-e][1,4,2]dithiazine-1,1-dioxide designated as TPDD that did not inhibit GA biosynthesis was selected. The structure-activity relationships among the TPDD analogs were also obtained.
Subject(s)
Arabidopsis , Arabidopsis/metabolism , Gene Expression Regulation, Plant , Gibberellins/pharmacology , Gibberellins/metabolism , Mixed Function Oxygenases/metabolismABSTRACT
Ethylene is the only gaseous plant hormone that regulates several aspects of plant growth, from seedling morphogenesis to fruit ripening and organ senescence. Ethylene also stimulates the germination of Striga hermonthica, a root parasitic weed that severely damages crops in sub-Saharan Africa. Thus, ethylene response stimulants can be used as weed and crop control agents. Ethylene and ethephon, an ethylene-releasing compound, are currently used as ethylene response inducers. However, since ethylene is a gas, which limits its practical application, we targeted the development of a solid ethylene response inducer that could overcome this disadvantage. We performed chemical screening using Arabidopsis thaliana "triple response" as an indicator of ethylene response. After screening, we selected a compound with a thiourea skeleton and named it ZKT1. We then synthesized various derivatives of ZKT1 and evaluated their ethylene-like activities in Arabidopsis. Some derivatives showed considerably higher activity than ZKT1, and their activity was comparable to that of 1-aminocyclopropane-1-carboxylate. Mode of action analysis using chemical inhibitors and ethylene signaling mutants revealed that ZKT1 derivatives activate the ethylene signaling pathway through interactions with its upstream components. These thiourea derivatives can potentially be potent crop-controlling chemicals.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Arabidopsis/metabolism , Ethylenes/pharmacology , Ethylenes/metabolism , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Skeleton/metabolismABSTRACT
Ectopic expression of the apple 2-oxoglutarate-dependent dioxygenase (DOX, 2ODD) gene, designated MdDOX-Co, is thought to cause the columnar shape of apple trees. However, the mechanism underlying the formation of such a unique tree shape remains unclear. To solve this problem, we demonstrated that Arabidopsis thaliana overexpressing MdDOX-Co contained reduced levels of biologically active gibberellin (GA) compared with wild type. In summary: (i) with biochemical approaches, the gene product MdDOX-Co was shown to metabolize active GA A4 (GA4 ) to GA58 (12-OH-GA4 ) in vitro. MdDOX-Co also metabolized its precursors GA12 and GA9 to GA111 (12-OH-GA12 ) and GA70 (12-OH-GA9 ), respectively; (ii) Of the three 12-OH-GAs, GA58 was still active physiologically, but not GA70 or GA111 ; (iii) Arabidopsis MdDOX-Co OE transformants converted exogenously applied deuterium-labeled (d2 )-GA12 to d2 -GA111 but not to d2 -GA58 , whereas transformants converted applied d2 -GA9 to d2 -GA58 ; (iv) GA111 is converted poorly to GA70 by GA 20-oxidases in vitro when GA12 is efficiently metabolized to GA9 ; (v) no GA58 was detected endogenously in MdDOX-Co OE transformants. Overall, we conclude that 12-hydroxylation of GA12 by MdDOX-Co prevents the biosynthesis of biologically active GAs in planta, resulting in columnar phenotypes.
Subject(s)
Genes, Plant/genetics , Gibberellins/metabolism , Malus/genetics , Plant Growth Regulators/metabolism , Trees/genetics , Arabidopsis , Dioxygenases/metabolism , Genes, Plant/physiology , Ketoglutaric Acids/metabolism , Malus/growth & development , Malus/metabolism , Malus/physiology , Plant Growth Regulators/physiology , Plant Proteins/genetics , Plant Proteins/metabolism , Plant Proteins/physiology , Plants, Genetically Modified , Trees/growth & development , Trees/metabolism , Trees/physiologyABSTRACT
Hydroxycinnamic acid amides are involved in various developmental processes as well as in biotic and abiotic stress responses. Among them, the presence of spermidine derivatives, such as N1,N8-di(coumaroyl)-spermidine and N1,N8-di(sinapoyl)-spermidine, and their biosynthetic genes have been reported in Arabidopsis, but their functions in plants are still unknown. We chemically synthesized the above-mentioned spermidine derivatives to assess their physiological functions in Arabidopsis. We evaluated the growth and development of chemically treated Arabidopsis and demonstrated that these compounds inhibited seed germination, hypocotyl elongation, and primary root growth, which could be due to modulation of plant hormone homeostasis and signaling. The results suggest that these compounds are regulatory metabolites that modulate plant growth and development.
Subject(s)
ArabidopsisABSTRACT
Strigolactones (SLs) are carotenoid-derived plant hormones involved in the development of various plants. SLs also stimulate seed germination of the root parasitic plants, Striga spp. and Orobanche spp., which reduce crop yield. Therefore, regulating SL biosynthesis may lessen the damage of root parasitic plants. Biosynthetic inhibitors effectively control biological processes by targeted regulation of biologically active compounds. In addition, biosynthetic inhibitors regulate endogenous levels in developmental stage- and tissue-specific manners. To date, although some chemicals have been found as SL biosynthesis inhibitor, these are derived from only three lead chemicals. In this study, to find a novel lead chemical for SL biosynthesis inhibitor, 27 nitrogen-containing heterocyclic derivatives were screened for inhibition of SL biosynthesis. Triflumizole most effectively reduced the levels of rice SL, 4-deoxyorobanchol (4DO), in root exudates. In addition, triflumizole inhibited endogenous 4DO biosynthesis in rice roots by inhibiting the enzymatic activity of Os900, a rice enzyme that converts the SL intermediate carlactone to 4DO. A Striga germination assay revealed that triflumizole-treated rice displayed a reduced level of germination stimulation for Striga. These results identify triflumizole as a novel lead compound for inhibition of SL biosynthesis.
Subject(s)
Biosynthetic Pathways/drug effects , Heterocyclic Compounds, 3-Ring/metabolism , Imidazoles/pharmacology , Lactones/metabolism , Germination/drug effects , Imidazoles/chemistry , Molecular Structure , Oryza/drug effects , Oryza/metabolism , Plant Roots/drug effectsABSTRACT
Strigolactones (SLs) are small carotenoid-derived molecules that possess a wide spectrum of functions, including plant hormonal activities and chemical mediation of rhizosphere communication with both root parasitic plants and symbiotic arbuscular mycorrhizal fungi. Chemicals that regulate the functions of SLs may therefore have the potential to become widely used in agricultural applications. For example, various SL analogs and mimics have been developed to reduce the seed banks of root parasites in the field. Other analogs and mimics act selectively to suppress branching, with weak, or no stimulation, of germination in root parasites. In addition, some antagonists for SL receptors have been developed based on the mechanisms of SL perception. A better understanding of the modes of action of SL perception by various receptors will help to support the design of SL analogs, mimics, and antagonists with high activity and selectivity. Here, we review the compounds reported so far from the viewpoint of their selectivity to their targets, and the possibilities for their use in agriculture.
Subject(s)
Crops, Agricultural/drug effects , Lactones/pharmacology , Plant Development/drug effects , Plant Growth Regulators/pharmacology , Agriculture/methods , Crops, Agricultural/growth & development , Lactones/agonists , Lactones/antagonists & inhibitors , Plant Growth Regulators/agonists , Plant Growth Regulators/antagonists & inhibitorsABSTRACT
PURPOSE: This multicenter, randomized controlled study evaluates the safety of early oral feeding following gastrectomy, and its effect on the length of postoperative hospital stay. METHODS: The subjects of this study were patients who underwent distal gastrectomy (DG) or total gastrectomy (TG) for gastric cancer between January 2014 and December 2015. Patients were randomly assigned to the early oral feeding group (intervention group) or the conventional postoperative management group (control group) for each procedure. We evaluated the length of postoperative hospital stay and the incidence of postoperative complications in each group. RESULTS: No significant differences in length of postoperative stay were found between the intervention and control groups of the patients who underwent DG. The incidence of postoperative complications was significantly greater in the DG intervention group. In contrast, the length of postoperative stay was significantly shorter in the TG intervention group, although the TG group did not attain the established target sample size. CONCLUSION: Early oral feeding did not shorten the postoperative hospital stay after DG. The higher incidence of postoperative complications precluded the unselected adoption of early oral feeding for DG patients. Further confirmative studies are required to definitively establish the potential benefits of early oral feeding for TG patients.
Subject(s)
Enteral Nutrition/methods , Feeding Methods , Gastrectomy , Length of Stay , Postoperative Care , Stomach Neoplasms/surgery , Adult , Aged , Female , Gastrectomy/methods , Humans , Incidence , Male , Middle Aged , Postoperative Complications/epidemiology , Postoperative Period , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: The necessity of surgical treatment of liver metastases of gastric cancer is still controversial. PATIENTS AND METHODS: We conducted a multicenter retrospective cohort study of liver-limited metastasis of gastric cancer treated surgically between 2000 and 2010. In this study, 103 patients were registered, with nine patients excluded from the analysis as they did not meet the eligibility criteria. RESULTS: Of the 94 patients, 69 underwent surgical resection, 11 underwent surgical resection combined with radiofrequency ablation or microwave coagulation therapy for small or deep tumors, and 14 underwent radiofrequency ablation or microwave coagulation therapy only. Synchronous and metachronous metastases were found in 37 and 57 patients, respectively. The 3- and 5-year overall survival rates of all the patients were 51.4 and 42.3 %, respectively. The 3- and 5-year relapse-free survival rates were 29.2 and 27.7 %, respectively. No significant difference in prognosis was observed between the patients who underwent surgical resection and those who underwent ablation therapy. The patients with hepatic solitary lesions and low-grade lymph node metastases of primary gastric cancer had significantly better overall survival and relapse-free survival. CONCLUSIONS: To our knowledge, this study is the largest series and first multicenter cohort study of liver-limited metastasis of gastric cancer. The study indicated that patients with a single liver metastasis with a grade lower than N2 lymph node metastasis of the primary lesion are the best candidates for liver resection.
Subject(s)
Catheter Ablation/methods , Gastrectomy/methods , Hepatectomy/methods , Liver Neoplasms/surgery , Stomach Neoplasms/surgery , Aged , Female , Follow-Up Studies , Humans , Liver Neoplasms/secondary , Lymphatic Metastasis , Male , Neoplasm Invasiveness , Neoplasm Staging , Prognosis , Retrospective Studies , Stomach Neoplasms/pathology , Survival RateABSTRACT
BACKGROUND: Oral uracil-tegafur and leucovorin (UFT/LV) therapy for elderly patients with metastatic colorectal cancer (mCRC) requires careful handling in Western countries because of a high incidence (≥20 %) of grade 3 diarrhea. However, its efficacy and safety for elderly Asian patients have not been investigated. METHODS: In this multicenter cooperative phase II study, the eligibility criteria were: age of 75 years or older, no prior chemotherapy, and histologically confirmed colorectal cancer with one or more measurable lesions. UFT 300 mg/m(2)/day and LV 75 mg/day were administered orally for 28 days followed by a 7-day rest period. RESULTS: Twenty-one patients were enrolled in this study (prior to study termination after approval of bevacizumab), and all patients were eligible for efficacy and safety analysis. The median age was 79 years (range, 75-83 years). The majority of patients (95 %) had ECOG Performance Status 0 or 1. The overall response rate was 33 % (95 % confidence interval [CI], 18-53 %). The median progression-free and overall survivals were 5.3 months (95 % CI 4.0-7.9 months) and 18 months (95 % CI 13-21 months), respectively. Grade 3 or greater adverse events included anorexia (10 %), diarrhea (10 %), and leukopenia (5 %). These results were compatible with those seen in Japanese patients in a previous bridging study between Japan and the US, in which patients under 75 years old were evaluated. CONCLUSIONS: UFT/LV therapy was safe and feasible in elderly Japanese patients with mCRC, and further study of UFT/LV therapy in combination with bevacizumab is warranted.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Administration, Oral , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Asian People , Disease-Free Survival , Female , Humans , Leucovorin/administration & dosage , Leucovorin/adverse effects , Male , Tegafur/administration & dosage , Tegafur/adverse effects , Uracil/administration & dosage , Uracil/adverse effectsSubject(s)
Brain , Dura Mater , Brain/diagnostic imaging , Brain/surgery , Dura Mater/diagnostic imaging , Dura Mater/surgery , HumansABSTRACT
INTRODUCTION: Laparoscopic resection has been reported as reasonable for patients with gastrointestinal stromal tumors (GISTs). In this study, we report the feasibility of the laparoscopic approach for GIST of the stomach. We also discuss the laparoscopic approach for GIST larger than 5 cm, which is reported to be difficult to treat by laparoscopic surgery. MATERIALS AND METHODS: We retrospectively reviewed 22 patients with GIST of the stomach resected by laparoscopic or open procedures between January 2006 and February 2014. RESULTS: Laparoscopic resections were performed in 9 patients and open resections in 13 patients. Curative resections with negative resection margins were successfully completed for all patients. Although the size of the tumors was greater in open surgery cases than in laparoscopic patients (P = 0.03), the loss of blood was lower and the hospital stay was shorter in laparoscopic cases (P = 0.01 and 0.003, respectively). Laparoscopic resection was performed for 2 patients with GISTs larger than 5 cm. Both were located at greater curvature, and curatively resected without any complications or recurrence. DISCUSSION: Our experience suggests that laparoscopic surgery for GISTs of the stomach, including those larger than 5 cm, may be feasible after careful deliberation of its indications. Laparoscopic resection for GIST was associated with lower loss of blood and shorter hospital stay in comparison with open resection.
Subject(s)
Gastrointestinal Stromal Tumors/surgery , Stomach Neoplasms/surgery , Aged , Gastrectomy , Humans , Laparoscopy , Male , Middle Aged , Retrospective Studies , Stomach Neoplasms/pathology , Treatment OutcomeABSTRACT
BACKGROUND: We conducted a phase II trial to evaluate the efficacy and safety of preoperative chemotherapy with docetaxel (DTX) plus S-1 for resectable advanced gastric cancer. PATIENTS AND METHODS: A total of 47 patients from 14 centers were centrally registered. Patients received DTX (35 mg/m(2)) on days 1 and 15, and daily oral administration of S-1 (80 mg/m(2)/day) for days 1-14 every 4 weeks for two courses, followed by gastrectomy with D2 lymphadenectomy. The primary endpoint was pathological response rate (pRR). This study was registered in the UMIN clinical trial registry (UMIN000000875). RESULTS: The primary endpoint pRR was 47 % (90 % confidence interval (CI), 34-60 %; p < 0.0001). The response rate to preoperative chemotherapy using Response Evaluation Criteria in Solid Tumors (RECIST) was 34 %. Forty-six patients (98 %) underwent surgery, and curative resection was performed in 44 patients. Thirty-seven patients completed the protocol treatment. The most common toxicities of neoadjuvant chemotherapy were grade 3/4 neutropenia (42 %), febrile neutropenia (4 %), grade 2 anorexia (21 %), and fatigue (15 %). Treatment-related death and operative mortality was not observed in this study. CONCLUSIONS: The combination of docetaxel and S-1 was well tolerated. This is promising as a preoperative chemotherapy regimen for patients with potentially resectable advanced gastric cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Gastrectomy , Lymph Node Excision , Neoadjuvant Therapy , Stomach Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Combined Modality Therapy , Docetaxel , Drug Combinations , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Staging , Oxonic Acid/administration & dosage , Preoperative Care , Prognosis , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Stomach Neoplasms/surgery , Survival Rate , Taxoids/administration & dosage , Tegafur/administration & dosageABSTRACT
Strigolactones (SLs) are plant hormones that regulate shoot branching. In addition, SLs act as compounds that stimulate the germination of root parasitic weeds, such as Striga spp. and Orobanche spp., which cause significant damage to agriculture worldwide. Thus, SL agonists have the potential to induce suicidal germination, thereby reducing the seed banks of root parasitic weeds in the soil. Particularly, phenoxyfuranone-type SL agonists, known as debranones, exhibit SL-like activity in rice and Striga hermonthica. However, little is known about their effects on Orobanche spp. In this study, we evaluated the germination-inducing activity of debranones against Orobanche minor. Analysis of structure-activity relationships revealed that debranones with electron-withdrawing substituents at the 2,4- or 2,6-position strongly induced the germination of Orobanche minor. Lastly, biological assays indicated that 5-(2-fluoro-4-nitrophenoxy)-3-methylfuran-2(5H)-one (test compound 61) induced germination to a comparable or even stronger extent than GR24, a well-known synthetic SL. Altogether, our data allowed us to infer that this enhanced activity was due to the recognition of compound 61 by the SLs receptor, KAI 2d, in Orobanche minor.
Subject(s)
Germination , Lactones , Orobanche , Plant Growth Regulators , Plant Weeds , Germination/drug effects , Orobanche/drug effects , Orobanche/growth & development , Orobanche/chemistry , Lactones/pharmacology , Lactones/chemistry , Plant Growth Regulators/pharmacology , Plant Growth Regulators/chemistry , Structure-Activity Relationship , Plant Weeds/drug effects , Plant Weeds/growth & development , Seeds/drug effects , Seeds/growth & development , Seeds/chemistry , Molecular StructureABSTRACT
PURPOSE: Perforated diverticulitis (PD) remains a serious acute abdominal condition. The aim of this study was to evaluate indications for emergency surgery in patients ≥80 years of age with PD. METHOD: Twenty patients ≥80 years of age and 28 younger patients who underwent emergency surgery for PD from January 2002 to December 2011 were studied. The demographics and postoperative outcomes were compared. RESULTS: The preoperative characteristics, mortality rate, and postoperative complications were similar between these two groups. All seven patients ≥80 years of age with an American Society of Anesthesiologists (ASA) score of 2 survived after surgery. All five patients with a Mannheim peritonitis index (MPI) score of ≥26 in the elderly group died after surgery. There were significant associations between the mortality, the MPI and ASA score in patients ≥80 years of age. CONCLUSIONS: Best supportive care may be an alternative for patients ≥80 years of age with PD, an ASA score of ≥3 or an MPI score of ≥26.
Subject(s)
Digestive System Surgical Procedures , Diverticulitis, Colonic/surgery , Emergency Treatment , Health Status Indicators , Intestinal Perforation/surgery , Severity of Illness Index , Age Factors , Aged, 80 and over , Asian People , Digestive System Surgical Procedures/mortality , Diverticulitis, Colonic/mortality , Emergencies , Emergency Treatment/mortality , Female , Humans , Intestinal Perforation/mortality , Male , Peritonitis/mortalityABSTRACT
Intestinal malrotation is a congenital abnormality and is rarely seen in the adulthood. Most adult cases would be classified to the non-rotation type with Ladd's band and Ladd procedure is the treatment of choice. A 66 year-old woman admitted to our hospital due to duodenum obstruction. Several tests revealed that she had intestinal malrotation previously undiagnosed. Operative findings showed the fusion of duodenum with jejunum by the incomplete Treitz ligament. There was no Ladd's band and the right colon was unfixed. Dissection of the fusion completely released her symptom and she discharged without any complication. This is the first report of untypically intestinal malrotation in the adulthood without Ladd's band.
Subject(s)
Digestive System Surgical Procedures/methods , Duodenal Obstruction/etiology , Duodenal Obstruction/surgery , Intestinal Volvulus/congenital , Aged , Digestive System Abnormalities , Duodenal Obstruction/diagnosis , Female , Humans , Intestinal Volvulus/complications , Intestinal Volvulus/diagnosis , Intestinal Volvulus/surgery , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Cyclopropene derivatives have been used as extremely reactive units in organic chemistry owing to their high ring-strain energy. They have become popular reagents both for bioorthogonal chemistry and for chemical biology because of their small size and ability to be genetically encoded. In this context, we conducted an exploratory study to identify the biologically active cyclopropenes that affect normal plant growth. We synthesized several cycloprop-2-ene-1-carboxylic acid derivatives and evaluated their effects on the early growth stage of Arabidopsis thaliana. Eventually, we identified the chemicals that affect apical hook development in Arabidopsis thaliana. Their mode of action is different from those of ethylene receptor inhibition and gibberellin biosynthesis inhibition. We expect that some of the chemicals reported here can be new tools in chemical biology to determine useful molecular targets for herbicides or plant growth regulators.
ABSTRACT
Strigolactones (SLs), phytohormones that inhibit shoot branching in plants, promote the germination of root-parasitic plants, such as Striga spp. and Orobanche spp., which drastically reduces the crop yield. Therefore, reducing SL production via chemical treatment may increase the crop yield. To design specific inhibitors, it is valid to utilize the substrate structure of the target proteins as lead compounds. In this study, we focused on Os900, a rice enzyme that oxidizes the SL precursor carlactone (CL) to 4-deoxyorobanchol (4DO), and synthesized 10 CL derivatives. The effects of the synthesized CL derivatives on SL biosynthesis were evaluated by the Os900 enzyme assay in vitro and by measuring 4DO levels in rice root exudates. We identified some CL derivatives that inhibited SL biosynthesis in vitro and in vivo.
ABSTRACT
The apocarotenoid zaxinone is a recently discovered regulatory metabolite required for proper rice growth and development. In addition, zaxinone and its two mimics (MiZax3 and MiZax5) were shown to have a remarkable growth-promoting activity on crops and a capability to reduce infestation by the root parasitic plant Striga through decreasing strigolactone (SL) production, suggesting their potential for application in agriculture and horticulture. In the present study, we developed a new series of MiZax via structural modification of the two potent zaxinone mimics (MiZax3 and MiZax5) and evaluated their effect on plant growth and Striga infestation. In general, the structural modifications to MiZax3 and MiZax5 did not additionally improve their overall performance but caused an increase in certain activities. In conclusion, MiZax5 and especially MiZax3 remain the likely most efficient zaxinone mimics for controlling Striga infestation.
Subject(s)
Oryza , Research , Agriculture , Crops, Agricultural , HorticultureABSTRACT
BACKGROUND: The purpose of this study was twofold: (1) to compare S-1 with infusional 5-fluorouracil (FU) to determine which would be a better partner of paclitaxel (PTX), and (2) to compare a concurrent strategy with a sequential one, the latter strategy being the one that is widely used in Japanese general practice. METHODS: The 161 eligible patients were randomized into four arms to receive the following regimens: A (sequential), intravenous 5-FU at 800 mg/m(2) for 5 days every 4 weeks followed by weekly PTX at 80 mg/m(2); B (sequential), S-1 at 80 mg/m(2) for 4 weeks and 2-week rest followed by PTX; C (concurrent), intravenous 5-FU at 600 mg/m(2) for 5 days and weekly PTX at 80 mg/m(2) every 4 weeks; and D (concurrent), S-1 for 14 days and PTX at 50 mg/m(2) on days 1 and 8 every 3 weeks. The primary endpoint was the overall survival (OS) rate at 10 months. RESULTS: The ten-month OS rates in arms A, B, C, and D were 63, 65, 61, and 73%, respectively. The OS was best in the concurrent S-1/PTX arm, with a mean survival time of 15.4 months, but no significant difference was observed between the four arms. Response rates were higher in the concurrent arms than in the sequential arms. CONCLUSION: Our study did not show sufficient prolongation of survival with the concurrent strategy to proceed to a phase-III trial; however, the sequential arms showed survival comparable to that in the concurrent arms, with less toxicity. In patients who are ineligible for cisplatin (CDDP), sequential treatment starting with S-1 and proceeding to PTX would be a good alternative strategy, considering quality of life (QOL) and the cost-benefits of an oral agent as first-line treatment.