Enhancement of T cell proliferative response against autologous cancer cells of a metasatic renal cell carcinoma patient after unexplained regression

The unexplained regression of a metastasis of renal cell carcinoma (RCC) is rare phenomenon. While an immune mechanism has been proposed for spontaneous or unexplained regression of RCC, only limited data are available regarding immunological response. We report a case of a 62-year-old man with RCC whose paravertebral pleural tumor regressed after the withdrawal of interferon-alpha. In the present case, we demonstrate the enhancement of T cell proliferative response against autologous RCC cells secondary to the unexplained regression using the mixed-lymphocyte tumor culture. To our knowledge, the enhancement of an antitumor immunity secondary to an unexplained regression of RCC has not previously been reported.     

Solid phase peptide synthesis of human endothelin precursor peptide using two-step hard acid deprotection/cleavage methods

Syntheses are described for the putative human and porcine biosynthetic precursors (hET-38 and pET-39) of endothelin, with the sequence previously deduced from human- and porcine-cDNA coding for prepro-endothelin. The Boc based solid phase synthetic method was applied, followed by weak hard acid, trimethylsilyl bromide, cleavage. The peptide removal from the resin was optimally accomplished with hydrogen fluoride. Disulfide bridges were formed by air-oxidation, and the linkage modes determined by enzymic (Endoproteinase Asp-N) digestion and HPLC. Five additional C-terminally elongated endothelin homologs were also synthesized. For alternative synthesis of pET-39, the use of trimethylsilyl tri-fluoromethanesulfonate for the removal of peptide from the resin generated a major side product, which was characterized. hET-38 was found to be less effective in vitro, when compared to endothelin. The vasoconstrictor activity in vitro of other related peptides was comparable to that of hET-38.     

Heinz Body Hemolytic Anemia Induced by DQ-2511, a New Anti-ulcer Drug, in Dogs

DQ-2511, a new anti-ulcer drug, was administered to beagle dogsfor 4 weeks to investigate the mechanism whereby this drug inducedhemolytic anemia and its reversibility in comparison with ß-acetylphenylhydrazine.Hemolytic anemia accompanied by an increase in the number ofcells containing Heinz bodies that was preceded by a markeddecrease in blood-reduced glutathione concentration was observedin dogs receiving 600 mg/kg of DQ-2511, but only a slight increasein the methemoglobin level was noted.ß-Acetylphenylhydrazine,however, caused hemolytic anemia accompanied by marked increasesin both Heinz body-containing cells and methemoglobin concentration,but the blood-reduced glutathione concentration was not decreasedconsistently with the formation of Heinz bodies. Hemolytic anemiadisappeared after a 4-week recovery period in the dogs thatreceived DQ-2511. These results suggest that decreases in reducedglutathione in erythrocytes play an important role in the anemiaand Heinz body formation induced by DQ-2511, but not by ß-acetylphenylhydrazine.     

Prostaglandin E-type receptor subtypes and gastroduodenal bicarbonate secretion in rats

Abstract We investigated the relationship between prostaglandin E-type receptor (EP receptor) subtypes and gastroduodenal HCO₃^- secretion in rats. Under urethane anaesthesia, a stomach mounted in an ex vivo chamber or a proximal duodenal loop was perfused with saline and the HCO₃^- secretion was measured at pH 7.0 using a pH-stat method and by adding 10 mmol/L HCl. Prostaglandin E₂ (PGE₂, i.V.) increased HCO₃^- secretion in both the stomach and duodenum; this action was verapamil sensitive and only in the duodenum was potentiated by isobutylmethyl xanthine (IBMX). Duodenal HCO₃^- secretion was also stimulated by both sulprostone (EP₁/EP₃ agonist), enprostil (EP₁/EP₃ agonist), misoprostol (EP₂/EP₃ agonist), 11-deoxy PGE₁ (EP₃/EP₄ agonist) and ONO-NT-012 (EP₃ agonist), but was not affected by either butaprost (EP₂ agonist) or 17-phenyl-ω-trinor-PGE₂ (EP₁ agonist). In contrast, gastric HCO₃^- secretion was stimulated by sulprostone, enprostil and 17-phenyl-ω-trinor-PGE₂, but not by misoprostol, butaprost, 11-deoxy PGE₁ or ONO-NT-012. The EP₁ antagonist SC-51089 inhibited the HCO₃^- stimulatory action of sulprostone in the stomach but not in the duodenum. Isobutylmethyl xanthine potentiated the HCO₃^- response to sulprostone in the duodenum, while verapamil reduced the response in both the stomach and duodenum. These results suggest that PGE₂ stimulates HCO₃^- secretion via different EP receptor subtypes in the stomach and duodenum: in the former the EP₁ receptors linked to Ca²⁺ and in the latter, the EP₃ receptors coupled with both cAMP and Ca²⁺.     

The effect of bunazosin on monocrotaline-induced pulmonary hypertension in rats

In order to estimate the long-term hemodynamic and histologic effects of bunazosin hydrochloride on primary pulmonary hypertension (PPH), for which effective internal therapy has not yet been proposed, we produced subacute pulmonary hypertension in 6 week old Sprague-Dawley rats by injecting one dose of monocrotaline. Bunazosin (10 mg/kg) was administered intraperitoneally every day and bodyweight and hemodynamic parameters were measured. Right ventricle (RV) and left ventricle with septum (LV + S) were weighed separately. Medial thickness of the small pulmonary artery was calculated. In the bunazosin group, the increase of right ventricular systolic pressure (RVSP) as pulmonary arterial systolic pressure and the ratio of RVSP to pulmonary flow were limited, without causing systemic hypotension, compared to the control group. Weight ratio of RV/(LV + S) had a tendency to be limited in the bunazosin group. As for medial thickness, there was no significant difference between the two groups. It may be concluded that bunazosin hydrochloride should be considered for clinical trials in treatment of PPH in humans.     

In-vivo Microdialysis Study of the Distribution of Cisplatin into Brain Tumour Tissue after Intracarotid Infusion in Rats With 9L Malignant Glioma

Simultaneous brain microdialysis in tumour and non-tumour tissues has been used for kinetic determination of the local distribution of an anticancer agent, cisplatin, in rats. Rat brain was implanted with 9L malignant glioma and cisplatin (3.5 mg kg^?) was administered as a selective intracarotid infusion for 30 min to rats prepared for brain microdialysis. The amount of platinum in the dialysate collected from tumour and non-tumour brain tissues was determined by atomic absorption spectrophotometry, as representative of cisplatin. Total and free platinum concentrations in plasma were also measured. Free platinum is accumulated preferentially in the tumour tissue and the brain tumour distribution coefficient (the ratio of brain tumour platinum AUC to plasma free platinum AUC, where AUC is the area under the platinum concentration-time curve) was 0.69, although there was little distribution into normal brain tissue. Drug binding to plasma proteins was 65%. It is concluded that simultaneous microdialysis is an easy and available method for assessing in-vivo local pharmacokinetics and distribution of cisplatin in tumour and non-tumour tissues of the brain.