Summary Background : Mitogen‐activated protein (MAP) kinases, including extracellular signal‐regulated kinases (ERK),c‐Jun NH2‐terminal kinases (JNK) and p38 MAP kinase (p38 MAPK) are important intermediates of the signal‐transduction pathway from the cell surface to the nucleus. Expression of cyclooxygenase (COX)‐2, associated with proliferation, apoptosis or both of gastrointestinal cancer cells, is mediated through MAP kinase families. However, the correlation between respective MAP kinase signals and COX‐2 in the proliferation of gastric and colon cancer cells has not been well elucidated. Aim : We examined the effect of selective inhibitors of MAP kinases and COX‐2 on serum‐induced proliferation of gastric (MKN45) and colon (HT29) cancer cells. Methods : After 24‐h serum starvation, cancer cells were stimulated with 2% serum and COX‐2 inhibitors (NS398 10 µmol/L, or etodolac 100 µmol/L) or 1 h after preincubation with inhibitors for ERK (PD98059 20 µmol/L) or p38 MAPK (SB203580 10 µmol/L). Phosphorylated MAP kinases and COX‐2 protein were evaluated by Western blotting, and the proliferation of cancer cells was estimated by 3H‐thymidine incorporation. Transcription factors nuclear factor‐κB and CREB were assayed by an electorophoretic mobility shift assay. Results : Serum increased the proliferation of MKN45 and HT29 cells by 280% and 200%, respectively, compared with the control levels (100%). In both cancer cells, phosphorylated MAP kinases were increased within 30 min after stimulation. PD98059 and SB203580 inhibited the serum‐induced proliferation of MKN45 by 21% and 51% and of HT29 by 81% and 69%, respectively. NS398 and etodolac inhibited the proliferation of HT29 by 21% and 41%, respectively, but not that of MKN45. PD98059 and SB203580 also suppressed serum‐induced expression of COX‐2 protein in HT29 cells. In addition to the activation of MAP kinases and COX‐2, activities of nuclear factor‐κB and CREB were also increased during HT29 cell proliferation. Conclusions : These results suggest that the correlation of MAP kinases with COX‐2 induction for cell proliferation differs between MKN45 and HT29 cells.
Objective: S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase, and potassium oxonate (Oxo), a reducer of gastrointestinal toxicity. S-1 has safe and potent antitumor effects in patients with gastric cancer via these respective functions. However, the plasma 5-FU concentration is suspected to accumulate in patients with renal dysfunction, because 50% of the CDHP is excreted into the urine. There are no useful data on safety and efficacy of S-1 in chronic renal failure patients maintained on hemodialysis (HD). We examined the influence of HD on the pharmacokinetics (PK) of S-1 and its therapeutic efficacy in liver metastases from gastric cancer. Methods: For the HD patient, the dose of S-1 in a single-administration study was set at 50 mg/body/day (41.7% of the recommended dose of 80 mg/m2/day). S-1 was given to the patient 24 h after HD. Blood samples were obtained before administration and 2, 4, 6, 8, and 24 h thereafter and 1, 2, 4, and 72 h after the following HD session. The PK parameters (5-FU, CDHP, Oxo, and FT) were measured, and Cmax, Tmax, AUC0–24, and T1/2 were calculated. The dose of consecutive or maintained administrations was determined. Results: Both an increase in Cmax and an elongation of T1/2 for 5-FU, CDHP, and Oxo, but not for FT, occurred in this case as compared with controls. The AUC0–24 of 5-FU in this case was similar to that of controls at the standard dose. After HD, 87.8, 54.5, 77.4, and 66.2% of 5-FU, CDHP, Oxo, and FT, respectively, were eliminated. A slight accumulation of CDHP did not alter the 5-FU PK. Consecutive or maintained S-1 oral administration at the same dose showed similar effects on all PK parameters of a single-administration test. Liver metastases almost totally regressed with no adverse events 4 weeks after S-1 treatment (50 mg/body/day three times a week). Conclusion: Adjusted doses of S-1 according to the results of PK studies may provide therapeutic safety and high efficacy in liver metastases from gastric cancer, even in chronic renal failure patients maintained on HD.
Endoscopic ultrasonography-guided fine-needle aspiration biopsy (EUS FNAB) is a relatively new technique for obtaining specimens with excellent imaging power. The convex type of echoendoscope used with EUS FNAB provides images perpendicular to the endoscope, which differ from those of popular radial echoendoscopes and, hence, require different usage techniques. Color flow imaging is used to avoid the vessels in and around the mass during puncturing. EUS FNAB for submucosal tumors is sometimes difficult because the needle slips easily, and the gastrointestinal wall tends to be stretched when pushing the needle, which can be solved by making a dimple on the wall before puncturing. Lesions of the pancreas head, especially those at the uncus, and lymph nodes near the superior mesenteric artery are also difficult because of their distance from the endoscope and the resultant bending of the needle. Tissue sampling is more successful when the angle between the endoscope and the needle is kept at just less than 45 degrees, as this helps to transmit the hand force to the needle effectively. The complication rate of EUS FNAB is reportedly 1-2%, and so the technique is considered a safe modality, except for cystic lesions of the pancreas. Recent histological evidence is needed before applying medical therapies, such as chemoradiation and surgery, especially when imaging modalities alone cannot supply the evidence of malignancy; hence increasing importance of EUS FNAB is expected.
EUS may be useful for predicting the prognosis of patients with pancreatic head cancer, based on the accuracy it provides in evaluating locoregional spreading.
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