Study on heterotransplantation of human malignant urogenital tumors in nude mice: establishment of the tumor line in nude mice from human primary ureteral tumor and its characteristics

The tumor line in nude mice is one of the most important experimental animal models for oncodevelopmental studies. We implanted a human ureteral tumor into nude mice, established the tumor line, AM-UT-1, and maintained it by serial transplantation. The characteristics of this tumor line in nude mice are reported. Histologically, the original tumor was a transitional cell carcinoma (grade II, stage B). The transplanted tumor grew locally and had a constant growth pattern during serial passage until the 13th passage in nude recipients and maintained the basic histological, immunohistochemical findings of the original tumor. Both original tumor and serial transplanted tumor had carcinoembryonic antigen (CEA)-producing activity. A high level of serum CEA was also recognized in nude mice.     

Inhibition of Na+,K+-ATPase activity by phospholipase A2 and several lysophospholipids: possible role of phospholipase A2 in noradrenaline release from cerebral cortical synaptosomes

p-Bromophenacyl bromide (PBPB), quinacrine and indomethacin, which inhibit phospholipase A2 (PLA2; EC 3.1.1.4) activity in several tissues, caused a dose-dependent inhibition of prelabelled [3H]noradrenaline ([3H]NA) release evoked by high concentrations of K+ from rat cerebral cortical synaptosomes. Release of prelabelled [3H]NA was caused by natural lysophosphatidic acid (LPA; 10(-6)-10(-5) g mL-1) and lysophosphatidylcholine (LPC; 10(-6)-10(-5) g mL-1) and synthetic LPA (6 x 10(-6), 2 x 10(-5) M) and LPC (6 x 10(-6), 2 x 10(-5) M), but not by natural lysophosphatidylserine (LPS; 10(-5) g mL-1), lysophosphatidylethanolamine (LPE; 10(-5) g mL-1) and lysophosphatidylinositol (LPI; 10(-5) g mL-1). The release evoked by natural LPA and LPC could be inhibited only marginally by PBPB and quinacrine. Phosphatidic acid (PA)-specific and phosphatidylcholine (PC)-specific PLA2 activities from rat cerebral cortical synaptosomes were stimulated in incubation medium containing high concentrations of K+ or calcium ionophore A23187. Low concentrations of PLA2 (10(-6)-10(-8) g mL-1, from bee venom) inhibited the synaptic membrane Na+,K+-ATPase activity in incubation media with intracellular levels of free Ca2+. Several lysophospholipids (LPLs), metabolites of the PLA2 type, also inhibited the synaptic membrane Na+,K+-ATPase activity in a dose-dependent manner. The minimum effective concentrations of natural LPA, LPC, LPS, LPI and LPE were 10(-6), 4.7 x 10(-6), 10(-5), 4.7 x 10(-5) and 4.7 x 10(-5) g mL-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Study on pruritus in hemodialysis patients and the antipruritic effect of neurotropin: plasma levels of C3a, C5a, bradykinin and lipid peroxides

The causes of pruritus in patients undergoing hemodialysis and the mechanism of the antipruritic effect of Neurotropin, an extract isolated from the inflamed dermis of rabbits inoculated with vaccinia virus and clinically used in Japan as an analgesic and antiallergic drug, were investigated by measuring the levels of C3a, C5a, bradykinin and lipid peroxides in venous blood collected before dialysis, and at 15 min and 4 hr after starting hemodialysis. C3a increased considerably in pruritic patients compared to non-pruritic patients at 15 min after starting hemodialysis. Neurotropin significantly suppressed the C3a level and improved the condition of pruritic patients. There was no significant difference in the level of bradykinin between pruritic patients and non-pruritic patients. Therefore, bradykinin was not thought to be related to the incidence of pruritus in such patients. A tendency towards lowering of the levels of lipid peroxides in the patients' plasma by Neurotropin was also observed. It seems possible that elevation of C3a may be one of the underlying causes for the appearance of pruritus, and that Neurotropin may exert its antipruritic effect through suppression of the activation of C3 in patients undergoing hemodialysis.     

Radiotherapy for patients with localized hormone‐refractory prostate cancer: results of the Patterns of Care Study in Japan

OBJECTIVE

To evaluate the clinical results of radiotherapy (RT) for patients with regionally localized hormone‐refractory prostate carcinoma (HRPC).

PATIENTS AND METHODS

As part of a Patterns of Care Study in Japan, a nationwide survey was conducted of RT for patients with prostate adenocarcinoma. We reviewed the detailed information of 140 patients with regionally localized HRPC who received RT between 1996 and 1998, and between 1999 and 2001, in 117 randomly selected institutes in Japan. The median (range) age of the patients was 74 (51–94) years, and their tumours were defined as well (14), moderately (51) or poorly (54) differentiated, or of unknown differentiation (21). The median (range) interval between hormonal therapy (HT) and RT was 32.5 (1.1–168.4) months. Ninety‐five patients had T3‐4 tumours and 28 had regional lymph node metastases before treatment. The median (range) prostate‐specific antigen levels before the initial HT and before RT were 35.0 (1.5–276) and 10.0 (0.06–760.3) ng/mL, respectively. External beam RT was administered, with a median total dose of 66 Gy; 70 patients (50%) received pelvic irradiation.

RESULTS

At a median follow‐up of 20.7 months, the 5‐year overall and clinical progression‐free survival rates (95% confidence interval) were 48.1 (36–60)% and 36.7 (26–47)%, respectively. Although there were distant metastases in 46 patients, only six had local progression. There was late morbidity of grade ≥3 in six patients.

CONCLUSION

To the best of our knowledge, this study comprises the largest series of regionally localized HRPC treated with RT reported to date. RT might have a limited role for HRPC, because in most patients RT failed, with distant metastasis.     

A chronic toxicity study of josamycin in F344 rats.

The chronic toxicity of josamycin was examined in Fischer 344 (F344) rats. Groups of 10 males and 10 females were given the test compound in the diet at concentrations of 0 (control), 0.02, 0.1, 0.5 or 2.5% for 52 weeks. Daily intake of josamycin was 0, 10, 50, 260 and 1310 mg/kg body weight in males and 0, 10, 60, 290 and 1460 mg/kg body weight in females, respectively. Body weight gain was significantly (P<0.05) reduced in the male 2.5% group but no noticeable changes were found in food intake. In hematological examination, the platelet count was significantly (P<0.01) lower in the male groups given 0.02% or more of josamycin and in the 2.5% female group as compared with the control group values in a dose-dependent manner. In serum biochemical examination, blood urea nitrogen was significantly (P<0.05 and P<0.01, respectively) higher in males given 0.5 and 2.5% and total bilirubin was significantly (P<0.05) higher in females receiving 2.5% as compared with those of the control group. No death occurred at any dose levels during the dosing period. At necropsy, with the exception of cecal enlargement in the groups given more than 0.1% josamysin and a significant (P<0.01) increase in the relative liver weight of females in the 2.5% group, no particular findings related to the administration were observed. Histopathologically, the incidence and severity of liver bile duct proliferation in female 2.5% group were significantly (P<0.01) greater than those of the control group. Other histological changes found in the treated and control groups were similar to the spontaneous lesions in this strain of rats in terms of the incidence and severity. Interestingly, the josamycin treatment reduced the development of altered liver cell foci in females in a dose-dependent manner. Thus, it is concluded that, under the present experimental conditions, josamycin induces bile duct proliferation in female F344 rats at a high dose of 1460 mg/kg body weight. Based on the decrease of platelet count found in males given 10 mg/kg body weight or more, the no-observed-adverse-effect level (NOAEL) was estimated to be less than 10 mg/kg body weight.     

Hyperbaric oxygen therapy for Wegener''s granulomatosis with cyclophosphamide-induced hemorrhagic cystitis

A 49-year-old man with Wegener's granulomatosis, who had been treated with cyclophosphamide, was admitted to our hospital experiencing gross hematuria. The hemorrhage was refractory to multiple conventional treatments. It progressed but later was resolved after a course of hyperbaric oxygen therapy.     

N-methyl-D-aspartate, quisqualate and kainate receptors are all involved in transmission of photic stimulation in the suprachiasmatic nucleus in rats.

In order to clarify the neuronal transmission mechanism of photic stimulation in the suprachiasmatic nucleus (SCN), the effects of agonists and antagonists for excitatory amino acid receptors on N-acetyltransferase (NAT) activity in the pineal gland were observed following the microinjection of drugs into both sides of the nuclei. N-Methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, and kainate (which are selective agonists for three different subtypes, i.e. NMDA, quisqualate and kainate receptors, respectively) significantly decreased NAT activity similarly to the suppressive effect of light. Moreover, compared with a control group, all the groups pretreated with a selective competitive antagonist for NMDA receptor (D-2-amino-5-phosphonovalerate or 3-((+-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonate), or a selective non-competitive antagonist for non-NMDA receptors (Joro spider toxin-3 or 1-naphthylacetyl spermine) partially blocked the suppressive effect of photic stimulation on NAT activity. These results suggest that NMDA, quisqualate and kainate receptors are all involved in mediating photic stimulation in the SCN.     

Modification of the cytotoxic effect of peplomycin by cepharanthine

The cytotoxicity of peplomycin modified by cepharanthine, was studied on in vitro cultured Chinese Hamster V-79 cells. Cepharanthine alone showed almost no cytotoxicity on this tumor system. It was revealed that cepharanthine enhanced the cell killing action of peplomycin and also promoted the recovering process from the effects of peplomycin. The enhancing effect increased with an increase of the concentration at the lower concentrations but there were limitations at the higher concentrations. The bi-phasic properties specific to peplomycin on the dose-survival curves were unchanged even in combination with cepharanthine was observed in the recovering process from the effects of peplomycin. From these results, cepharanthine seemed not to affect on the mechanism of action of peplomycin.     

Prophylactic effects of neuroleptics in symptom-free schizophrenics: a comparative dose-response study of timiperone and sulpiride

Remitted schizophrenic outpatients were prophylactically treated to prevent relapse with three different doses of timiperone or sulpiride for a year in a double-blind controlled study employing a randomized design. Each drug's ability to prevent relapse was by counting the number of subjects with different outcomes (remission, relapse, adverse reactions) during the trial and/or the number of symptom-free days for each patient before any sign of relapse or adverse reactions appeared. Patients were randomly assigned to the following drugs, which were orally administered once every night: placebo; timiperone 1 mg, 3 mg, 6 mg; sulpiride 100 mg, 300 mg, 600 mg. Data from previous studies involving haloperidol and propericiazine were utilized as a retrospective placebo group to compare the characteristics of the four drugs for maintenance treatment of remitted schizophrenic outpatients. Both timiperone and sulpiride increased the number of patients in remission and decreased the number of patients who relapsed, compared with the placebo group. With timiperone, there was an especially marked increase in the number of patients who showed signs of adverse reactions compared with sulpiride. Sulpiride was the only drug that increased the number of dose-dependent symptom-free days. However, both of these drugs significantly increased the number of symptom-free days compared with placebo. By comparing the dose-response curves of four drugs tested in the same fashion, haloperidol and sulpiride were superior to propericiazine and timiperone because they displayed a wider dose range for the maintenance treatment of remitted schizophrenic outpatients.