[The efficacy of S-1 monotherapy as a 2nd/3rd-line therapy for unresectable recurrent colon cancer: Kanagawa conference of clinical oncology (KCCO)].

OBJECTIVE: The efficacy of S-1 as part of a 2nd/3rd-line therapy in cases of advanced recurrent colon cancer was studied. SUBJECTS AND METHODS: The efficacy of treatment with S-1 (initial dosage: 80 mg/m(2)) was studied in 19 patients with advanced recurrent colon cancer in whom PD was observed after pretreatment with 5-FU-based combination chemotherapy had been performed during the period from December 2003 to April 2006. Patients who underwent a course that exceeded 1 month after the pretreatment and who met the criteria for the appropriate use of S-1 were selected as subjects. RESULTS: The median age was 65 years (45 to 75 years old) with 10, 6, and 3 patients having a PS score of 0, 1, and 2, respectively, and the details of the duration of the pretreatment was that 12 and 7 patients respectively received 2nd-and 3rd-line therapy. The median duration of the treatment with S-1 was 141 days, and the number of subjects with PR, SD, and PD who underwent S-1 treatment was 2, 7, and 6, respectively, with a response rate of 13. 3% and a disease control rate of 60. 0%. The progression free survival time and the overall median survival time were 5. 4 months and 13. 9 months, respectively. Regarding the effectiveness according to treatment line, particularly in the subjects who were administered S-1 as part of the 2nd-line therapy, good results were observed, thus showing a response rate of 20% and an overall median survival time of 13. 9 months, which exceeded 1 year. The incidence of adverse events was 58%(11 and 19), and the major side effects were neutropenia in 31. 6% (6 and 19) and leukopenia in 21. 1% (4 and 19) of the patients, which are both mild and showed a grade of 2 or lower. CONCLUSION: The use of S-1 as part of a 2nd/3rd-line therapy in cases of advanced recurrent colon cancer may contribute to good prognoses.

Differences between scirrhous and non-scirrhous human gastric carcinomas from the aspect of proMMP-2 activation regulated by TIMP-3.

Gastric carcinomas can be classified into scirrhous carcinomas (SC), i.e. 'linitis plastica' or Borrmann 4 gastric cancer, and non-scirrhous carcinomas (NSC). SC are characterized by diffuse invasive growth patterns with marked fibrosis, frequent peritoneal dissemination and lymph-node metastases and poor prognosis, while NSC show medullary growth patterns and common hematogenous metastases. To study the differences in local expression levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) between SC and NSC, we examined the expression of MMPs and TIMPs in human gastric carcinoma tissues by several methods including sandwich-enzyme immunoassay systems, gelatin zymography, reverse transcriptase-polymerase chain reaction (RT-PCR), real-time quantitative PCR, immunoblotting, immunohistochemistry and in situ zymography. Of the seven MMPs and two TIMPs tested, only proMMP-2 levels were remarkably higher in SC than in NSC (P < 0.01), and proMMP-2 activation ratio was significantly lower in SC than in NSC (P < 0.05). TIMP-3 mRNA levels were remarkably about 2-fold higher in SC than in NSC tissues (P < 0.01). TIMP-3 production in SC was confirmed by immunoblotting and TIMP-3 was immunolocalized to stromal fibroblasts in SC. TIMP-3 mRNA levels inversely correlated with proMMP-2 activation ratios, although the expression levels of MT1-MMP and MT2-MMP were not different in SC and NSC. By in situ zymography, gelatinolytic activity appeared to be weaker in SC than in NSC. All these data suggest that proMMP-2 activation is down-regulated by TIMP-3 expressed in scirrhous gastric carcinomas. Our findings may explain the differences in clinical behaviors of SC and NSC.

Matrix metalloproteinase inhibitor, marimastat, decreases peritoneal spread of gastric carcinoma in nude mice.

Marimastat, a matrix metalloproteinese inhibitor, was examined for the ability to prevent peritoneal dissemination of a human gastric cancer xenograft, TMK-1. Even with novel approaches such as molecular targeting of cancer chemotherapy, peritoneal dissemination of gastric cancer has little sensitivity to anticancer drugs, and it is impossible to inhibit its growth completely. Intraperitoneal injection of TMK-1 into nude mice at 5 x 10( 5) cells / body resulted in carcinomatous peritonitis that mimicked clinical cases. Continuous administration of marimastat (18 mg / kg / day) from 24 h after the tumor inoculation successfully inhibited the growth of peritoneal dissemination nodules. Combined administration of marimastat (18 mg / kg / day) and mitomycin C (MMC, 2 mg / kg) showed synergistic inhibition of growth of peritoneal dissemination, being superior to MMC alone (2 mg / kg). Although marimastat alone could not increase survival time with statistical significance, combined administration of marimastat and MMC had a survival benefit with statistical significance. The combination of marimastat and MMC increased the preventive effect on peritoneal dissemination. Marimastat seems to be a candidate for the prevention of peritoneal spread of gastric carcinoma.