Hideho Takada

Phase II study of oral S‐1 for treatment of metastatic colorectal carcinoma

The goal of the current study was to evaluate the objective response rate and toxicity associated with the oral fluoropyrimidine S‐1 (a combination of tegafur, 5‐chloro‐2,4‐dihydroxypyridine, and potassium oxonate) in patients with previously untreated metastatic colorectal carcinoma.

Physiologic and anatomic assessment of patients with rectocele.

Clinical, physiologic, and anatomic assessments were carried out in 22 female patients with symptomatic rectocele (Group A), 15 patients with asymptomatic rectocele (Group B), and 14 subjects having no rectocele (Group C). Resting anal pressure, rectal pressure, rectal compliance, anorectal inhibitory reflex, and rectal sensation did not differ among the groups. Proctography revealed that the lengths of the rectocele during attempted defecation in groups A (1.6 [1.0–3.5] cm) (median and range) and B (1.6 [1.0–3.0] cm) were significantly greater than that in Group C (0.4 [0.1–0.9] cm) (P<0.001 in both groups). Median pelvic floor descent at rest in Groups A (4.3 [1.6–7.5] cm) (median and range) and B (4.3 [1.3–6.9] cm) were significantly greater than that in Group C (2.5 [1.2–5.0] cm) (P<0.001 andP<0.02, respectively). These results indicate that rectocele is not associated with any physiologic change apart from a significant increase of pelvic floor descent.

Changing Site Distribution of Colorectal Cancer in Japan

AbstractPURPOSE: In North America and other high-risk areas, there has been a proximal shift in the subsite distribution of colorectal cancer. We wanted to determine whether any similar change has occurred in Japan, and where the incidence of this disease has increased sharply. METHODS: Data from the Reports of the Japanese Society for Cancer of the Colon and Rectum were used to analyze the time trend of colorectal cancer in Japan between 1974 and 1994 according to the patients’ age at diagnosis and sex, and the site of the tumor within the colon or rectum. RESULTS: The percentage of patients over the age of 70, especially females, increased. The increase in the percentage of right-sided colon cancer in colorectal cancer cases was accompanied by a continuous decline in the percentage of rectal cancer in both sexes at all ages. In general, the percentage of right-sided colon cancer in colon cancer cases was stable in men, but increased in women. The rate among patients older than 70 years increased in men, but predominated and remained stable in women. No proximal shift in colon cancer was found in either sex under the age of 69. CONCLUSION: These findings indicated that a proximal shift in the subsite distribution of colorectal cancer has occurred in Japan. This rightward shift of colorectal cancer is due to the decreasing proportion of rectal cancer. Furthermore, the increasing proportion of older patients, especially females, may be another major determinant of the changing colon cancer subsite distribution.

Endocrine cells and prognosis in patients with colorectal carcinoma

Using chromogranin (CG) immunohistochemical staining, the prognostic significance of endocrine differentiation was investigated in 212 patients with primary colorectal adenocarcinoma (including 6 patients with mucosal carcinoma). CG‐immunoreactive cells were found to be an integral component of the tumor in 67 of 206 patients (32.5%, excluding mucosal carcinoma). The intra‐cellular localization of CG in the CG‐immunoreactive cells in cancer tissue was completely different from that in the normal endocrine cells of the large bowel. In addition, morphologic changes such as nuclear hyperchromasia and pleomorphism also indicated that the CG‐immunoreactive cells in the cancer tissue were malignant. The tumors were divided into three groups based on the frequency of CG‐immunoreactive cells: Group I (n = 139), negative; Group II (n = 38), less than 1 positive cell/mm2; and Group III (n = 29), more than 1 positive cell/mm2. No correlation was observed between CG‐immunoreactivity (CG‐IR) and tumor location, grade, depth of invasion, or stage, regardless of lymph node involvement. However, patients with numerous endocrine tumor cells (Group III) had a significantly worse prognosis compared with patients without endocrine cells (Group I) (multivariate Coxs model, P < 0.01). Similar findings were observed in patients with node‐negative tumor (multivariate Coxs model, P < 0.05). These results indicated that the neuroendocrine differentiation is an independent prognostic factor and that CG‐immunohistochemistry is useful for detecting a subgroup with a worse prognosis among patients with colorectal cancer.

Absence of colorectal cancer metastasis to the cirrhotic liver

Hepatic metastasis of colorectal cancer was found in 40 (16%) of 250 patients with colorectal cancer treated in our department during the past 5 years. Liver cirrhosis was not found among the 40 patients with metastases (16%) but was present in 46 (21.9%) of the 210 nonmetastatic patients, with a significant difference between the two groups (p less than 0.001). The rate of patients who were positive for hepatitis B surface antibody was 10% in the metastatic group and 34.3% in the nonmetastatic group, with a significant difference (p less than 0.01). These findings suggest that colorectal cancer does not metastasize to the injured liver, especially the cirrhotic liver.

Effects of fatty acids on liver metastasis of ACL‐15 rat colon cancer cells

The effects of eicosapentaenoic acid [EPA; n-3 polyunsaturated fatty acid (PUFA)], linoleic acid (LA; n-6 PUFA), and palmitic acid (PA; saturated fatty acid) on 1,2-dimethylhydrazine-induced F344 rat colon carcinoma cells (ACL-15) were investigated in vivo and in vitro. The number and size of liver metastatic foci via a superior mesenteric vein injection of ACL-15 cells in F344 rats were significantly inhibited in the EPA-treated group compared with the LA-treated group (p < 0.01); the PA-treated animals and those fed commercial rodent chow (standard diet) demonstrated intermediate values. In a dot immunoblotting assay, vascular cell adhesion molecule 1 expression on ACL-15 cells was downregulated by EPA-ethyl ester treatment and upregulated by LA-ethyl ester treatment compared with the untreated control cells, whereas the expression of matrix metalloproteinase 1 and 2 was not influenced by the fatty acid ethyl esters. In a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, EPA-ethyl ester suppressed ACL-15 cell growth in a schedule-dependent manner, and LA-ethyl ester showed schedule-dependent stimulation. In contrast, PA demonstrated no regulatory effect on cell growth at lower concentrations (< or = 5 mg/ml) but concentration-dependent inhibition at higher concentrations. According to our in vivo cell kinetic study, the difference in tumor growth at the metastatic site was due to different tumor cell proliferation rates; the cell loss rate was not altered. Therefore, the inhibitory effect of liver metastasis on ACL-15 cells by EPA can be explained by a decreased ability of tumor cell adhesion to the capillary bed (low expression of vascular cell adhesion molecule 1) and a lower potential of tumor cell proliferation (low mitotic rate) at the secondary site.

Conjugated Docosahexaenoic Acid Is a Potent Inducer of Cell Cycle Arrest and Apoptosis and Inhibits Growth of Colo 201 Human Colon Cancer Cells

Abstract: The effect of conjugated docosahexaenoic acid (CDHA) on the inhibition of colon cancer cell growth was examined in the colo 201 human colon cancer cell line, and the effect was compared with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). CDHA was a more potent tumor cell growth inhibitor than DHA and EPA by colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay (IC50 for 72 h: 31.6 μM, 46.8 μM, and 56.6 μM, respectively). CDHA inhibited cell cycle progression, due to accumulation of cells in G1 phase, which involved increased p21Cip1/Waf1 and decreased cyclin D1, cyclin E, and proliferating cell nuclear antigen expression; the p53 and cyclin A levels were unchanged. Induction of apoptosis was confirmed by the appearance of sub-G1 populations, and apoptosis cascade involved upregulation of the apoptosis-enhancing proteins (Bak and Bcl-ϰS) and downregulation of the apoptosis-suppressing proteins (Bcl-ϰL and Bcl-2). CDHA modulated cell cycle regulatory proteins and apoptosis-related proteins, similar to the effects of DHA. CDHA at a dietary dose of 1.0% significantly inhibited growth of colo 201 cells transplanted in nude mice.

Dietary Docosahexaenoic Acid Suppresses N-Methyl-N-Nitrosourea-Induced Mammary Carcinogenesis in Rats More Effectively Than Eicosapentaenoic Acid

We comparedthe effects of identical amounts but different proportions of dietary n-3 polyunsaturated fatty acids (PUFAs) on N-methyl-N-nitrosourea (MNU)-induced mammary cancer in a rat model. The ability of dietary docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to suppress mammary cancer was evaluated. Female Sprague-Dawley rats were randomly assigned to three groups and maintained on diets containing 10% fatty acid consisting of EPA, a 1:1 mixture of EPA-plus-DHA, or DHA. The experimental diet was started after administration of MNU at 49 days of age, and the rats were maintained on the respective diets until the largest mammary tumor reached ≷ 1 cmin diameter or until the end of the study period (20 wk after MNU). All histologically detected mammarycarcinomas were evaluated, irrespective of size. The DHAdiet was associated with significant suppression of the carcinogenic effect of MNU compared with the EPA and EPA-plus-DHA diets: tumor incidence decreased to 23% (3/13) compared with 73% (11/15) and 65% (12/17) (P<0.01 andP<0.05, respectively); tumor multiplicity decreased to 0.23 compared with 1.67 and 1.59 (P < 0.01 and P < 0.05, respectively). There was no significant difference in tumor latency among the DHA, EPA, and EPA-plus-DHA groups (119, 105, and 117 days, respectively). Over 20 wk, the fatty acid composition of serum and mammary fat tissue reflected differences in the dietary n-3 PUFAs. Although DHA suppressed MNU-induced mammary carcinogenesis more effectively than EPA, generalized steatosis including mammary fat tissue appeared in all three groups.

Synergistic action of apoptosis induced by eicosapentaenoic acid and TNP‐470 on human breast cancer cells

The effects of eicosapentaenoic acid (EPA) and an angiogenesis inhibitor (TNP‐470) on the suppression of breast cancer cell growth were examined in five human breast cancer cell lines (MDA‐MB‐231, T‐47D, MCF‐7, KPL‐1, and MKL‐F). In all five cell lines, EPA and TNP‐470 alone both showed tumor growth inhibition in a time‐ and dose‐dependent manner, and in combination, a synergistic effect was seen at high concentrations. EPA plus TNP‐470 treatment evoked apoptosis as confirmed by the appearance of sub G1 populations, by DNA fragmentation, and by cell morphology. With the combination, the expression of Bax and Bc1‐xS, the apoptosis‐enhancing proteins, was more up‐regulated and that of Bcl‐2 and Bcl‐xL, the apoptosis‐suppressing proteins, was more down‐regulated compared to the use of EPA or TNP‐470 alone, suggesting that their synergistic effect was due to an acceleration of apoptosis.

Dietary docosahexaenoic acid protects against N-methyl-N-nitrosourea-induced retinal degeneration in rats.

The effect of dietary intake of specific types of fatty acids on retinal degeneration due to N-methyl-N-nitrosourea (MNU)-induced photoreceptor cell apoptosis was evaluated. Fifty-day-old female Sprague-Dawley rats were given a single intraperitoneal injection of 50 mg kg(-1) body weight of MNU, and were then switched to one of five different diets containing the following fatty acids at the following weight percentages: 10% linoleic acid (LA); 9.5% palmitic acid (PA) and 0.5% LA; 9.5% eicosapentaenoic acid (EPA) and 0.5% LA; 4.75% EPA, 4.75% docosahexaenoic acid (DHA) and 0.5% LA; or 9.5% DHA and 0.5% LA. When rats developed MNU-induced mammary tumors with a diameter of > or =1 cm, or at the termination of the experiment (20 weeks after MNU injection), retinal tissue samples were obtained and examined. Incidence and severity of retinal damage were compared by histologic examination. MNU-induced retinal degeneration was prevented in rats fed the diet containing 9.5% DHA (4.75% DHA was less effective), whereas it was accelerated in rats fed the 10% LA diet. Over the course of the 20-week experimental period, the fatty acid composition of serum reflected differences in dietary fatty acids. The present results indicate that a diet containing 9.5% DHA can counteract MNU retinotoxicity in the rat retina. DHA may play a role in protection against MNU-induced photoreceptor cell apoptosis in the rat retina.