The effect of anticancer drugs on superoxide dismutase (SOD) activity was investigated in two cancer cell lines (NA cells and HeLa S3 cells). The NA cells were derived from a squamous cell carcinoma of the tongue. Bleomycin, mitomycin C, cisplatin, and 5-fluorouracil were used as anticancer drugs. SOD activities in the cancer cells were found to be enhanced after administration of these drugs; SOD activity increased in a dose-dependent manner at concentrations from 1.2 to 30μg/ml of bleomycin, and reached maximum 6h after the administration of 2.0μg/ml of the drug. NaF, a glycolysis, inhibitor, enhanced SOD activity both in the presence and absence of bleomycin, while KCN decreased SOD activity significantly. NaF and bleomycin showed an additive effect. These results suggest that SOD activity may be enhanced by anticancer drugs through several mechanisms.
Amino acid uptake by various tissues in cancer cachexia was studied by determination of the intracellular/extracellular distribution ratios of the non-metabolizable amino acid analog α-aminoisobutyric acid (AIB) in the tumor tissue, liver, and skeletal muscle of three groups of 8 rats each: freely-feeding control rats (FF group), rats bearing methylcholanthrene-induced sarcomas for 26 days (TB group) and pair-fed control rats matched by carcass weight with TB rats (PF group). AIB uptake by the soleus muscle measured 1h after its injection was significantly less in PF and TB rats than in FF rats. On the other hand, AIB uptake by the liver was significantly higher in PF and TB rats than in FF rats. AIB uptake by tumor tissue was 1.5 times that by the liver of TB rats. These results suggest that in PF rats, which suffered severe starvation, tissue depletion was associated with low amino acid uptake by muscle and transfer of amino acids to the liver, whereas in TB rats with malignant malnutrition it was associated with low amino acid uptake by muscle with transfer of amino acids to the tumor tissue.
A substrain of rats with inherited cataracts was established as an inbred strain on the basis of the prominent feature that spontaneous clearing of lens opacity occurs after the completion of the cataract. The clearing of lens opacity in these rats was confirmed by the observation of the morphological changes in lens fibers by light microscopy, and supported by the findings that the contents of water, water-soluble proteins, and high molecular weight proteins returned nearly to normal levels. This strain of rats was termed the “ICRL” rat. Another substrain, which is characterized by persistent cataract, was also established as an inbred strain and termed the “ICRF” rat.
Antitumor effect of sulfatide-inserted liposomes (composed of egg phosphatidylcholine, cholesterol, and sulfatide in a molar ratio of 5:4:1) containing entrapped adriamycin (ADM) against three types of human gastric cancers implanted in nude mice was examined by the subrenal capsule assay as an in vivo sensitivity test for antitumor agents. The results indicate that the antitumor effect of ADM-containing liposomes was equal or superior to that of free ADM in every tumor tested. To evaluate the clinical usefulness of these liposomes as drug carriers, we measured concentrations of ADM in tissues including tumors after the administration of the liposomes containing ADM, and found that the level in the heart was lower than in the case of free ADM. We also observed that the blood level remained high compared with the case of free ADM. The ADM concentration in the tumor tissue was initially lower, but became higher by 30-40h after the administration, than that in the tumors of animals injected with free ADM. The acute toxicity of ADM entrapped in liposomes as judged by the 50% lethal dose was less than that of free ADM. The body weight loss was also less with ADM-liposomes than with free ADM. Thus, we conclude that entrapment of ADM in sulfatide-inserted liposomes preserves the antitumor activity of ADM and reduces the side effects of the drug.
A convenient experimental animal model of cystathioninuria was obtained by the injection of propargylglycine into rats. The concentrations of propargylglycine at different times after the injection were measured in various tissues, urine, and serum by isotachophoresis. Cystathionine and its derivatives were also measured in several parenchymal tissues. The propargylglycine accumulated rapidly in various tissues and serum of the rats, and the content reached its maximum at about 2h after injection. The urinary excretion of propargylglycine was about 18% of the administered dose. Cystathionine metabolites, such as S-(3-hydroxy-3-carboxy-n-propyl)cysteine, S-(2-carboxyethyl)cysteine, S-(2-hydroxy-2-carboxyethyl)homocysteine, S-(carboxymethyl)homocysteine, N-acetylcystathionine, N-acetyl-S-(2-carboxyethyl)cysteine, and N-acetyl-S-(3-hydroxy-3-carboxy-n-propyl)cysteine, were also identified in various tissues of propargylglycine-treated rats.
The effects of lidocaine on cerebral metabolic changes during and after forebrain Ischemia (10min) in a rat model were studied by in vivo31P-NMR spectroscopy. Rat brains were made ischemic for 10min by bleeding to 40mmHg with subsequent application of bilateral carotid artery occlusion. Forebrain Ischemia caused a decrease in intracellular high-energy phosphates and in intracellular pH (pHi) in both control and lidocaine-treated groups, but its extent was smaller in the lidocaine-treated group than in the control group. Moreover, lidocainetreated group showed a faster return to the preischemia level in cerebral energy metabolism than the control group after forebrain ischemia. Thus, lidocaine was shown by 31P-NMR spectroscopy to have a protective effect, particularly in relation to cerebral high-energy phosphates.
A single oral administration of ethanol (5g/kg) to fasted rats significantly increased the hepatic content of ATP and of total adenine nucleotides after a lag period of 1h. The ADP content gradually decreased, and the AMP content increased. There was no change in the energy charge. The phosphorylation state significantly increased at 3h and thereafter, and the adenylate kinase mass-action ratio was elevated during the intoxication. The IMP content significantly decreased at 3h and thereafter. A small but significant increase in the hypoxanthine content was noted only in the early phase during the intoxication. This early increase after the ethanol administration was not enhanced by the pretreatment with allopurinol, by which the hepatic activities of xanthine oxidase and xanthine dehydrogenase were inhibited by more than 90%. Xanthine was detected only in the liver extracts from rats pretreated with allopurinol, but there was no significant effect of the ethanol loading on the xanthine content. These results demonstrate that, during acute intoxication with a large dose of ethanol, the overall metabolism of adenine nucleotides shifts toward their accumulation rather than degradation, that the increase in hypoxanthine is rather small and transient, and that xanthine is produced from metabolites other than hypoxanthine.
Serum levels of Zn, Cu, Se, and Mn in 72 hospital patients suffering from liver cirrhosis (LC), hepatocellular carcinoma (HCC), or chronic hepatitis (CH) were determined by atomic absorption spectrometry, and the results were compared with those obtained from 151 healthy adults serving as controls. Serum Cu levels in subjects with HCC and LC were significantly elevated, whereas both Zn and Se levels were lowered. Subjects with CH also showed a decrease in Se level. Consequently, a marked increase (>40%) in the Cu/Zn ratio of the sera of both HCC and LC groups was observed. There were no significant differences in Mn levels between the controls and the diseased groups, except for the slight increase shown by the LC group. Changes in the level of these trace metals were found to be independent of the individual metals.