The cross-resistance pattern of daunorubicin (DNR) in adriamycin (ADR)- and mitoxantrone (MTN)-resistant sublines was examined by measuring DNA strand-break and drug accumulation by flow injection analysis (FIA). Drug accumulation and retention were lower in both the resistant sublines compared with their values for sensitive ones. The cytotoxicity studies showed that ADR- and MTN-resistant cells were 15 and 12 fold cross-resistant to DNR. A significant reduction in DNR-induced DNA damage was observed in both the resistant sublines even at the same intracellular concentration, suggesting the role of altered topoisomerase II activity in resistance. A good positive correlation between cytotoxicity and strand-break results emphasizes the significance of DNA strand-break measurement to monitor development of drug resistance.
Ascorbic acid has been reported to have corrective influences on the alteration of metabolic processes observed during ageing. We determined the effect of ascorbic acid supplementation (20mg/100g body weight) for 15, 30, and 60 days on young and aged rats. Organ weight and ascorbic acid content of the liver, spleen, and kidney as well as their deoxyribonucleic acid and ribonucleic acid contents were low in aged rats, although a considerable increase in the values of these parameters was noted after supplementation with ascorbic acid; and for 30 days the magnitude of the increase rose further after supplementation for 60 days. The organ weights and ascorbic acid and nucleic acid contents increased markedly only on prolonged ascorbic acid supplementation (i.e., 60 days) in young rats.
Adjuvant hyperthermia enhances the response of melanoma to irradiation or antineoplastic drugs. Radiation in combination with a targeted drug delivery system combining a thermosensitive liposome-encapsulated antitumor drug with hyperthermia may thus result in enhancement of therapeutic efficacy for more effective management of melanoma. The present study was based on this rationale. The therapeutic effect of radiation alone, or in combination with thermosensitive liposome-encapsulated melphalan and hyperthermia, was determined on B16F10 murine melanoma transplanted into C57B1/6 mice. This multimodality regimen resulted in marked enhancement of the antitumor efficacy in treated animals, as determined by significant tumor growth regression (p<0.001) and prolongation of survival, compared with the level of enhancement seen in animals receiving single-modality treatment. The results suggest that radiothermochemotherapy using radiation in combination with heat-mediated selective delivery of liposomal melphalan to tumor tissue would result in more effective management of melanoma.
Dietary administration of phenolics, gallic acid, and its synthetic analogue propylgallate at varying dose levels for the period of 4 and 8 weeks to inbred male Swiss mice resulted in a significant increase in hepatic cytochrome P-450 (Cyt P-450) without any alteration in arylhydrocarbon hydroxylase (AHH) and cytochrome b5 (Cyt b5) activities. The activity of glutathione-S-transferase (GST) showed a significant elevation by these phenolics in both liver and lungs. However, they had a differential effect on the levels of reduced glutathione (GSH) in both organs. Increased levels of GST and GSH elicited by these phenolics may protect the organism from the insult of various toxic carcinogenic chemicals.
Using rats we examined the effects on liver mitochondrial functions of the long-term intake of a high-fat diet based on beef tallow or safflower oil. Forty-eight rats were divided into three dietary groups: a low-fat diet group and two high-fat ones (beef tallow and safflower oil). The low-fat diet provided 7, 73, and 20% of the total energy as fat, carbohydrate, and protein, respectively; and two high-fat diets, 45, 35, and 20% of energy, respectively. Rats were isoenergetically fed the appropriate diet for 4 months. The state-3 respiration of the mitochondria was significantly higher in the two high-fat diet groups than in the low-fat diet group, when both succinate and β-hydroxybutyrate were used as substrates for the respiration. However, there was no difference between the two high-fat diet groups. The groups were ranked in terms of cytochrome a content in their mitochondria as follows: low-fat diet group<beef tallow diet group<safflower oil diet group. The citrate synthase activity of the liver was also significantly higher in the two high-fat diet groups than in the low-fat one, but no difference was obtained between the two former. However, the mitochondrial DNA concentration in liver was not different among the three dietary groups. From these results, we conclude that long-term intake of high-fat diets increases the oxidative activity of liver mitochondria and that differences in the type of dietary fatty acids do not markedly alter mitochondrial functions.
Using streptozotocin-induced diabetic rats, we examined the effects of zinc supplementation and insulin treatment on the metabolic availability of vitamin A. All diabetic animals exhibited an elevated plasma glucose (>18mmol/liter) level within 48h of intravenous streptozotocin injection. The untreated diabetic rats exhibited a reduction in body weight gain, with a 50% increase in daily food intake. In diabetic animals treated with insulin for 4 weeks, the plasma glucose, body weight gain, and daily food intake were comparable to those of the non-diabetic controls. The plasma concentration of vitamin A was significantly reduced in the diabetic animals, whereas the hepatic content of vitamin A in them was significantly elevated. Treatment with implantable insulin resulted in both plasma and liver concentrations of vitamin A returning to the control non-diabetic levels. Dietary zinc supplementation (120μg/g diet for 4 weeks) failed to improve the plasma concentration of vitamin A. These results suggest that the impaired metabolic availability of vitamin A in the presence of diabetes is caused by insulin deficiency.
The effect of catechin on lipid metabolism was investigated in rats. Catechin at doses ranging from 0.1 to 100mg/kg BW was administered daily by gastric incubation to rats fed a normal laboratory diet. Catechin exerted no negative impact of food intake and thereby no retardation of growth. Maximum hypocholesterolemic activity was detected at a dose of 10mg/kg BW/day. The hypocholesterolemic activity of the drug was found not to be due to a decreased cholesterogenesis, but to a higher rate of degradation and excretion of cholesterol.
The content and composition of polyunsaturated fatty acids (PUFA) in the plasma total lipid fraction of 51 Japanese children (age 3-10) with atopic eczema and those in age-matched healthy controls (n=30) were studied by a simplified method for fatty acid analysis with gas-liquid chromatography (GLC). The PUFA content of the plasma total lipid (p<0.001) and the amounts of linoleic (18:2 n-6, p<0.01), dihomo-γ-linolenic (20:3 n-6, p<0.05), and arachidonic (20:4 n-6, p<0.05) acids were significantly lower in the atopic patients than in the control subjects. When atopic patients were fed candy-type jellies containing γ-linolenic acid-rich oil (180mg/day as the amount of γ-linolenic acid) for 8 weeks, the lower levels of PUFA significantly rose to those of the healthy controls. No side effects were observed in the PUFA profiles, n-6 and n-3 long-chain metabolites, or in clinical evaluations. The results indicate that the dietary intake of γ-linolenic acid-rich oil is an efficient additional therapy for young patients with atopic eczema who have altered states of fatty acid metabolism.