Glucose-6-phosphatase activity in rat liver parenchyma during azo-dye carcinogenesis

The glucose-6-phosphatase (C-6-Pase) activity was investigated by the Wachstein and Meisel method in preneoplastic rat liver parenchyma, as well as in normal liver and hepatomas induced by 4-dimethylaminoazobenzene (DAB). Normal liver shows a high G-6-Pase activity restricted to the cytoplasm of hepatocytes. At early stages of DAB feeding, the centrolobular degenerating zones give a coarser reaction while portal areas retain a normal activity. In cirrhotic liver, the intensity of the reaction varies greatly from one nodule of regeneration to another but is relatively uniform within each nodule. Hyperbasophilic foci are found in nodules with either high or low G-6-Pase activity. The foci developing from highly active nodules show a loss of G-6-Pase activity and the tumors are negative. It appears from these studies that a) the variations in G-6-Pase activity observed in regenerating nodules play no role in the development of hyperbasophilic foci and hepatomas, and b) the loss of activity occurring in hyperbasophilic foci and tumors probably represents a secondary feature of the neoplastic transformation.     

Glucose-6-phosphate dehydrogenase deficiency and lung cancer: a hospital based case-control study

A hospital based case-control study was conducted to test the hypothesis of a lower lung cancer risk in G6PD-deficient subjects. Cases were 156 male patients with lung cancer, admitted to "Binaghi" Hospital, Local Health Unit (USL) 20, Cagliari (Italy), between January 1984 and November 1986. Controls were 235 male patients, admitted to the same hospital in the same time period, for diseases other than cancer (all types) and hemolytic anemia. No decrease of the lung cancer risk was found in G6PD-deficient subjects. This result, in line with recent reports in the literature, suggests that the genetic condition of G6PD deficiency does not provide significant protection against the development of lung cancer in humans.     

Glucose-6-phosphate dehydrogenase deficiency and cancer in a Sardinian male population: a case-control study

A case-control study was conducted to test the hypothesis whether the genetic condition of glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with a reduced risk of cancer. One hundred and eighty seven male cancer patients admitted to hospitals in Cagliari (Sardinia, Italy), between November 1984 and March 1986, were compared with 186 male patients with other diseases, except hemolytic anemia, admitted to the same hospitals in the same period. In contrast to previous reports, our study found no reduction of cancer risk in G6PD-deficient subjects. The study had sufficient statistical power to detect a 0.5-fold decrease in the risk of cancer. The recent suggestion from other studies that tumoral cells of G6PD-deficient subjects can produce their own G6PD, seems to be consistent with this negative finding. Among those subjects presenting some level of erythrocyte G6PD activity, the average enzyme activity was significantly higher in cancer patients than in controls. This finding is consistent with previous experimental studies suggesting a positive correlation between cell proliferation and G6PD activity.     

Polyamine metabolism in tumor, spleen and liver of tumor-bearing rats

A brain tumor, originally induced by weekly IV injections of N-nitro-somethylurea in CD Fisher rats and subsequently carried in serial subcultures, was inoculated SC in the flank of CD Fisher rats. The synthesis and concentrations of the polyamines were studied at various times after the beginning of tumor growth. Higher activities of ornithine decarboxylase, S-adenosylmethionine decarboxylase and higher concentrations of putrescine, spermidine and spermine were observed in the periphery when compared to the center of the solid tumor, and correlated with a higher growth rate in the periphery of the tumor. In the serum of rats with advanced tumors the concentration of spermidine was higher than in the serum of normal rats. Furthermore, putrescine was detectable in the serum of tumor-bearing rats but not in normal rats. The tumor, which grows in a well-defined non-invasive manner, caused increased concentrations of putrescine and spermidine in spleen, and of spermidine in liver, at the time of most rapid growth. The increased polyamine concentrations may denote increased proliferation in the spleen and liver and are presumably part of an immunological response of the host animal to the growing tumor.     

Glucose-6-phosphate dehydrogenase (G6PD) activity in tumoral tissues of G6PD-deficient subjects affected by larynx carcinoma

The activity of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the hexose monophosphate (HMP) shunt pathway, was measured in both normal and tumoral larynx tissues from normal and G6PD deficient subjects. Significant increases of this enzymatic activity were found in tumoral tissues of both normal and G6PD deficient subjects, who were characterized by very low levels of G6PD activity in erythrocytes as well as in larynx tissue.     

Metabolism of 6-mercaptopurine in the erythrocytes, liver, and kidney of rats during multiple-dose regimens

Purpose: To describe the metabolism of 6-mercaptopurine (6-MP) in erythrocytes and tissues of rats after repeated administration of 6-MP at two dose levels and to provide evidence that in vivo modulation of 6-MP anabolism can be obtained by simultaneous treatment with ribavirin or hydroxyurea, two inhibitors of enzymes involved in the bioactivation of 6-MP to the active 6-thioguanine nucleotides (6-TGN). Methods: Rats were treated i.p. with 6-MP at 12.5 and 25 mg/kg daily for 12 days and erythrocyte, liver, and kidney levels of 6-mercaptopurine nucleotides (6-MPN) and 6-TGN were investigated during the accumulation phase and for 50 days after the end of treatment. In combination studies, ribavirin at 75 and 100 mg/kg per day (for 6-MP, 25 and 12.5 mg/kg per day) or hydroxyurea at 200 mg/kg per day were given i.p. for 12 days. The measurements of thionucleotide levels in rat samples were performed by high-pressure liquid chromatography (HPLC). Results: The maximal concentration (C_max) and the area under the concentration versus time curve (AUC) of 6-MPN and 6-TGN in erythrocytes and tissues increased significantly after the administration of 6-MP at 25 mg/kg per day as compared with 12.5 mg/kg per day. In particular, the C_max and AUC of 6-TGN in erythrocytes of rats treated with 6-MP at 25 mg/kg per day were approximately 5-fold higher than the 6-TGN values observed following treatment at 12.5 mg/kg per day. Moreover, 6-TGN levels in erythrocytes were significantly higher than those of 6-MPN (910.9 ± 53.1 and 286.8 ± 23.4 pmol/8 × 10⁸ cells for 6-TGN and 6-MPN, respectively, P < 0.05) after treatment with 6-MP at 25 mg/kg per day. The administration of ribavirin, an inhibitor of inosine monophosphate dehydrogenase, in association with 6-MP increased the amount of 6-MPN detected in erythrocytes and tissues while reducing 6-TGN levels in samples. The production and accumulation of 6-MPN and 6-TGN were increased in erythrocytes and tissues by hydroxyurea, an inhibitor of ribonucleotide reductase. Finally, a significant correlation between thionucleotide concentrations and erythrocyte counts was observed. Conclusion: The overall results demonstrate that 6-MP is actively metabolized in rats and that its biotransformation can be modulated by agents acting on enzymes of the purine metabolism, resulting in significant changes in erythrocyte and tissue levels of 6-MPN and 6-TGN. These findings provide evidence that the rat is a suitable model for investigation of the metabolism of 6-MP and its possible pharmacologic modulation. Received: 17 December 1997 / Accepted: 29 June 1998     

Vitamin B6 and cancer: a novel pyridoxal 5-phosphate conjugate in tumor cells and blood of cancer patients

Studies on the metabolic transformations of labeled pyridoxine showed that its utilization by tumor animals and tumor cells differs greatly from that seen in control animals. When [3,4-14C] and/or tritium labeled pyridoxine at the 6th ring carbon is administered i.p. to tumor-bearing animals and its fate is subsequently determined at different time intervals (using HPLC separation of the labeled metabolites following acid extraction from tissues), in addition to other differences, synthesis of a novel labeled product occurs which begins with the onset of tumor growth. It is either absent or present only at minimal levels in normal animals and regenerating rat liver. It is present in all tumor sources examined to date, i.e. serum of tumor rats, a spectrum of rat hepatomas, solid human tumors, tumor cells in culture and plasma of cancer patients. The novel product is a conjugate of pyridoxal 5'-phosphate with the structure Adenosine-N6-Diethylthioether-N1- Pyridoximine-5'-phosphate. This communication reports on the occurrence and distribution of the novel product in different tumor tissues and cells as well as the blood of cancer patients with active disease and in remission, and in normal volunteers. The results show significantly higher levels of this product in the blood of patients with different malignancies and in the active state. The novel vitamin B6 compound may be a good candidate as a marker for tumor presence and/or metastasis.     

Glucose-6-phosphatase activity of Reed-Sternberg and Hodgkin cells

The glucose-6-phosphatase (G-6-Pase) enzyme cytochemical reaction was successfully applied on lymph node imprints, after introducing the appropriate modifications related to fixation and to composition of the substrate solutions. Using this method we studied the G-6-Pase cytochemical profile on lymph node imprint preparations from 30 patients with Hodgkin's disease. Three cases had the histologic subtype of lymphocyte predominance, 14 the modular sclerosis, 11 the mixed cellularity and two the lymphocyte depleted. A strong G-6-Pase positivity was found in the Reed-Sternberg (RS) and Hodgkin cells of the mixed cellularity type, while the RS and Hodgkin cells of the other subtypes were less positive. The rest of the cell population present were G-6-Pase negative, with the exception of plasma cells which exhibited a strong G-6-Pase cytoplasmic positivity. We concluded from our study that RS and Hodgkin cells resemblance to plasma cells and therefore they may be of B-cell origin. In addition it appears that RS and Hodgkin cells express different functional properties in the various histologic subtypes of the disease.     

Effect of Zajdela ascites hepatoma on the activity and synthesis of liver histidase of tumor-bearing rats

The synthesis of histidase occurs only in free polyribosomes. The relative content of histidase synthesizing polyribosomes in rat liver, in Zajdela ascites hepatoma cells and in the liver of tumor-bearing rats is equal to 1.35%, 0.11% and 0.57%, respectively (of the total amount of free polyribosomes). It was found that hepatoma cell sap has an inhibitory effect on the synthesis of proteins in the cell-free system reconstructed from polyribosomes and cell sap of control rats.     

Metabolic characteristics of xenobiotics in the liver of tumor-bearing rats

A study of the condition and function of a multienzymatic monoxygenase system in liver microsomes of rats bearing experimental Pliss' lymphosarcoma and Zajdela's ascites hepatoma showed synthesis and function of the key enzymes of the hydroxylating microsomes of the liver being inhibited and, consequently, drug metabolism slowed down.