Expression of matrix metalloproteinases in gastric carcinoma and possibility of clinical application of matrix metalloproteinase inhibitor in vivo.
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Acetamides↗
Biomedical subjects
K Kumai
Publications and source records attributed to K Kumai.
Cell-specific expression of the diphtheria toxin A-chain coding sequence under the control of the upstream region of the human alpha-fetoprotein gene.
BACKGROUND AND OBJECTIVES: Development of the system to express a suicide gene selectively in tumor cells is essential for gene therapy. We constructed a plasmid containing the diphtheria toxin A (DTA) fragment linked to human alpha-fetoprotein (AFP) promoter and enhancer, and tested whether it can exert its cytocidal effect selectively on AFP-producing cells. METHODS: The chloramphenical acetyltransferase (CAT) reporter gene or DTA gene was linked to the 5' upstream region of the AFP gene. The plasmids were transfected into AFP-producing or non-producing cells by the lipopolyamine-coated DNA method. Expression of CAT activity and effects on cell growth of transfected cells were assessed. RESULTS: When the AFP-producing cells HuH-7 or HepG2 were cotransfected with CAT reporter plasmid and pAF5.1DTA plasmid, the CAT activity was greatly suppressed. In contrast, cotransfection with pAF5.1DTA-R, the inversely inserted DTA gene, did not inhibit CAT activity. Furthermore, cell growth of HuH-7 cells transfected with pAF5.1DTA plasmid was significantly inhibited compared with HuH-7 cells transfected with DTA-R plasmid. CONCLUSIONS: Our results indicate that selective killing of AFP-producing cells will be attained by introducing the DTA gene linked to the promoter and enhancer region of AFP.
Carcinoma, Hepatocellular↗
Curative laparoscopic surgery for early gastric cancer: five years experience.
Sixty-one patients who were diagnosed with mucosal gastric cancer have been successfully treated with two laparoscopic techniques at our institute from March 1992 to March 1997. One is laparoscopic wedge resection of the stomach using a lesion-lifting method for lesions of the anterior wall, the lesser curvature, and the greater curvature of the stomach. The other is laparoscopic intragastric mucosal resection for lesions of the posterior wall of the stomach and near the cardia or the pylorus. Indications are as follows: (1) preoperatively diagnosed mucosal cancer; (2) <25 mm diameter elevated lesions; and (3) <15 mm diameter depressed lesions without ulcer formation. Patients were discharged in 4 to 8 days uneventfully. There was no major complication or mortality. The resected specimens had sufficient surgical margins horizontally (16 +/- 5 and 8 +/- 4 mm, respectively) and vertically. In one patient histologic examination revealed slight tumor infiltration into the submucosal layer with lymphatic invasion. He underwent gastrectomy with lymph node dissection 1 month after surgery. Otherwise, histologic examination revealed curative surgery. All patients in the series have survived during the 4- to 65-month follow-up period. There have been two recurrences in the series, both of which were found near the staple line 2 years after the initial surgery and were still mucosal lesions. They were successfully treated by open gastrectomy and laser irradiation. A separate early gastric cancer was found 2 years after the initial surgery in one patient, who then underwent curative open gastrectomy. In conclusion, if the patients are selected properly, these laparoscopic procedures are curative, minimally invasive treatment for early gastric cancer.
Adult↗
Preventive effect of matrix metalloproteinase inhibitor, R-94138, in combination with mitomycin C or cisplatin on peritoneal dissemination of human gastric cancer cell line TMK-1 in nude mice.
R-94138, a matrix metalloproteinase inhibitor, was examined for the ability to prevent peritoneal dissemination of a human gastric cancer xenograft, TMK-1. When the supernatant of a co-culture of TMK-1 cells and human normal fibroblast cells was subjected to gelatin zymography, it was clear that the protein expression of MMP-2 had been inhibited by R-94138. When TMK-1 was injected intraperitoneally (i.p.) into nude mice at 5 x 10(5) cells/body, the resulting peritoneal dissemination mimicked clinical carcinomatous peritonitis. When the maximum tolerated dose of mitomycin C (MMC) or cisplatin (DDP) was given 12 h after the tumor inoculation, peritoneal dissemination was completely inhibited, while the effect of R-94138 was limited when it was given i.p. at a dose of 20 mg/kg in a schedule of q.d. x 5 starting 12 h after tumor injection. MMC and DDP also suppressed peritoneal dissemination when they were administered 1 week after the tumor inoculation at a single dose of 2 and 3 mg/kg i.p., respectively. R-94138 inhibited peritoneal dissemination when it was administered i.p. at a dose of 30 mg/kg in a schedule of q.d. x 5 starting from 1 week after tumor injection. The combination of MMC and R-94138 increased the preventive effect on peritoneal dissemination. R-94138 seems to be a promising candidate to prevent peritoneal dissemination of gastric cancer.
Acetamides↗
Dihydropyrimidine dehydrogenase activity and messenger RNA level may be related to the antitumor effect of 5-fluorouracil on human tumor xenografts in nude mice.
We investigated the correlation between tumor sensitivity to 5-fluorouracil (5-FU) and the enzymatic activity and mRNA levels of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) using human tumor xenografts in nude mice. Three gastric carcinoma xenografts (SC-1-NU, St-4, and H-111), two colon carcinoma xenografts (Co-4 and Col-3-JCK), one pancreatic carcinoma xenograft (PAN-3-JCK), and one breast carcinoma xenograft (MX-1) were inoculated into nude mice. When the resultant tumors reached 100-300 mg, 5-FU was administered i.p. at a dose of 60 mg/kg in a schedule of three times every 4 days, and the antitumor activity of 5-FU was evaluated as the relative mean tumor weight in treated mice compared to control mice. Xenografts were also inoculated into untreated nude mice. When tumors weighed 200-300 mg, tumor tissues were resected for measurement of tumoral TS and DPD. TS and DPD activities were detected by the TS-binding assay and a radioenzymatic assay, respectively. mRNA levels were measured by semiquantitative reverse transcription-PCR, with glyceraldehyde-3-phosphate dehydrogenase coamplified as an internal standard. TS and DPD activities ranged from 84.7 to 775.5 fmol/mg protein and from not detectable to 79.7 pmol/min/mg protein, respectively. TS and DPD mRNA levels ranged from 0.51 to 9.90 and from not detectable to 0.93, respectively. The enzymatic activities of TS and DPD were correlated with observed mRNA levels. DPD levels were significantly correlated with 5-FU sensitivity, with high DPD activity and high DPD mRNA level resulting in low sensitivity to 5-FU. In contrast, no correlation between TS level and 5-FU sensitivity was observed. Tumoral DPD activity and DPD mRNA level may be useful indicators in predicting the antitumor activity of 5-FU.
Animals↗
[Antitumor effect of a matrix metalloproteinase inhibitor, TA-2516 (Marimastat), on a nude mouse model of intraperitoneal seeding of stomach cancer].
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Animals↗
[Antineoplastic effect of novel agents, UCN-01 on human tumor cells transplanted in nude mice].
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Alkaloids↗
Lymph node metastasis of early gastric cancer with submucosal invasion.
BACKGROUND: A clinicopathological study of early gastric cancer with submucosal invasion was carried out in relation to lymph node metastasis. METHODS: A retrospective study was conducted of 245 patients with submucosal gastric cancer treated by gastrectomy combined with D2 lymph node resection between 1985 and 1994 in a university hospital. RESULTS: Lymph node metastasis was observed in 34 patients (14 per cent). The mortality rate due to recurrence in patients with lymph node metastasis (three of 34) was significantly higher than in those without lymph node metastasis (five (2 per cent) of 211) (chi2 = 3.95, 1 d.f., P < 0.05). Tumour size, depth of invasion, lymphatic involvement of cancer cells and preoperative diagnosis of advanced cancer correlated significantly with the presence of lymph node metastasis. When the submucosal carcinomas were classified into three categories according to depth of invasion by dividing the submucosal (sm) layer into three equal parts, sm1, sm2 and sm3, the incidence of lymph node metastasis increased from 2 per cent to 12 and 20 per cent respectively. CONCLUSION: When the pathological report reveals sm1 invasion after laparoscopic or endoscopic surgery, reoperation should not be necessary because sm1-carcinomas with diameters of less than 2 cm do not usually metastasize to the lymph nodes.
Adult↗
[Laparoscopic surgery for early gastric cancer--its advantages and pitfalls].
We have successfully established two different laparoscopic procedures for early gastric cancer since March 1992, which are laparoscopic wedge resection of the stomach using a lesion-lifting method and laparoscopic intragastric mucosal resection. The indication is as follows; (A) mucosal cancer, (B) < 25 mm, if the lesion is elevated type, (C) < 15 mm and Ul (-), if the lesion is depressive type. The advantages of these methods are; 1) minimally invasiveness, 2) sufficient surgical margin, 3) feasibility of detailed histology, 4) feasivility of perigastric lymph node dissection. In contrast, there are several problems to be solved, which are; 1) preoperative diagnostic accuracy of the depth of cancer invasion, 2) possibility of reoperation because of sm invasion or lymphatic or venous invasion in final histology, 3) possibility of postoperative stenosis after laparoscopic intragastric mucosal resection for the lesion near the cardia, 4) incidence of metachronous multiple gastric cancer. In conclusion, if the indication is properly selected, these laparoscopic procedures are curative and minimally invasive treatment for early gastric cancer.
Gastric Mucosa↗
[Human tumor sensitivity to 5-fluorouracil influenced by dihydropyrimidine dehydrogenase mRNA in the tumor].
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Animals↗
Characteristics of Helicobacter pylori strains isolated from patients with different gastric diseases.
The pathogenesis of chronic gastritis, gastric ulcer, duodenal ulcer, gastric cancer, and remnant gastritis is considered to be related to infection by Helicobacter pylori. The purpose of this study was to investigate the characteristics of H. pylori strains isolated from patients with various gastric diseases. Fifty strains of H. pylori were clinically isolated at Keio University Hospital and were assessed for (i) vacuolating cytotoxin (VT) production, by cytotoxic assay using rabbit kidney (RK) 13 cells; (ii) the expression of cytotoxin associated gene (cagA), by polymerase chain reaction; and (iii) motility on a semi-solid plate. Positivity for VT production by H. pylori strains isolated from patients with chronic gastritis, gastric ulcer, duodenal ulcer, gastric cancer, and remnant gastritis, was 100%, 89%, 92%, 100%, and 60%, respectively. There was no significant difference in the incidence of positivity for cagA among the strains isolated from different gastric diseases. Swarming distances, which indicate motility of H. pylori strains, were 12.7, 13.2, 12.8, 16.6 and 9.2mm in strains from chronic gastritis, gastric ulcer, duodenal ulcer, gastric cancer, and remnant gastritis, respectively, with H. pylori isolated from remnant gastritis showing significantly less motility than H. pylori isolates from other diseases. There were no significant differences in VT production and cagA positivity among the H. pylori strains.
Animals↗
The role of stromal cells in the expression of interstitial collagenase (matrix metalloproteinase-1) in the invasion of gastric cancer.
BACKGROUND AND OBJECTIVES: In one of the steps of tumor invasion and metastasis, tumor cells must invade surrounding tissues and degrade the components of the basement membranes. Interstitial collagenase (matrix metalloproteinase-1: MMP-1) has been also investigated in relation to cancer invasion and metastasis. METHODS: We investigated the formation and mechanism of MMP-1 expression using gastric cancer cell lines and gastric fibroblasts derived from normal gastric mucosa by ELISA and immunohistochemistry. RESULTS: Production of MMP-1 protein in gastric fibroblasts was stimulated significantly by adding the conditioned medium of MKN-74. Localization of MMP-1 protein in the xenografted gastric cancer cell lines was heterogeneous according to different cell lines. CONCLUSIONS: These results suggested that the production of MMP-1 protein in tumor invasion was regulated by interaction between stromal cells, particularly fibroblasts, and tumor cells.
Animals↗
Surgical management of gastric leiomyosarcoma: evaluation of the propriety of laparoscopic wedge resection.
Laparoscopic surgery has been applied to malignant gastric tumors. To evaluate the propriety of laparoscopic wedge resection for gastric leiomyosarcoma it is necessary to question whether lymph node dissection is necessary for the surgical management of gastric leiomyosarcoma. A retrospective study on open surgery cases of gastric leiomyosarcoma was performed to address this issue. The clinical records of 28 patients with gastric leiomyosarcoma who had had surgery were examined. The patients who underwent open surgery were divided into a systematic lymph node dissection (SLND) group (n = 9) and a nondissection (non-D) group (n = 19). No patient had lymph node metastasis at the time of operation or recurrence, and statistical analysis showed no difference between the SLND and non-D groups in terms of survival rates. These data suggest that SLND might not be necessary for the surgical management of gastric leiomyosarcoma and that laparoscopic wedge resection of the stomach can be considered a first-line treatment for gastric leiomyosarcoma.
Adult↗
Matrix metalloproteinase gene expression in chronic gastric ulcer: a potential role of eosinophils in perforation.
Gene expression of matrix degrading enzymes was investigated in surgical specimens of perforated gastric ulcers. In these ulcers, the inflammatory cells infiltrating into the granulation tissue were granulocytes, particularly eosinophils. The extracellular matrix of the stomach wall consists mainly of collagen types I and III, which are selectively degraded by matrix metalloproteinase-1 (MMP-1). MMP-1 mRNA was detected in the cytoplasm of infiltrating cells, suggesting that eosinophils play an important role in ulcer recurrence and in perforation of the stomach wall. The degree of eosinophil infiltration into an ulcer base may be a useful marker for the risk of perforation. Patients showing this marker may benefit from a prophylactic therapy for preventing severe complications. The control of MMP gene expression represents a potential strategy for the treatment of recurrent gastric ulcer.
Adult↗
Expression of interstitial collagenase (matrix metalloproteinase-1) in gastric cancers.
The expression of matrix metalloproteinase-1 (MMP-1) gene and the presence of MMP-1 protein in gastric cancer were examined by in situ hybridization and immunohistochemistry. Expression of the interstitial collagenase (MMP-1) gene was detected within the stroma of the neoplastic glands, and infiltration of eosinophils was observed to be associated with regions of MMP-1 gene expression. The degree of eosinophilic infiltration correlated with the level of MMP-1 mRNA expression. Immunostaining showed localization of MMP-1 protein in the stromal cells, and additionally in the neoplastic glands. These findings indicate that the stromal cells may play an important role in the expression of MMP-1, and suggest a pathophysiological role for MMP-1 in the invasion and metastasis of gastric cancer.
Adenocarcinoma↗
[Jejunal pouch interposition after total gastrectomy].
The results and procedures of interposed jejunal pouch after total gastrectomy for gastric cancer are reported. Basic requirements of reconstruction after total gastrectomy are 1) formation of a food reservoir, 2) maintenance of duodenal continuity, 3) avoidance of reflux esophagitis, 4) gradual emptying of reservoir into the small intestine. Since 1950's, several procedures of gastric substitutes have been reported. But they were not widely performed. Because scientific evaluation of the value of gastric substitutes was difficult and the operative procedures were time consuming and complicated. With an increasing ratio of early gastric cancer in 1990's, the importance of post-operative QOL, such as food intake and body weight maintenance, in patients after total gastrectomy has been recognized. Our procedure is a double lumen jejunal pouch distal to a interposed jejunum. The length of interposed jejunum is 20 cm and that of pouch is 10 cm. Using surgical staplers, this procedure is safe and simple. Jejunal pouch interposition leads to a satisfactory symptomatic and nutritional result in gastrectomized patients.
Gastrectomy↗
Antitumour activity of cis-diamminedichloroplatinum (II) against human tumour xenografts depends on its area under the curve in nude mice.
A pharmacodynamic analysis of cis-diamminedichloroplatinum(II) (DDP) was conducted using two human gastric cancer xenografts, SC-1-NU and MKN-45, and one human breast cancer xenograft, MX-1, grown serially in BALB/c nu/nu mice. DDP was administered intraperitoneally (i.p.) at a total dose of 5, 10, or 20 mg/kg in a schedule of q7d x 3 or (qd x 5) x 3. DDP was also administered i.p. to BALB/c +/? mice, whose plasma was used for the assay of total and free platinum by the atomic absorption method. A total dose of 20 mg/kg DDP seemed to be the maximum tolerated dose that was effective on MX-1 and SC-1-NU. When the totally administered doses were equivalent, the antitumor effects of the q7d x 3 and (qd x 5) x 3 schedules were similar to each other. The antitumor activity of DDP against MKN-45 was dependent on the total administered dose as well as the area under the curve of free and total platinum in the plasma. Side effects were significantly reduced using a schedule of (qd x 5) x 3 in terms of body and spleen weight loss when a total of 10 or 20 mg of DDP per kg was administered. These results suggest that DDP would be useful when administered using a daily schedule for obtaining the same antitumor activity as that of bolus injection but with reduced adverse effects.
Animals↗
Pharmacokinetics of cis-diamminedichloroplatinum (II) given as low-dose and high-dose infusions.
A pharmacokinetic analysis of cis-diamminedichloroplatinum (II) (DDP) was conducted comparing low-dose daily bolus infusions, and high-dose drip infusions. Eight patients with gastric cancer were treated with low-dose daily bolus infusions of DDP to a total daily dose of 75 mg/m2 bid for 5 days. Four patients with esophageal cancer and one patient with gastric cancer were treated with high-dose drip infusions of DDP to a total daily dose of 70-80 mg/m2. Side effects were assessed in all the patients, and the platinum concentration in plasma was determined by an atomic absorption method. The peak plasma concentration (Cmax) and area under the curve (AUC) were calculated in four cases of the low-dose therapy, and three cases of the high-dose therapy. The side effects of DDP were evaluated according to the World Health Organization (WHO) grading, paying particular attention to nausea/vomiting, appetite loss, renal toxicity, and bone marrow suppression. The incidence of nausea/vomiting and appetite loss was significantly reduced with low-dose daily bolus infusions when compared to the high-dose drip infusions. Bone marrow toxicity and renal toxicity were similar with both administration methods, although hydration was required for the high-dose drip infusions to prevent renal toxicity. The peak plasma concentration (Cmax) of total and free platinum, and the area under the curve (AUC) of total platinum, were similar with both administration methods, while the AUC of free platinum was higher with the low-dose daily bolus infusions compared to the high-dose drip infusions. The time when the concentration of total platinum was > 1 microgram per ml (holding time) was significantly longer with the high-dose drip infusions than with the low-dose daily bolus infusions. The present study suggests that low-dose daily bolus infusions of DDP would be useful in reducing gastrointestinal toxicity, without reducing the area under the curve which is important for antitumor activity.
Adult↗