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      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

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          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 5×10 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. ×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. ×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.

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          Most cited references 20

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          Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation.

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            Growth-promoting effect of gastrin on human gastric carcinoma cell line TMK-1.

            A human gastric carcinoma cell line TMK-1 was established in vitro by the soft agar method from SC-6-JCK, a poorly differentiated adenocarcinoma xenotransplanted in nude mice. TMK-1 cells had a doubling time of approximately 35 hr and showed carcinoembryonic antigen (CEA), alpha 1-antitrypsin and secretory component immunoreactivity. Ultrastructurally, the tumor cells were characterized by numerous mitochondria, tubulovesicles and intracytoplasmic canaliculi filled with abundant microvilli. The growth of TMK-1 cells was promoted by 10nM human gastrin (G-17), 2 microM tetragastrin or 2 microM pentagastrin, among which human gastrin showed the most effective growth promotion. Moreover, incorporation of [3H]thymidine into TMK-1 cells was stimulated by gastrin in a dose-dependent manner. The content of cyclic adenosine 3',5'-monophosphate (cAMP) in TMK-1 cells was increased by gastrin treatment but decreased to the control level within 10 min. cAMP-dependent protein kinase was also activated by gastrin administration.
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              Surgical/pathologic-stage migration confounds comparisons of gastric cancer survival rates between Japan and Western countries.

              Possible causes underlying the substantial differences in gastric cancer survival rates observed between Japan and the West were examined in a randomized trial comparing the Western R1 resection with limited lymphadenectomy and the Japanese R2 resection with extended lymphadenectomy. The effect of four factors associated with lymphadenectomy on microscopic tumor-node-metastasis (TNM) staging, and on stage-specific survival rates was assessed in 473 curatively resected patients. After application of extended lymphadenectomy, additional information on N status was available, only in R2 resections with up-staging to N2 status in 30% of patients. The calculated effect of this stage migration on known 5-year survival rates was as follows: an increase of 1% in TNM stage Ia, 2% in Ib, 7% in II, 15% in IIIa, and 15% in IIIb. A further increase in survival was observed by stage migration to N3 or N4 status, due to selective extension of lymphadenectomy to clinically overt metastases located outside the allocated level of clearance (contamination). Incomplete lymphadenectomy of N1- or N2-level stations indicated for dissection (noncompliance) demonstrates that more migration can occur when strictly adhering to the protocol. Examining more nodes per N level (diligence) induces even more migration, since the number of nodes that were histologically examined per N level correlated significantly with nodal status (lymph node-negative [N-] or lymph node-positive [N+]). These factors explain, at least partially, superior stage-specific survival rates after R2 compared with R1 resections, without a real survival benefit in individual patients.

                Author and article information

                Jpn J Cancer Res
                Jpn. J. Cancer Res
                Japanese Journal of Cancer Research : Gann
                Blackwell Publishing Ltd (Oxford, UK )
                January 1999
                : 90
                : 1 ( doiID: 10.1111/cas.1999.90.issue-1 )
                : 116-121
                [ 1 ]Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku‐ku, Tokyo 160‐8582,
                [ 2 ]Medical Chemistry Research Laboratories,
                [ 3 ]Biological Research Laboratories and
                [ 4 ]R&D, Planning and Management Department, Sankyo Co., 1‐2‐58 Hiromachi, Shinagawa‐ku, Tokyo 140‐8710
                Author notes
                [* ] To whom correspondence should be addressed. E‐mail: miyasan@
                Page count
                References: 24, Pages: 6
                Custom metadata
                January 1999
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.6.9 mode:remove_FC converted:04.11.2015


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