A new 5-lipoxygenase selective inhibitor derived from Artocarpus communis strongly inhibits arachidonic acid-induced ear edema

Natural compounds isolated from the Indonesian plant, Artocarpus communis, inhibit 5-lipoxygenase of cultured mastocytoma cells. One of five compounds, AC-5-1, strongly inhibits 5-lipoxygenase with a half-inhibition dose of 5 +/- 0.12 X 10(-8) M. However, prostaglandin synthesizing activity is not inhibited until 10(-5) M. AC-5-1 is a highly selective inhibitor for 5-lipoxygenase. The AC-5-1 at 10(-5) M inhibits 96% of leukotriene C4 synthesis of mouse peritoneal cells facilitated by calcium-ionophore. Arachidonic acid-induced ear edema of mice, an in vivo inflammatory model, involving leukotriene induction, is strongly inhibited by AC-5-1 in a dose-dependent manner. The inhibition is the strongest of any inhibitors of 5-lipoxygenase reported previously. Since the natural compound AC-5-1 can selectively inhibit 5-lipoxygenase and affect in vivo inflammation, it will be interesting to investigate the role of leukotrienes on inflammation and other physiological processes.     

Effects of sex difference, gonadectomy and estradiol on N-ethyl-N-nitrosourea-induced trigeminal nerve tumors in rats

The occurrence of trigeminal nerve tumors (TNTs) induced byneonatal administration of N-ethyl-N-nitrosourea (ENU) in WF? LE F₁ (F₁ rats was studied with special reference to sex difference,effect of gonadectomy and estradiol (E₂) administration. Experimentalgroups 1–6 were treated with 40 mg ENU/kg of body weightneonatally. They consisted of male, female, castrated male,ovariectomized female, E₂ pellet (0.1 mg, s.c.) supplementedand gonadectomized male and female rats respectively. Rats ofgroups 7–12 served as the respective controls withoutENU. All the rats were killed at 8 months of age. Levels ofserum E₂ and E₂ receptor (ER) of the TNTs were also examined.It was noted that the incidence of TNT was higher in males (79%)than in females (48%, P < 0.05) and did not change by castrationin males (91%) but increased in ovariectomized female rats (74%,P < 0.05). Administration of E₂ followed by gonadectomy inhibitedthe occurrence of TNTs in male rats (59%) but not in femalerats (60%). No TNT was observed in any control groups. Kidneytumors were the second most frequent tumors next to nervoussystem tumors in the present experiment. The incidence of kidneytumors was much higher in females (38%) than in males (4%, P< 0.05) and decreased by ovariectomy, whereas it increasedin male rats by E₂ administration. ER levels of TNTs and trigeminalnerve tissue were < 1 fmol/mg protein. These results suggestthat in rats treated with ENU neonatally, E₂ has an inhibitoryeffect on the induction of TNTs but may not be regulated throughER. E₂ also shows a promoting effect on kidney tumorigenesis.     

Persistence of enterocolitis following diversion of faecal stream in Hirschsprung's disease

Mucosal defence mechanisms of the excluded bowel were studied in 12 patients with Hirschsprung's disease. The entire resected segment of colon obtained following Swenson's operation was cut at 0.5-cm intervals and serially examined by routine haematoxylin and eosin staining, immunocytochemistry, and mucin histochemistry. Seven patients who had clinical evidence of enterocolitis prior to defunctioning colostomy showed histological and immunological evidence of enterocolitis (crypt abscesses, ulceration, leucocyte aggregation, Paneth cell metaplasia, and marked immunocyte responses) in the excluded bowel even several months after diversion of the faecal stream. Mucin histochemistry showed marked depletion of neutral mucins and sulphomucins in the excluded bowel with inflammatory changes and reversal of the sialo- to sulphomucin ratio. These results indicate that patients with enterocolitis complicating Hirschsprung's disease have persistent inflammatory changes in the excluded large bowel after diversion of the faecal stream by colostomy. Environmental factors such as bacterial stimulation and proliferation probably cause inhibition of cell renewal, resulting in abnormalities of mucin fractions. Changes in mucin composition, which is an important mechanical and chemical factor of the mucosal defence mechanism, may lead to altered susceptibility to bacterial degradation and hence may be important in the pathogenesis of enterocolitis. Offprint requests to: P. Puri     

Diagnosis of allied functional bowel disorders using monoclonal antibodies and electronmicroscopy

There are a number of conditions that clinically resemble Hirschsprung's disease despite the presence of ganglion cells on rectal biopsies. These conditions have been described under various names. There have been no systematic studies to date to distinguish these conditions from one another. We examined biopsy and surgical specimens from 19 cases of allied functional bowel disorders in an attempt to establish the most appropriate diagnostic procedure. Suction rectal biopsy and full thickness surgical biopsy specimens were examined by enzyme histochemistry (AChE), immunocytochemistry (monoclonal antibody D7), silver impregnation, and electronmicroscopy. Monoclonal antibody D7, which was produced in our own laboratory, is a good marker of autonomic nervous system. This unique antibody allowed us to distinguish various neuronal abnormalities of the bowel except the abnormalities of the argyrophil plexus, which were diagnosed by silver staining. Eight of the 19 cases had a smooth muscle disorder that was only diagnosed on electronmicroscopy. Our data suggest that the vast majority of allied functional bowel disorders can be diagnosed by examining a full thickness rectal biopsy by immunocytochemistry (D7 monoclonal antibody), silver impregnation, and electronmicroscopy.     

Susceptibility of NB-I Neuroblastoma Cells to Tumoricidal Activity of Monocytes Activated by γ-Interferon

The purpose of this study was to examine the susceptibility of NB-I human neuroblastoma cells to direct cellular cytotoxicity mediated by peripheral blood monocytes from pediatric cancer patients receiving chemotherapy. Nonactivated monocytes from patients showed spontaneous cytotoxicity to NB-I neuroblastoma cells (37 ± 18%) but only marginal cytotoxicity to A375 melanoma cells (21 ± 14%) at the effector:target cell ratio of 20:1. This spontaneous cytotoxicity to NB-I cells was observed only after >24 h of cocultivation and was proportional to the effector:target cell ratio. Activation of monocytes by recombinant human interferon γ (rIFN) (1×10⁴ U/ml) consistently and strongly enhanced their tumoricidal activity to NB-I cells (87 ± 6%) and this tumoricidal activity was even superior to that observed against A375 cells, which are known to be extremely sensitive to lysis by activated monocytes. In contrast, activation of monocytes by lipopolysaccharide (LPS, 1 μg/ml) had no effect on monocyte-mediated lysis of NB-I cells, while A375 cells were equally lysed by rIFN- and LPS-activated monocytes, thus suggesting that different mechanisms are involved in the monocyte-mediated lysis of A375 melanoma and NB-I neuroblastoma cells. Susceptibility of the neuroblastoma cell line to monocyte-mediated cytotoxicity has not been reported so far and our results may have some clinical implication if this observation can be extended to other neuroblastoma cell lines as well.     

CDDP-ACR treatment in patients with recurrent ovarian cancer with prior chemotherapy containing CDDP--a preliminary study of a 14-day continuous infusion of CDDP with ACR

Six patients with recurrent ovarian cancer who had prior chemotherapy were studied for the clinical efficacy of CDDP-ACR treatment. Five out of the 6 had received CDDP a total doses of 1,320, 780, 750, 475, and 340 mg. CDDP-ACR therapy consisted of continuous infusion of CDDP at a daily dose of 10 mg/m2 over 14 days (total CDDP doses; 140 mg/m2) and of intermittent infusion of ACR (aclarubicin) at a dose of 20 mg/body every other day (total ACR doses: 140 mg). There were one CR and five PR and a response rate up to 100% was noted. Toxicity was manifested in slight nausea or vomiting, but there was no nephrotoxicity. However bone marrow was severe. Thrombocytopenia less than 50,000/mcl in 4 pts (67%) and leukopenia less than 1,000 mcl in 3 pts (50%). The mean filterable platinum exposure measured by area under the concentration-time curve (AUC) was as high as 19.7 +/- 6/0 mg.hr/ml. In conclusion the bone marrow toxicity in this regimen was severe, but the therapeutic efficacy was promising. Further studies on the appropriate infusion time and the minimum effective dose of CDDP are needed.