Curcumin (diferuloylmethane), widely used as a spice and coloring agent in food, possesses potent antioxidant, anti-inflammatory and anticarcinogenic properties. Recently, curcumin was further demonstrated to have an antimetastatic effect in mice. In this study, we attempted to clarify the possible mechanisms of this latter effect of curcumin. A highly invasive SK-Hep-1 cell line of human hepatocellular carcinoma (HCC) was selected for this study. An in vitro assay, without or with Matrigel matrix, was used to quantitate cellular migration and invasion. Gelatin-based zymography was adapted to assay the secretion of matrix metalloproteinase (MMP). We found that curcumin, at 10 microM, inhibited 17.4 and 70.6% of cellular migration and invasion of SK-Hep-1, respectively. Compared with a less invasive human HCC cell line, Huh-7, SK-Hep-1 showed a much higher MMP-9 secretion. Further, and parallel with its anti-invasion activity, curcumin inhibited MMP-9 secretion in SK-Hep-1 in a dose-dependent fashion. We conclude that curcumin has a significant anti-invasion activity in SK-Hep-1 cells, and that this effect is associated with its inhibitory action on MMP-9 secretion.

Antineoplastic Agents↗

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Racial/ethnic and educational differences in the estimated odds of recent nitrite use among adult household residents in the United States: an illustration of matching and conditional logistic regression.

This article compares estimates of the relative odds of nitrite use obtained from weighted unconditional logistic regression with estimates obtained from conditional logistic regression after post-stratification and matching of cases with controls by neighborhood of residence. We illustrate these methods by comparing the odds associated with nitrite use among adults of four racial/ethnic groups, with and without a high school education. We used aggregated data from the 1994-B through 1996 National Household Survey on Drug Abuse (NHSDA). Difference between the methods and implications for analysis and inference are discussed.

Administration, Inhalation↗

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Factors predictive of survival in patients with node-positive colorectal cancer in Taiwan.

BACKGROUND/AIMS: Preoperative CEA levels, depth of tumor penetration, and the number of positive lymph nodes were reported as independent factors prognostic of survival in colorectal cancer patients. This study was carried out in an effort to evaluate the prognostic significance of these three factors in patients with Dukes' C colorectal cancer in Taiwan. METHODOLOGY: Between 1992 and 1994, a total of 112 patients with node-positive colorectal cancer were evaluated retrospectively at the Veteran General Hospital-Taipei. All patients underwent potentially curative surgery and received 5-fluorouracil based adjuvant chemotherapy. Reference to the Dukes' classification was according to the classical criteria described in 1932 for carcinoma of the rectum and adapted for use in colonic tumors. Data on the location of the tumor, depth of penetration, number of positive lymph nodes, degree of tumor differentiation, and preoperative CEA levels were analyzed to understand their association with survival. Blood samples for CEA measurement were taken a few days before operation. A multivariate analysis using the Cox's proportional hazards regression model was then performed to determine the most important independent predictors of survival among all the possible variables. RESULTS: Using univariate analysis the number of positive lymph nodes (P < 0.001), penetration of the bowel wall (P < 0.001), and preoperative CEA levels (P < 0.001) were found as significant prognostic factors, while the degree of tumor differentiation, location of the tumor, age and sex were not significant. Using multivariate Cox analysis the number of positive lymph nodes, penetration of the bowel wall, and preoperative CEA levels were still found as independent prognostic factors in node-positive colorectal cancer patients. CONCLUSIONS: Data obtained from our study indicates that preoperative CEA levels, depth of tumor penetration, and the number of positive lymph nodes were independent prognostic factors in Dukes' C colorectal cancer patients. They could serve as appropriate modifications of the initial Dukes scheme in node-positive diseases.

Carcinoembryonic Antigen↗

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Randomized trial comparing weekly bolus 5-fluorouracil plus leucovorin versus monthly 5-day 5-fluorouracil plus leucovorin in metastatic colorectal cancer.

BACKGROUND/AIMS: The purpose of this study was to compare the efficacy and toxicity profiles of weekly intravenous (i.v.) bolus injection of 5-fluorouracil plus low-dose leucovorin with the Mayo Clinics' monthly 5-day schedule of 5-fluorouracil and leucovorin in the treatment of metastatic colorectal cancer. METHODOLOGY: A total of 96 patients with previously untreated metastatic colorectal cancer were randomized to receive either a weekly i.v. bolus injection of 5-fluorouracil 400 mg/m2 plus leucovorin 20 mg/m2 (weekly arm), or i.v. bolus injection of 5-fluorouracil 425 mg/m2 plus leucovorin 20 mg/m2 for 5 consecutive days every 4 or 5 weeks (monthly arm). Therapy was continued until disease progression or unacceptable toxicity appeared. In the presence of disease progression, the study regimen was stopped and second-line treatment was instituted after the patient was discontinued from this study. RESULTS: There was no significant difference of response rates between both regimens. The response rate were 14.3% in the weekly arm (2 CR and 5 PR, 95% CI: 2.6-25.2%) and 10.6% in the monthly arm (1 CR and 4 PR; 95% CI: 6.5-32.3%), respectively (P = 0.8957). The survival times were also similar between the two (P = 0.4207, log-rank test). The median survival were 15.8 months in the monthly arm and 18.4 months in the weekly arm. Hematologic toxicity was minimal in both arms. However, the monthly arm produced a higher toxicity in severe (grade 3-4) diarrhea (14.9% vs. 2%; P = 0.029) and stomatitis (8.5% vs. 0; P = 0.054). CONCLUSIONS: Weekly bolus injection of 5-fluorouracil and low-dose leucovorin achieved a similar response rate and survival as compared with the Mayo Clinics' monthly 5-day schedule, but severe toxicity was less commonly seen using the weekly regimen. As current chemotherapeutic treatment for metastatic colorectal cancer is largely palliative rather than curative, the weekly bolus regimen may be a more favorable approach in managing metastatic colorectal cancer.

Aged↗

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Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions.

Curcumin (diferuloylmethane), a yellow substance from the root of the plant Curcuma longa Linn., has been demonstrated to inhibit carcinogenesis of murine skin, stomach, intestine and liver. However, the toxicology, pharmacokinetics and biologically effective dose of curcumin in humans have not been reported. This prospective phase-I study evaluated these issues of curcumin in patients with one of the following five high-risk conditions: 1) recently resected urinary bladder cancer; 2) arsenic Bowen's disease of the skin; 3) uterine cervical intraepithelial neoplasm (CIN); 4) oral leucoplakia; and 5) intestinal metaplasia of the stomach. Curcumin was taken orally for 3 months. Biopsy of the lesion sites was done immediately before and 3 months after starting curcumin treament. The starting dose was 500 mg/day. If no toxicity > or = grade II was noted in at least 3 successive patients, the dose was then escalated to another level in the order of 1,000, 2,000, 4,000, 8,000, and 12,000 mg/day. The concentration of curcumin in serum and urine was determined by high pressure liquid chromatography (HPLC). A total of 25 patients were enrolled in this study. There was no treatment-related toxicity up to 8,000 mg/day. Beyond 8,000 mg/day, the bulky volume of the drug was unacceptable to the patients. The serum concentration of curcumin usually peaked at 1 to 2 hours after oral intake of crucumin and gradually declined within 12 hours. The average peak serum concentrations after taking 4,000 mg, 6,000 mg and 8,000 mg of curcumin were 0.51 +/- 0.11 microM, 0.63 +/- 0.06 microM and 1.77 +/- 1.87 microM, respectively. Urinary excretion of curcumin was undetectable. One of 4 patients with CIN and 1 of 7 patients with oral leucoplakia proceeded to develop frank malignancies in spite of curcumin treatment. In contrast, histologic improvement of precancerous lesions was seen in 1 out of 2 patients with recently resected bladder cancer, 2 out of 7 patients of oral leucoplakia, 1 out of 6 patients of intestinal metaplasia of the stomach, I out of 4 patients with CIN and 2 out of 6 patients with Bowen's disease. In conclusion, this study demonstrated that curcumin is not toxic to humans up to 8,000 mg/day when taken by mouth for 3 months. Our results also suggest a biologic effect of curcumin in the chemoprevention of cancer.

Adult↗

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Penta-acetyl geniposide: isolation, identification and primary effect on C6 glioma cells in vitro.

A new compound, penta-acetyl geniposide [(Ac)5-GP], was obtained from modified extract of Gardenia Fructus (San-jee-chee in Chinese). Spectral studies including ultraviolet (UV), mass (MS), nuclear magnetic resonance (NMR), infrared (IR) and elemental analysis (EA) have suggested the chemical structure of the compound as 1-(beta-D-2',3',4',6'-tetraacetyl- glucopyranosyloxy)-1,4a,5,7a-tetrahydro-7-(acetomethyl)-c yclopentapyran-4-carboxylic acid methyl ester. The antitumor bioactivity of (Ac)5-GP in vitro was studied. It exhibited the activities of reduced plating efficiency and inhibition of DNA synthesis in cultured C-6 glioma cells, but had little effect on RNA and protein synthesis. These results implied that the acetylated iridoid glycoside of Gardenia Fructus is biologically active as an antitumor agent against C-6 glioma cells in culture.

Animals↗

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Photodynamic anticancer agent merocyanine540 inhibits cell growth by apoptosis.

Several merocyanine compounds have been described as inducing photosensitization of tumor cells resulting in cell death. We studied the merocyanine540 (MC540) which induced apoptosis in well/moderately differentiated (HT29, Skco-1) and poorly differentiated (COLO205, SW480, COLO320HSR) colorectal carcinoma cell lines. These cells were incubated with MC540 in the presence or absence of white light. Light activated MC540 can induce death in these cells and poorly differentiated cells being the most sensitive. In the absence of light, MC540 only induced apoptosis in COLO205 cells. MC540 also arrested HT29 cells at the G1 phase during cell cycle progression. In order to understand which genes regulated apoptosis and which genes regulated G1 arrest, the expression of p53 and Rb genes in MC540 treated cells was analyzed. The results indicated that the mechanism of MC540 induction is associated with two distinctive genetic responses namely inducing nuclear p53 proteins accumulation (COLO205), though this may be not essential for MC540 induced apoptosis, and overexpressing the unphosphorylated Rb proteins which may cause G1 arrest (HT29). Based on these findings, we proposed that one mechanism of MC540 induced cell apoptosis might relate to the expression of p53 and Rb genes in the target cells.

Apoptosis↗

PubMedDate not supplied

Absence of modulating effects of cytokines on antioxidant enzymes in peritoneal mesothelial cells.

OBJECTIVE: To investigate the modulation of superoxide dismutase, glutathione peroxidase, and catalase by cytokines and endotoxin in human peritoneal mesothelial cells. DESIGN: Cultured human peritoneal mesothelial cells were treated with various concentrations of interleukin-1 alpha, tumor necrosis factor-alpha (TNF-alpha), interleukin-6, interleukin-8, transforming growth factor-beta (TGF beta), and lipopolysaccharide. Cell morphology was observed and the activities of superoxide dismutase, catalase, and glutathione peroxidase were assayed. The antioxidant enzyme activities of human peritoneal mesothelial cells were also compared with those of human liver and kidney tissues. RESULTS: Interleukin-1 alpha, TNF alpha, TGF beta, and lipopolysacharide caused dose-dependent cytotoxicities in mesothelial cells. The activities of these three antioxidant enzymes did not change after treatment with cytokines and endotoxin. The total superoxide dismutase activity of confluent human peritoneal mesothelial cells was found to be greater than that of human liver and kidney tissues and was composed mostly of manganese superoxide dismutase activity. Furthermore, glutathione peroxidase and catalase activities of human peritoneal mesothelial cells were lower than those of human liver and kidney tissues. CONCLUSION: In human peritoneal mesothelial cells, lack of induction of antioxidant enzymes by inflammatory cytokines, as well as high superoxide dismutase activity accompanied by insufficient glutathione peroxidase and catalase activities may both contribute to the susceptibility of these cells to oxidative damage. Therefore, appropriate management to decrease oxidative injury to the peritoneum should be taken into consideration when treating long-term continuous ambulatory peritoneal dialysis patients.

Antioxidants↗

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Significance of nm23 mRNA expression in human hepatocellular carcinoma.

It has been proposed that nm23-H1, a candidate suppressor gene for metastasis, plays an important role in the metastasis of human tumors. In order to investigate its role in the human hepatocellular carcinoma (HCC), 18 matched pairs of tumorous and adjacent nontumorous liver tissues of hepatectomy from patients with HCC were studied by quantitative reverse transcription-PCR. Further analyses of the nm23-H1 gene were also done. The results of these molecular studies were correlated with the clinicopathologic features of the patients. Nm23-H1 transcript was expressed in all neoplastic and adjacent nontumorous liver tissue. The level of expression, however, did not correlate well with the extension or metastatic potential of the tumors. Instead, in 15 (83.3%) of 18 HCC, nm23-H1 expression was higher in the tumorous tissues, compared with the adjacent nontumorous tissues; and significantly higher levels of nm23-H1 mRNA expression was detected in HCC with poor differentiation (Edmonson classification, III and IV) than those with moderate differentiation (I and II). Southern blot analysis of nm23-H1 gene revealed neither amplification nor loss of heterozygosity of all HCC tissues examined. Direct sequencing of the nm23-H1 gene in all HCC tissues detected no mutations. Our findings suggested that increased nm23-H1 mRNA expression is correlated with HCC tumor progression.

Aged↗