allopurinol and Stomach-Neoplasms

Anti-tumor quinone, including mitomycin C (MMC), needs to be activated by bioreduction to exert its cytotoxic activities. The enzymes underlying this bioreductive activation have been the subject of extensive research on Mitomycin C. Cytochrome P450 reductase, cytochrome b5 reductase, xanthine oxidase, xanthine dehydrogenase and DT-diaphorase (DTD) have been shown to be involved in the reduction of MMC. The relationship between bioreductive enzymes and the cytotoxicity of quinone, however, has not been analyzed yet. In this study, we investigated the relationship between the bioreductive enzymes and the cytotoxicity of MMC. We carried out the following experiments and the following results were obtained. I) We isolated an MMC-resistant variant. This cell showed five-fold resistance to MMC as compared with the parental cell line. DTD was deficient in this resistant cell. II) We have examined the bioreductive enzyme activities of DTD and cytochrome P450 reductase and IC50's of MMC in 13 colon and gastric carcinoma cell lines. A positive correlation was not found between the enzyme activities and MMC sensitivities, but the cells with little or no DTD activity showed higher IC50 values compared to the other cell lines. III) To elucidate directly the role of DTD in MMC sensitivity, we introduced NQO1 gene into St-4 cells. NQO1 gene encodes DTD and St-4 cells have no DTD activity. All of the transfectants showed five- to ten-fold higher sensitivity to MMC as compared to the parental St-4 cells. The above data indicate that DTD is a critical determinant of sensitivity to MMC in aerobic conditions.

Topics: Antibiotics, Antineoplastic; Aziridines; Colonic Neoplasms; Cytochrome Reductases; Cytochrome-B(5) Reductase; Drug Screening Assays, Antitumor; Humans; Indolequinones; Indoles; Mitomycin; Mitomycins; NAD(P)H Dehydrogenase (Quinone); NADH, NADPH Oxidoreductases; NADPH-Ferrihemoprotein Reductase; Stomach Neoplasms; Tumor Cells, Cultured; Xanthine Dehydrogenase; Xanthine Oxidase

The aim of this study was to test the effect of antioxidant supplementation on enzymatic abnormalities and free radical-modified DNA adducts associated with premalignant changes in the gastric mucosa of elderly patients with HP-negative atrophic gastritis (CAG). Sixty patients with atrophic gastritis and intestinal metaplasia underwent a nutritional interview and a gastroscopy with multiple biopsy samples in the antrum that were processed for histology and for assaying: alpha-tocopherol, MDA, xanthine oxidase (XO), ornithine decarboxylase (ODC), and 8-OHdG. Patients were randomly allocated into three matched groups and supplemented for 6 months with (1) vitamin E, 300 mg/day; (2) multivitamin, two tablets t.i.d.; and (3) Immun-Age 6 g/day nocte (ORI, Gifu, Japan), a certified fermented papaya preparation with basic science-validated antioxidant/immunomodulant properties. Ten dyspeptic patients served as controls. Histology and biochemistry were blindly repeated at 3 and 6 months. CAG patients showed a significantly (P <.05) increased level of mucosal MDA and XO concentration that were reverted to normal by each supplementation (P <.05). All supplements caused a significant decrease of ODC (P <.01), but Immun-Age yielded the most effective (P < 0.05) and was the only one significantly decreasing 8-OhdG (P < 0.05). These data suggest that antioxidant supplementation, and, namely, Immun-Age, might be potential chemopreventive agents in HP-eradicated CAG patients and especially in the elderly population.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aging; Antioxidants; Deoxyguanosine; Dietary Supplements; DNA; DNA Adducts; Gastric Mucosa; Gastritis; Gastritis, Atrophic; Gene Expression Regulation; Humans; Models, Biological; Mucous Membrane; Oxidants; Oxidative Stress; Pilot Projects; Precancerous Conditions; Random Allocation; Reverse Transcriptase Polymerase Chain Reaction; Stomach Neoplasms; Up-Regulation; Vitamin E; Vitamins; Xanthine Oxidase

The influence of oxygen-derived free radical scavengers on survival in gastric cancer, with serosal invasion and metastases to the lymph nodes surrounding the stomach, was assessed in a prospective randomized controlled double-blind trial conducted for 5 years. To this end, allopurinol (inhibits the enzyme xanthine oxidase which is responsible for the formation of superoxide radicals and scavengers hydroxyl radicals) and dimethyl sulphoxide (DMSO; scavengers hydroxyl radicals) were used. Following potentially curative distal two-thirds partial gastrectomy, 228 patients making an uneventful recovery from surgery were randomized to the control group or to receive allopurinol (50 mg by mouth 4 times a day) or DMSO (500 mg by mouth 4 times a day). In 160 fully evaluable patients who were studied for 5 years, allopurinol and DMSO incurred a significant (p less than 0.01) survival advantage over the whole period of study. The similarity in efficacy between allopurinol and DMSO and the fact that the only action they share is scavenging oxyradicals suggest that these radicals mediate the aggressiveness of gastric cancer by producing tissue damage, thus allowing the cancer to spread. Consequently, oxygen-derived free radicals are implicated in the mechanism of gastric cancer, and removing them provides patients with a survival advantage.

Topics: Adult; Aged; Allopurinol; Carcinoma; Dimethyl Sulfoxide; Double-Blind Method; Female; Free Radical Scavengers; Humans; Male; Middle Aged; Stomach Neoplasms

The aim of the present study is to investigate possible effects of static magnetic field (SMF) on 5' nucleotidase (5'NT-CD73) and xanthine oxidase (XO) activities in cancerous and non-cancerous human gastric tissues in order to contribute to the elucidation of the anticancer activity of SMF. Cancerous and non-cancerous human gastric tissues removed from patients by surgical operations were used in the studies. SMF was created using two static magnets. Before and after treatment with SMF, 5'NT and XO activities in the tissue samples were measured. 5'NT activity was found to be lowered, but no significant change was observed in XO activity in the gastric tissues treated with the SMF. Our results suggest that SMF inhibits 5'NT enzyme in gastric tissues significantly. It is supposed that in addition to other proposed mechanisms, inhibition of purine catabolic activity due to inhibition of some key enzymes in the DNA turn-over like 5'NT might also play part in the anticancer activity of SMF.

Topics: 5'-Nucleotidase; Adenosine Deaminase; Humans; Magnetic Fields; Stomach; Stomach Neoplasms; Xanthine Oxidase

Acquired ichthyosis is a rare condition that can reveal an unsuspected haematological malignancy, thus allowing early diagnosis and management. If ichthyosis regresses under treatment for the haematological disorder, its recurrence reflects a turning point in the course of the disease and implies worsening of the prognosis.. The patients were examined at a joint dermatology/haematology consultation. The diagnosis of ichthyosis was based on clinical examination alone with no patients undergoing skin biopsy.. Our series included three men and two women aged 38 to 65 years consulting for a variety of reasons including asthenia, anaemia and adenopathy. Ichthyosis occurred 2 to 9 months after the initial symptoms of the blood disease. Lesions consisted of diffuse brown scales. The disease was associated with lymphadenopathy and biological inflammatory syndrome. Two patients were presenting non-Hodgkin lymphoma, one had Hodgkin's disease, one had chronic myeloid leukaemia in progression and one had an undifferentiated lymphomatous process. Treatment was based on chemotherapy and emollients. The ichthyosis progressed in step with the underlying malignancy in all cases, with regression being complete in three cases, partial in one case and absent in one case.. In rare cases, acquired ichthyosis reveals systemic disease, and may be of infectious, endocrine or drug origin; it may also be idiopathic. However, it is most often a paraneoplastic syndrome with cutaneous expression encountered during haematological malignancies. Because of the variety of causative blood dyscrasias, ichthyosis cannot be used to guide their diagnosis, although it remains a reliable monitoring tool.. Acquired ichthyosis should prompt the clinician to search for a neoplastic condition, primarily a haematological disorder, guided by other associated signs, given that in our study, skin lesions generally appear to precede signs of the blood disease.

Topics: Adult; Aged; Allopurinol; Anemia; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bleomycin; Cyclophosphamide; Doxorubicin; Etoposide; Female; Hematologic Neoplasms; Hodgkin Disease; Humans; Ichthyosis; Imatinib Mesylate; Leukemia, Myeloid, Accelerated Phase; Lung Neoplasms; Lymphoma, B-Cell; Male; Middle Aged; Paraneoplastic Syndromes; Parotid Neoplasms; Piperazines; Platelet Aggregation Inhibitors; Prednisone; Procarbazine; Pyrimidines; Retrospective Studies; Rituximab; Schizophrenia; Stomach Neoplasms; Vincristine

Xanthine oxidoreductase (XOR) is a key enzyme in the degradation of DNA, RNA and high-energy phosphates. About half of the patients with breast cancer have a decrease in XOR expression. Patients with breast cancer with unfavourable prognosis are independently identified by the loss of XOR.. To assess the clinical relevance of XOR expression in gastric cancer.. XOR levels were studied by immunohistochemistry in tissue microarray specimens of 337 patients with gastric cancer and the relation between XOR expression and a series of clinicopathological variables, as well as disease-specific survival, was assessed.. XOR was moderately decreased in 41% and was undetectable in another 14% of the tumours compared with the corresponding normal tissue. Decreased XOR was associated with advanced stage, deep tumour penetration, diffusely spread tumour location, positive lymph node status, large tumour size, non-curative disease, cellular aneuploidy, high S-phase fraction and high cyclooxygenase-2 expression, but not with p53 expression or Borrmann classification. Down regulation of XOR was associated with unfavourable outcome, and the cumulative 5-year gastric cancer-specific survival in patients with strong XOR expression was 47%, compared with 22% in those with moderate to negative expression (p<0.001). This was also true in patients with stage I-II (p = 0.01) and lymph node-negative (p = 0.02) disease, as well as in patients with smaller (< or =5 cm) tumours (p = 0.02).. XOR expression in gastric cancer may be a new marker for a more aggressive gastric cancer biology, similar to that previously reported for breast cancer.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; Cytoplasm; Female; Follow-Up Studies; Gastric Mucosa; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Protein Array Analysis; Stomach Neoplasms; Survival Analysis; Xanthine Oxidase

We have examined the mechanism of 1-methyl-3-nitro-1-nitrosoguanidine (MNNG)-induced gastric cancer with respect to the production of hydroxyl free radical (OH). Nucleophilic attack by H2O2 on the nitroso group of MNNG produces 1-methyl-3-nitroguanidine (MNG) and the intermediate peroxynitric acid (ONOOH), which splits into hydroxyl free radical (OH) and nitrogen dioxide leading to the formation of nitric and nitrate ions in water. Xanthine oxidase (XO) induces the production of O2.- or H2O2 from molecular oxygen, depending on the overall level of enzyme reduction. In this study, we examined OH production by the reaction of MNNG with H2O2 derived from the XO-HX system containing XO and the purine substrate hypoxanthine by ESR using the spin trapping reagent 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO). OH was produced in the XO-HX-DMPO system with addition of MNNG (the MNNG-XO-HX-DMPO system) under aerobic conditions, but was not in the XO-HX-DMPO system, and production of OH was inhibited by catalase but not by superoxide dismutase, suggesting that OH was produced by the reaction of MNNG with H2O2 derived from the XO-HX system. The production of OH was significantly increased with increase in the reducing activity of XO, though that of O2.- was not, also suggesting the O2(.-)-independent .OH production. The productions of nitrite ion and MNG in the MNNG-XO-HX system were determined by the colorimetric method and HPLC, respectively. Based on these findings, we conclude that .OH was produced by homolytic split of the intermediate ONOOH formed by nucleophilic attack of H2O2 derived from the XO-HX system on MNNG.

Topics: Cell-Free System; Cyclic N-Oxides; Electron Spin Resonance Spectroscopy; Humans; Hydrogen Peroxide; Hydroxyl Radical; Methylnitronitrosoguanidine; Spin Labels; Stomach Neoplasms; Xanthine Oxidase

Adenosine deaminase (ADA), 5'-Nucleotidase (5NT), Xanthine oxidase (XO), Cu-Zn Superoxide dismutase (SOD) and Catalase (CAT) activities were determined in gastric juices from patients with gastric cancer, ulcer, gastritis and from healthy subjects. Enzyme activities were given as units per ml gastric juice and units per mg protein in gastric juice. ADA, 5NT and XO activities were found lower and protein concentrations were found higher in the cancer group than controls. There was however no significant difference between Cu-Zn SOD activities of the cancer and control groups. In all groups including control one, we could not find catalase activities in most of the samples. On the other hand, ADA, 5NT activities and protein concentrations in the gastric juice were lower in the gastritis group than control group. In the ulcer group, we found higher Cu-Zn SOD and XO activities and lower 5NT activity and protein concentrations compared with control values. In an attempt to establish statistical correlations between mean enzyme activities, pH and protein concentrations in the gastric juices of the groups, we found noticeable intra and inter-correlations, which indicated possible relations between DNA and free radical metabolizing enzymes.

Topics: 5'-Nucleotidase; Adenosine Deaminase; Adult; Aged; Catalase; Female; Free Radicals; Gastric Juice; Gastritis, Atrophic; Humans; Male; Middle Aged; Stomach Neoplasms; Stomach Ulcer; Xanthine Oxidase