Multi-modal treatment of primarily using continuous subcutaneous interferon-α injection in combination with surgery and/or radiotherapy

PURPOSE: Thirty-nine renal cell carcinoma patients with bony metastasis were intensively treated, primarily with immunotherapy using natural type interferon-alpha (IFN-alpha) continuous subcutaneous injection in combination with surgical resection and radiation therapy. Long-term survival was achieved, including three patients with complete response. The results of this study are presented. METHODS: The mode of administration of IFN-alpha was as follows: natural-type IFN-alpha (25,000,000 IU) was dissolved in 60 mL of distilled water and administered via continuous subcutaneous injection (0.5 mL/h) as 'one course of the treatment'. Two courses of IFN-alpha therapy were given 2 weeks preoperatively, while 13 courses of IFN-alpha therapy were given postoperatively (one course per week). Thus, 15 courses of IFN-alpha therapy were administered during the trial period. Thereafter, IFN-alpha therapy was repeated either every week or every other week depending on the condition of the patient. Additionally, blood levels of IFN-alpha were monitored for four patients following initiation of IFN-alpha continuous subcutaneous injection therapy. RESULTS: Immediately after injection of IFN-alpha, blood levels of IFN-alpha started to rise, reaching 40.5 IU/mL on average at 24 h after initiation of IFN-alpha therapy. Thereafter, blood levels of IFN-alpha remained high and measurable blood levels of IFN-alpha were maintained for up to 24 h after completion of IFN-alpha injection. As a whole, IFN-alpha was detectable for 6-8 days and Cmax (maximum blood concentration of IFN) was 167 IU/mL. Thirty-nine patients with bony metastases were treated as follows: IFN mono-therapy (19 patients), IFN and radiation therapy (15 patients) and IFN and surgical resection of bony metastases (five patients). Fourteen patients survived and the details of these 14 patients are as follows: complete response in three cases, partial response in two, no change in six and progressive disease in three. Twenty-five patients died of renal cell carcinoma. The overall 5-year survival rate was 35.0%. CONCLUSIONS: These findings indicate that IFN-alpha continuous subcutaneous injection therapy is a useful modality for renal cell carcinoma patients with bony metastasis if administered in combination of radical nephrectomy and radiation therapy.     

Activation and Inactivation of a Variety of Mutagenic Compounds by the Reconstituted System Containing Highly Purified Preparations of Cytochrome P-450 from Rat Liver

Activation and Inactivation of a Variety of Mutagenic Compoundsby the Reconstituted System Containing Highly Purified Preparationsof Cytochrome P-450 from Rat Liver. KAWANO, S., KAMATAKI, T.,MAEDA, K., KATO, R., NAKAO, T., AND MIZOGUCHI, I. (1985). Fundam.Appl. Toxicol. 5, 487–498. Six cytochrome P-450 preparationsfrom phenobarbital (PB)-treated rats and two preparations fromß-naphthoflavone (BNF)-treated rats were purified.Using Salmonella typhimurium TA98 the ability of these cytochromeP-450 preparations to mutagenically activate and inactivatea variety of carcinogens was examined. High- and low- spin formsof cytochrome P-448 isolated from BNF-treated rats (BNF-IIaand IId) activated various carcinogens. Both forms activated2-aminofluorene, benzo[a]pyrene, and dibenz[a,c]anthracene.However, o-aminoazotoluene and 2-nitrofluorene were activatedonly by the low-spin form, and aflatoxin B1 only by the high-spinform. In contrast, only limited carcinogens were activated bysome preparations from PB-treated rats. 2-Aminofluorene wasactivated by four PB-inducible preparations (PB-Ia, Ic, Id,and IIa), but only moderately. Unexpectedly, however, the mostprominent activation of benzo[a]pyrene was observed with onepreparation (PB-Id) from PB-treated rats. Direct mutagens tothe S. typhimurium, 4-NQO and AF-2, were markedly inactivatedby NADPH-cytochrome c (P-450) reductase without cytochrome P-450,One PB-inducible form (PB-Ic) inactivted 2-nitrofluorene, andthe high- spin form of P-448 (BNF-IIa) inactivated AF-2     

Effect of cholestasis induced by organic anion on the lipid composition of hepatic membrane subfractions and bile in rats

Several organic anions inhibit the secretion of cholesterol and phospholipid into bile without affecting total bile acid secretion (uncoupling). The uncoupling induced by sulphobromophthalein (BSP) alters the fatty acid composition of biliary lecithin. The purpose of this study was to investigate the relationship between the lipid composition of bile and of liver subcellular membrane fractions during BSP-induced uncoupling. After depletion of the bile salt pool, rats fitted with a bile duct cannulus were infused with sodium taurocholate given either alone or with BSP. Bile was collected and liver microsomes and canalicular membranes were isolated for analysis of lipid composition. In bile, uncoupling increased the cholesterol/phospholipid ratio (C/P ratio) and the saturated/unsaturated fatty acid ratio (S/U ratio) in phosphatidylcholine. The C/P ratio was increased in the canalicular membrane, but the membrane phosphatidylcholine S/U ratio decreased during uncoupling. In microsomes, the S/U ratio of membrane phosphatidylcholine was slightly increased, but the C/P ratio was unaffected during uncoupling. These results support the hypothesis that an increased secretion of hydrophobic phosphatidylcholine species from the canalicular membrane into bile reduces the proportion of hydrophobic phosphatidylcholine species in the canalicular membrane during uncoupling. The decreased contribution of hydrophobic phosphatidylcholine species may ameliorate the decrease in membrane fluidity resulting from the accumulation of cholesterol in the canalicular membrane and stimulate the synthesis of hydrophobic phosphatidylcholine species in the microsomes.     

South American pemphigus foliaceus: electron microscopy and immunoelectron localization of bound immunoglobulin in the skin and oral mucosa

Five skin and two oral biopsies from patients with South American pemphigus foliaceus (SAPF) were studied by electron and immunoelectron microscopy for the ultrastructural localization of bound immunoglobulin in epidermal and oral lesions. Electron microscopy showed the tonofilament-desmosome complex to be preserved in the various layers of the epidermis. Immunoglobulin was bound over the plasma membrane and permeated the desmosomal junctions both in the skin and oral mucosa, thus suggesting that pemphigus antibodies are attached to the glycocalyx. It appears that the initial injury in SAPF acantholysis involves the glycocalyx and that it might be caused by interaction with intercellular antibodies present in the patient's serum.     

An estimation of human bile metastability: Clinical application of a sensitive cholesterol crystal growth assay

The formation of cholesterol monohydrate crystal initiates cholesterol gallstone formation. The nucleation time (NT), a light microscopy method, is used currently to estimate human bile metastability. Recently, a cholesterol crystal growth (CCG) assay utilizing photometric turbidity to quantitate cholesterol crystallization was developed using model bile systems. The object of this study was to determine whether this novel CCG assay was applicable to the quantitative assessment of native human bile metastability. Human gall-bladder bile samples were collected from patients undergoing cholecystectomy. There were five patients with cholesterol gallstone and five stone-free patients. A significant correlation between the onset time measured by the CCG assay and the NT observed by light microscopy was found in our modified assay condition where interference by bilirubin was negligible (P < 0.01). Also, the growth rate measured by the CCG assay significantly correlated with the NT (P < 0.05). These results indicate that the CCG assay is applicable to quantitative assessment of human bile metastability reflected by cholesterol crystal nucleation and that the cholesterol crystal growth is also conveniently estimated by this method.     

The Aggregation of Bovine Serum Albumin in Solution and in the Solid State

Abstract— The aggregation of bovine serum albumin (BSA) in the solid state and in solution was studied to elucidate the effect of water mobility on the aggregation rate and mechanism. The results suggest that the freeze-dried BSA forms covalently-bonded aggregates via disulphide bonding during storage in the moistened solid state and in solution. The aggregation rate largely depended on the water content. The freeze-dried BSA to which a small amount of water was added (in the moistened state) was found to be more liable to aggregation than that in solution. The aggregation rate in the moistened solid state exhibited a maximum at a very low level of moisture. In contrast, the aggregation rate in solution increased with increasing ratio of water to protein (with decreasing protein concentration). The results suggest that the increased rate is related to the increase in water mobility, as measured by the spin-lattice relaxation time, T₁, of water using ¹⁷O NMR, with increasing ratio of water to protein.