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A study was conducted to analyze the interconversion and metabolic fate of 8-oxoguanine-containing ribonucleotides in mammalian cells. Bio-Rad protein assay kits were utilized with bovine serum albumin to obtain protein concentration. Experimental results indicated that the ribonucleotide reductase may prevent the influx of potent genotoxic substrates from the oxidized ribonucleotide pool.

O 6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that transfers methyl groups from O 6-methylguanine to itself. Alkylation of DNA at the O 6 position of guanine is an important step in the induction of mutations in the organism by alkylating agents. The O 6-methyl G:T mismatch is recognized by the mismatch-repair (MMR) pathway. The biliary duct is highly exposed to alkylating agents because of its anatomical location. We examined 39 surgically resected gallbladder carcinomas and 35 extrahepatic bile duct carcinomas and evaluated the expression of MGMT and MMR protein (hMLH1 and hMSH2) by immunohistochemical staining. MGMT-negative staining was detected in 59.0% of gallbladder carcinoma specimens and 60.0% of extrahepatic bile duct carcinoma specimens. In gallbladder carcinoma, hMLH1- and hMSH2-negative staining was observed in 51.3% and 59.0%, respectively, whereas in extrahepatic bile duct carcinoma, the respective values were 57.1% and 65.7%. MGMT-negative staining correlated with hepatic invasion in gallbladder carcinoma and with poor prognosis in both types of tumor. Furthermore, a combined MGMT and MMR status was shown to be a more significant prognostic biomarker in both tumor types. Combined MGMT and MMR is a possible prognostic marker that probably reflects an accumulation of genetic mutations. [ABSTRACT FROM AUTHOR]

Background: O6-Methylguanine-DNA methyltransferase MGMT is an enzyme that repairs O6-methylguanine, a promutagenic DNA base damaged by endogenous and environmental alkylating agents. There are few reports that describe whether or not abnormal MGMT expression correlates with the prognosis in human solid cancers. Methods: The expression of MGMT was immunohistochemically evaluated in 60, 62, 105, and 46 paraffin-embedded samples from patients with curatively resected hepatocellular, gastric, colorectal, and breast cancers, respectively. Results: The expression of MGMT was a positive predictive factor for overall survival in hepatocellular P = .005 and gastric cancers P < .001 and for relapse-free survival in breast cancers P < .001. MGMT-positive gastric tumors n = 42 were correlated with the absence of serosal invasion P = .045, lymph node metastasis P = .006, intestinal type P = .018, and low pathological tumor, node, metastasis stage P < .001. All breast tumors that recurred locally after operation were MGMT negative P = .004. The clinicopathologic characteristics of colorectal cancers with respect to MGMT expression did not significantly differ. Conclusions: The expression of MGMT is a predictive prognostic marker in patients with hepatocellular, gastric, and breast cancers. These findings may help to establish therapeutic strategies for patients with these types of solid cancer. [ABSTRACT FROM AUTHOR]

The human mutT homolog, hMTH1, suppresses spontaneous mutations by degrading the endogeneous mutagen, 8-hydroxy-dGTP. We previously reported the broad substrate specificity of hMTH1, which also degrades the oxidatively damaged purine nucleotides, 2-hydroxy-dATP, 8-hydroxy-dATP, 2-hydroxy-ATP, and 8-hydroxy-GTP, in addition to 8-hydroxy-dGTP. In this paper, we describe the hMTH1 activity for 8-chloro-dGTP, which could be formed in inflamed tissue by the reaction of dGTP with hypochlorous acid, a product of myeloperoxidase from activated human neutrophils. The hMTH1 protein was mixed with 1–20 μM of 8-chloro-dGTP and 8-hydroxy-dGTP, and the reaction products were quantified by anion-exchange HPLC to measure the pyrophosphatase reaction rate. The kinetic parameters revealed that 8-chloro-dGTP was degraded by hMTH1 with 50% efficiency as compared with that of 8-hydroxy-dGTP. This result suggests that 8-chloro-dGTP is an intrinsic substrate for hMTH1. [Copyright &y& Elsevier]

Signet ring cell carcinoma occurring in the biliary tract is extremely rare. We herein report the case of a 78-year-old Japanese woman demonstrating signet ring cell carcinoma of the lower bile duct with a rapid growth. Computed tomography of the pancreas head pointed out a circular thickness in the lower bile ductal wall and stenosis of the common bile duct. Cholangiography revealed tapering stenosis at the lower bile duct. Biopsy specimens taken from these lesions and scratched specimens taken from stenotic portion of the lower bile duct were analyzed and demonstrated signet ring cell carcinoma. To the best of our knowledge, this is the first reported case of primary signet ring cell carcinoma of the lower bile duct reported in the English literature. Based on our experience, signet ring cell carcinoma of the lower bile duct is considered to demonstrate both transmural dispersion and an aggressive nature.

Combined chemotherapy consisting of oral TS-1 and low-dose CPT-11 by hepatic arterial infusion is suggested to be a new effective treatment for multiple liver metastases from colorectal cancer. A 53-year-old man was diagnosed with multiple hepatic metastases from advanced colon cancer (Stage IV). The patient underwent partial resection of the colon and catheter insertion into hepatic artery for arterial infusion in November 2003. He was treated with postoperative combination chemotherapy consisting of UFT and low-dose CPT-11. UFT was administered orally at 400 mg/body/day everyday and CPT-11 was injected at 40 mg/body/week for 6 weeks, followed by a 2 weeks rest interval as 1 cycle. In spite of the reduction of metastatic liver tumors after 2 cycles of the chemotherapy, a metastatic pleural tumor appeared. Therefore, we judged the effect of the chemotherapy to be a progressive disease and changed UFT in the regimen to TS-1. TS-1 was administered orally at 80 mg/body/day under a 2-weeks-on and 1-week-off regimen for 3 times. CPT-11 was injected at 40 mg/body/week for 6 weeks, followed by a 3 weeks rest interval as 1 cycle. A stable disease was maintained for 3 months. Outpatient care was possible because no severe events were observed. Tumors showed a reduction rate of 37.4% after the combination therapy. The patient survived for 285 days after the operation.

A nucleotide pool sanitizing enzyme, the human MTH1 protein, hydrolyzes 2-hydroxy-dATP, 8-hydroxy-dATP, and 8-hydroxyd-GTP. To examine the substrate recognition mechanism of the MTH1 protein, ten nucleotide analogs (8-bromo-dATP, 8-bromod-GTP, deoxyisoinosine triphosphate, 8-hydroxy-dITP, 2-aminopurine-deoxyriboside triphosphate, 2-amino-dATP, deoxyxanthosine triphosphate, deoxyoxanosine triphosphate, dITP, and dUTP) were incubated with the protein. Of these, the former five nucleotides were hydrolyzed with various efficiencies. This results suggests the importance of the anti/syn-conformation and the functional groups on the 2 and 6-positions of the purine ring.