We investigated the occurrence of apoptotic cell death in 104 colorectal carcinomas by terminal-deoxynucleotidyl-transferase-mediated dUTP-diotin nick end-labeling (TUNEL) to determine whether apoptosis could be a useful prognostic factor. The apoptotic index (AI) was calculated as the percentage of positive cancer cells per 1,000 cancer cells, the median AI being 4.1, with a range of 1.9-4.7. Apoptosis was less frequently observed in tumors with higher malignant potential, such as those at advanced stages Dukes B, C and D, than those at Dukes stage A (P < 0.05); in tumors showing evidence of moderate differentiation than in well-differentiated tumors (P < 0.05); and in tumors with venous invasion or lymph node metastasis than in those without these features (P < 0.05). Moreover, the subgroup of patients with a low AI of < 4.1 had a significantly poorer survival rate than the subgroup with a high AI in tumors at Dukes stage C, the 5-year survival rates being 33% vs 68% (P < 0.05; Cox-Mantel). Our findings suggest that less apoptosis might result in a greater progression of colorectal carcinoma, and that the rate of apoptosis might be an indicator of the degree of malignancy. Thus it would appear that the frequency of apoptosis in tumor cells could be a useful prognostic factor in colorectal carcinoma.
The authors demonstrated enhanced apoptosis in gastric tumors after continuous intravenous infusion of 5-FU for 7 days. This result suggests that it may be possible to evaluate the effects of chemotherapy by detecting apoptotic cells.
Gamma-glutamylcysteine synthetase (␥-GCS) is a heterodimer consisting of heavy (␥-GCSh) and light (␥-GCSl) subunits. ␥-GCS catalyzes the rate-limiting de novo biosynthesis of glutathione (GSH), an abundant physiological antioxidant that plays important roles for regulating oxidative stress. Expression of ␥-GCSh and ␥-GCSl are sensitive to oxidative stress. To investigate whether expression of ␥-GCS is correlated with tumor progression, we used immunohistochemical approaches to examine 16 human colorectal adenomas and resected 57 carcinomas from untreated patients. In adjacent normal colorectal epithelium, levels of ␥-GCSh expression were low. Strong cytoplasmic staining for ␥-GCSh was detected in 3 (18.8%) adenoma and 48 (84.2%) carcinomas. The frequency of ␥-GCSh expression in carcinoma was significantly higher than in adenoma (p<0.0001). We used RNase protation assay and Western blot to determine levels of ␥-GCSh mRNA and protein from 10 pairs of matched carcinomas with adjacent normal controls. Elevated expression of both ␥-GCSh mRNA and protein were found in 6 cases, suggesting that transcriptional and/or posttranscriptional regulation play an important role in the upregulation of ␥-GCS during colorectal carcinogenesis. We also examined the expression of another redox-regulated gene, multidrug resistance protein 1 (MRP1). Strong staining for MRP1 was detected in 1 (6.3%) adenoma and 40 (70.2%) carcinomas. The frequency of MRP1 expression in carcinoma was significantly higher than in adenoma ( p<0.0001). Nuclear p53 expression was detected in 30 (52.6%) of carcinomas. There is a significant correlation between ␥-GCSh and MRP1 expression (p)310.0؍ but not between ␥-GCSh and p53. Since ␥-GCS is a sensor of oxidative stress, these results are consistent with the notion that oxidative stress is associated with colorectal tumor progression. © 2002 Wiley-Liss, Inc. Key words: ␥-GCSh; MRP1; colorectal neoplasmGlutathione (GSH) plays an important role in regulating intracellular redox conditions. Biosynthesis of GSH involves 2 enzymatic reactions: the first reaction involves the synthesis of glutamylcysteine through ␥-peptide bond formation between glutamate and cysteine and is catalyzed by the rate-limiting enzyme gamma-glutamylcysteine synthetase. 1 The second reaction is catalyzed by GSH synthetase, which conjugates glycine to glutamylcysteine. The mammalian ␥-GCS holoenzyme is a heterodimer that consists of a 73 kDa heavy subunit (␥-GCSh) and a 28 kDa light subunit (␥-GCSl). [2][3][4][5] The steady-state levels of ␥-GCSh and ␥-GCSl mRNA are increased in cultured cells exposed to prooxidants (-naphthoflavone, menadione, tert-butylhydorquinone and pyrrolidine dithiocarbamate, 6,7 ), antitumor agents (cisplatin, 8 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3 nitrosourea 9 ), cytokines (interleukin 1 10 ), etc. These cytotoxic agents are known to generate reactive oxygen species (ROS) and exert various degrees of oxidative stress to the cells. In all cases, induction of ␥-GCS is accompanied by the...
From these results, it seems possible that overexpression of p53 may not be a good prognostic indicator of colorectal cancer and may be influenced by environments of the tumor.
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