Analysis of Synergism in Hepatocarcinogenesis Based on Preneoplastic Foci Induction by 10 Heterocyclic Amines in the Rat

The effects of simultaneous treatment with 5 or 10 heterocyclic amines at low dose levels on hepatocarcinogenesis in rats were investigated using a medium-term liver bioassay protocol based on the two-stage carcinogenesis hypothesis with diethylnitrosamine initiation (200 mg/kg, i.p.). Five carcinogenic heterocyclic amines in experiment 1 (Trp-P-1, Glu-P-2, IQ, MelQ, MelQx) and experiment 2 (Trp-P-2, Glu-P-1, MeAαC, AαC, PhIP) were administered together or individually in the diet at levels of 1/1, 1/5, or 1/25 careinogenic doses, and all 10 chemicals were given at 1/10 or 1/100 levels in experiment 3. Induction of preneoplastic glutathione S -transferase placental form (GST-P)-positive foci in the liver was generally increased in the combination groups over the sums of the 5 or 10 individual effects. Thus, based on the heteroadditive concept, synergism was observed for each combination, being most obvious in the group given all 10 chemicals at the 1/10 dose levels. However, the values for the combined groups were generally close to the averages of the 5 or 10 data gained for the heterocyclic amines alone at the corresponding higher doses, indicating the possibility of isoadditivity. Based on these findings, we propose here a new statistical method for analysis of combined effects of multiple chemicals, and, using this, we demonstrated (true) synergism with some heterocyclic amine combinations. The importance of dose-response curves for evaluation of combination effects is discussed.     

Preservation of ovarian function and reproductive ability in patients with malignant ovarian tumors

In a study designed to determine the merit of preserving ovarian function and childbearing capability in women with unilateral malignant ovarian tumors, the results of radical surgery (n = 86) and conservative surgery (n = 106) were compared. The mean length of survival was slightly but not significantly shorter following conservative surgery. There were 15 recurrences (14%) and 11 deaths among the conservative surgery group. The incidence of metastasis to the preserved ovary was high. In the most cases restoration of normal menses was fairly rapid after initial treatment, but this appeared to depend on whether or not chemotherapy was given postoperatively, the specific agents used, and the duration of their administration. Hypergonadotropic hypogonadism was the most common finding among the anovulatory patients. Sixteen women experienced a total of 27 pregnancies and 18 normal infants were born. Abortion was induced when conception occurred during a course of chemotherapy. These findings are encouraging in terms of the feasibility of preserving childbearing capability in ovarian cancer patients. However, they also underscore the necessity for close, long-term follow-up, which will be improved as new technologies become available.     

Amyloid a protein amyloidosis in a patient with plasma cell dyscrasia

We report a 59-year-old man who was found to have plasma cell dyscrasia and amyloid A protein (AA) amyloidosis during the follow-up period of chronic inactive hepatitis C. Clinical manifestations such as swallowing disturbance, proteinuria and leg edema were associated with AA amyloid deposits in his tongue and kidneys. Although the relationship between these two diseases remains to be determined, the ability of peripheral blood mononuclear cells to degradate serum amyloid A protein was apparently reduced in this patient, compared with normal volunteers. This would, in part, account for the AA amyloid deposition in this patient.     

Effect of filtration leukocytapheresis therapy: modulation of white blood cell enzyme activities in patients with rheumatoid arthritis

We treated 12 patients with rheumatoid arthritis by filtration leukocytapheresis (FLCP) and evaluated its effect on leukocyte enzyme activities. We calculated the number of leukocytes removed and assessed the clinical response. We also evaluated the cellular enzyme activities of elastase and dipeptidylpeptidase IV (DPP IV). Out of 12 patients, 7 patients achieved 20% improvement for 4 weeks following FLCP. The FLCP treatment resulted in removal of 96% of granulocytes, 98% of monocytes, and 61% of lymphocytes. Granulocytes and monocytes with high elastase activity were effectively removed by FLCP. The elastase activity of granulocytes was increased 4 weeks after the last FLCP only in responders. On the other hand, the DPP IV activity of lymphocytes was low at 4 weeks after the last FLCP in responders. Modulation of leukocyte enzyme activities is one of the main effects of FLCP therapy and alteration of granulocytes, monocytes, and lymphocytes.     

Diagnosis of esophageal cancer using positron emission tomography

Fluorodeoxyglucose positron emission tomography (FDG-PET) is more accurate than computed tomography (CT) for evaluating lymph node metastases and for N staging, but less accurate than combined CT and endoscopic ultrasonography (EUS). Lymph nodes located adjacent to the primary lesion tend to be false negatives. We consider that combined FDG-PET and EUS is the most accurate for the detection of lymph node metastasis in esophageal cancer. FDG-PET is also more accurate than CT for detecting distant metastases and improves the detection of stage IV disease compared with the conventional staging modalities. For the diagnosis of recurrence except for perianastomotic recurrence, FDG-PET provides additional information and is more sensitive than conventional work-ups. FDGPET is a valuable tool for the noninvasive assessment of tumor response after neoadjuvant therapy. 11C-methionine (MET) is another tracer for PET that can be used to assess the metabolism of amino acids, since MET accumulates in esophageal malignant tumors. Choline-PET is more accurate than FDG-PET for the detection of mediastinal lymph node metastases.     

Age- and gender-related differences in carbohydrate concentrations of alpha1-acid glycoprotein variants and the effects of glycoforms on their drug-binding capacities

OBJECTIVE: Alpha(1)-acid glycoprotein (AAG) is a major binding protein for neutral and basic drugs because of its great drug affinity. AAG has three main genetic variants--F1, S, and A variants. Several attempts have been made to elucidate the differences in compositions of the carbohydrate moiety and structure-function relationships such as drug-binding differences. However, there have been few reports on age- and gender-related differences in compositions or concentrations of the carbohydrate moiety of AAG variants. The aim of this study was to clarify the age- and gender-related differences in carbohydrate concentrations and in drug-binding capacities of AAG glycoforms. METHODS: The sera used in this study were obtained from 32 healthy subjects (17 men and 15 women, aged 16-84 years). The AAG glycoforms were isolated by hydroxyapatite chromatography. The binding capacity of AAG to disopyramide (DP), which is a basic drug, was determined using the ultrafiltration method. The concentrations of N-acetylneuraminic acid (NeuAc) and monosaccharides in AAG were determined using high-pH anion-exchange chromatography with pulsed-amperometric detection. RESULTS: The mean plasma AAG concentration in the female subjects was significantly lower than that in the male subjects (0.67 +/- 0.12 mg/ml, mean +/- SD, in females, n = 15, versus 0.81 +/- 0.17 mg/ml in males, n = 17, P < 0.05), but no age-related differences were found (0.75 +/- 0.18 mg/ml in young subjects, n = 24, versus 0.77 +/- 0.12 mg/ml in older subjects, n = 8, n.s.). However, the degree of branching of the glycan chain in the female subjects was significantly lower than that in the male subjects (1.61 +/- 0.17 mol/mol, mean +/- SD, in females, n = 15, versus 1.75 +/- 0.23 mol/mol in males, n = 17, P < 0.05). There was a significant inverse relationship between the binding capacity of AAG to DP (Cb/AAG) and the degree of branching of the glycan chain. The binding capacity (Cb/AAG) decreased as the degree of branching in AAG glycans increased. The binding capacity (Cb/AAG) in the female subjects was significantly higher than that in the male subjects (2.79 +/- 0.59 mg/g AAG in females, mean +/- SD, n = 15, versus 2.37 +/- 0.29 mg/g AAG in males, n = 17, P < 0.05). CONCLUSION. The degree of branching of the glycan chain in AAG plays an important role in drug-binding capacity. Gender-related differences in drug-binding capacity (Cb/AAG) may be caused by differences in the ratios of the extent of branching of the glycan chain in AAG.     

In vitro permeation of beta-lactam antibiotics across rat jejunum and its correlation with oral bioavailability in humans

AIMS: To investigate the correlation between in vitro permeation of 11 beta-lactam antibiotics across rat jejunum and their oral bioavailability in humans. METHODS: The absorptive and secretory permeation across rat jejunum was evaluated and apparent permeability coefficients (P(app)) were determined. RESULTS: A steep, sigmoid-type curve was obtained for the relationship between P(app) in the absorptive permeation and human oral bioavailability. When the ratios of P(app) in the absorptive direction to P(app) in the secretory direction were plotted against human oral bioavailability, a much improved correlation was obtained (r = 0.98, P < 0.001). The addition of glycylglycine to both mucosal and serosal media modified the permeation of ceftibuten and cephalexin from the absorptive to the secretory direction. CONCLUSIONS: For 11 beta-lactam antibiotics rat intestinal permeation correlated well with human oral bioavailability, especially when corrected for secretory transport.     

Prevention by natural food anthocyanins, purple sweet potato color and red cabbage color, of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-associated colorectal carcinogenesis in rats initiated with 1,2-dimethylhydrazine

The potential of purple sweet potato color (PSPC) and red cabbage color (RCC), natural anthocyanin food colors, to modify colorectal carcinogenesis was investigated in male F344/DuCrj rats, initially treated with 1,2-dimethylhydrazine (DMH) and receiving 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the diet. After DMH initiation, PSPC and RCC were given at a dietary level of 5.0% in combination with 0.02% PhIP until week 36. No PSPC or RCC-treatment-related changes in clinical signs and body weight were found. Incidences and multiplicities of colorectal adenomas and carcinomas in rats initiated with DMH were clearly increased by PhIP. In contrast, lesion development was suppressed by RCC, or tended to be inhibited by PSPC administration. Furthermore, in the non-DMH initiation groups, induction of aberrant crypt foci (ACF) by PhIP was significantly decreased by RCC supplementation. The results thus demonstrate that while PhIP clearly exerts promoting effects on DMH-induced colorectal carcinogenesis, these can be reduced by 5.0% PSPC or 5.0% RCC in a diet under the present experimental conditions.     

Therapeutics for prion diseases]

Recent outbreaks of acquired forms of human prion diseases in younger people are promoting the development of prophylaxis and therapeutics. One possible target for therapeutic interventions is to inhibit the biosynthesis and accumulation of an abnormal isoform of prion protein, which is supposed to be a pathogen itself. Here, our current in-vitro and in-vivo data on anti-prion chemicals with amyloid binding capacity, represented by pentosan polysulfate and thioflavin-related chemicals, are presented, and structural aspects on the interaction between prion protein molecules and anti-prion chemicals including quinacrine are discussed. The current status of clinical trials using quinacrine or pentosan polysulfate is also reviewed. Finally, key structure(s) in the prion protein molecules, important to inhibit the conversion into abnormal prion protein molecules, are discussed in terms of pharmacology, and possibility of the in-silico rational drug design is also referred. Exploitation of anti-prion drugs should facilitate to solve the enigma of "prion" which can be the only creature against the central dogma, in addition to its contributing to the people with the illness or the people in high risks.