Activity of cytotoxic agents against clear cell carcinoma of the ovary which is intrinsically platinum-refractory

The aim of the present study was to evaluate cytotoxic agents active for clear cell carcinoma of the ovary (OCCA) which is intrinsically platinum-resistant. We first conducted in vitro chemosensitivity tests assessing antitumor activities of Various agents against OCCA using two cell lines (HAC-2 and KK) established from ascites of patients with pure OCCA. The most potent single agent was SN-38 (active substance of CPT-11 in vivo) in both cell lines. The second most potent agent was mitomycin-C (MMC) followed by doxorubicin (DOX) in HAC-2 and DOX followed by MMC in KK, respectively. In vivo chemosensitivity test of agents on HAC-2 transplanted into BALB/C nude mice demonstrated that MMC was most potent, followed by DOX and CPT-11. Moreover, a combination of CPT-11 and MMC exhibited the highest anti-tumor activity in this animal model. Cisplatin, etoposide, and paclitaxel were found to be ineffective in either the in vitro or in vivo experimental system. Clinical trial with a combination of MMC and CPT-11 are warranted in patients with OCCA.     

Inhibitory effect of oral administration of Lactobacillus casei on 3-methylcholanthrene-induced carcinogenesis in mice

The present study was designed to determine whether tumor induction by 3-methylcholanthrene (MC), a carcinogenic hydrocarbon, can be inhibited by oral administration of Lactobacillus casei strain Shirota (LC). C3H/HeN mice were divided into four groups and assigned to the following treatments: treated with MC and given control or LC-containing diet; treated with vehicle only and given control or LC-containing diet. MC (1 mg) was injected intradermally at 7 weeks of age and the tumor incidence was monitored; LC was mixed into a diet at a concentration of 0.05% (w/w) and the diet was fed from the day of MC injection throughout the study. Spleen cells were analyzed for the immune parameters at 12 and 16 weeks after the MC injection. Oral feeding of mice with LC reduced tumor incidence (P < 0.05). MC treatment lowered the in vitro response to concanavalin A (Con A) of spleen cells, the secretion of interleukin-2 in spleen cell culture after stimulation of the cells with Con A and the proportions of CD3⁺, CD4⁺ and CD8⁺ splenic cells. However, the analysis of the spleen cells obtained from the mice treated with MC and given the LC-containing diet revealed that these disrupted host immune parameters were maintained at the level of normal controls. These results suggest that oral feeding of mice with LC inhibits MC-induced tumorigenesis by modulating the disrupted host immune responses during MC carcinogenesis. Received: 14 April 1999     

The role of tumor necrosis factor (TNF)-α in the antitumor effect of intrapleural injection of Lactobacillus casei strain Shirota in mice

The involvement of several cytokines in the antitumor effect induced by intrapleural (i.pl.) injection of heat-killed cells of Lactobacillus casei strain Shirota (LC 9018) in mice was investigated. Injection of LC 9018 i.pl. into Meth A fibrosarcoma (Meth A)-bearing mice not only significantly prolonged the survival of the mice, but also effectively inhibited the accumulation of malignant pleural fluid in the thoracic cavity. In the thoracic cavity of tumor-bearing mice treated with LC 9018, we observed large amounts of several cytokines including interleukin (IL)-1β, interferon (IFN)-γ, IL-12 and tumor necrosis factor (TNF)-α. Both anti-IFN-γ and anti-IL-12 monoclonal antibody (mAb) treatments partially diminished the antitumor activity of LC 9018 in vivo, while the treatment of anti-IL-1β mAb did not influence the survival of the mice. However, anti-TNF-α mAb treatment completely abolished the antitumor effect of LC 9018 in vivo, suggesting that in this model LC 9018 has a survival-prolonging effect involving certain cytokines. Moreover, i.pl. injection of mouse recombinant TNF-α into Meth A-bearing mice pretreated with anti-TNF-α mAb partially restored the survival-enhancing effect of LC 9018. These results led us to conclude that TNF-α induced by i.pl. injection of LC 9018 plays an important role in the antitumor effect of LC 9018 in vivo. Received: 22 February 1999     

Lipoteichoic acids from Lactobacillus strains elicit strong tumor necrosis factor alpha-inducing activities in macrophages through Toll-like receptor 2

Lactobacilli are nonpathogenic gram-positive inhabitants of microflora. At least some Lactobacillus strains have been postulated to have health beneficial effects, such as the stimulation of the immune system. Here we examined the stimulatory effects of lactobacilli on mouse immune cells. All six heat-killed Lactobacillus strains examined induced the secretion of tumor necrosis factor alpha (TNF-alpha) from mouse splenic mononuclear cells, albeit to various degrees. When fractionated subcellular fractions of Lactobacillus casei were tested for NF-kappaB activation and TNF-alpha production in RAW264.7, a mouse macrophage cell line, the activity was found to be as follows: protoplast > cell wall > polysaccharide-peptidoglycan complex. Both crude extracts and purified lipoteichoic acids (LTAs) from two Lactobacillus strains, L. casei and L. fermentum, significantly induced TNF-alpha secretion from RAW264.7 cells and splenocytes of C57BL/6, C3H/HeN, and C3H/HeJ mice but not from splenocytes of C57BL/6 TLR2(-/-) mice. Lactobacillus LTA induced activation of c-Jun N-terminal kinase activation in RAW264.7 cells. Furthermore, in HEK293T cells transected with a combination of CD14 and Toll-like receptor 2 (TLR2), NF-kappaB was activated in response to Lactobacillus LTA. Taken together, these data suggest that LTAs from lactobacilli elicit proinflammatory activities through TLR2.     

Augmentation of antimetastatic effect on Lewis lung carcinoma (3LL) in C57BL/6 mice by priming with Lactobacillus casei

The augmentation of the antimetastatic effect of heat-killed cells of Lactobacillus casei YIT9018 (LC 9018) on Lewis lung carcinoma (3LL) in C57BL/6 mice by presensitization (priming) with LC 9018 was examined. Intralesional injection of LC 9018 into 3LL-bearing mice inhibited both the growth of the primary tumors and the formation of lung metastases, and this effect was significantly augmented by subcutaneous injection of LC 9018 before the tumor inoculation. In the LC 9018-primed mice, intraperitoneal administration of LC 9018 into syngeneic hosts after priming induced a high level of interleukin-2 (IL-2) and interferon- (IFN-) in the peritoneal cavity. At this time, T cells of the spleen cells from the LC 9018-primed mice proliferated and produced IL-2 when co-cultured with LC 9018 as antigen in vitro. Also, the phenotype of these T cells was found to be L3T4⁺ and Ly-2.2^– T cells by analysis by flow cytometry. These results suggest that LC 9018-reactive helper T (T_h) cells were induced by the priming and subsequent challenge with LC 9018, and that IL-2 or IFN-, which was produced by the activated LC 9018-reactive T_h cells, augmented a host immune response resulting the antitumor activity.     

Clinical outcome after cardiac operations in patients with cirrhosis

BACKGROUND: To evaluate the clinical outcome after cardiac operations in patients with cirrhosis, a retrospective study was undertaken. METHODS: Between 1989 and 2003, 18 patients with cirrhosis who underwent cardiac operations were identified. Their preoperative status and postoperative clinical results were assessed. RESULTS: Ten patients were classified as having Child-Pugh class A cirrhosis, 7 as having class B cirrhosis, and 1 as having class C cirrhosis. Fifteen of 18 patients underwent cardiac surgery using cardiopulmonary bypass, and the remaining 3 patients with class B cirrhosis received coronary artery bypass grafting without cardiopulmonary bypass. In patients undergoing cardiopulmonary bypass, 60% of those with class A cirrhosis and 100% of those with class B cirrhosis and class C cirrhosis had postoperative major complications, including infection, respiratory failure, renal failure, bleeding, and gastrointestinal disorder. One of 3 patients (33%) with class B cirrhosis undergoing coronary artery bypass grafting without cardiopulmonary bypass had major complications. The overall postoperative mortality rate was 17%. Hospital mortality of patients with class A cirrhosis, class B cirrhosis, and class C cirrhosis undergoing cardiopulmonary bypass was 0%, 50%, and 100%, respectively. None of 3 patients with class B cirrhosis undergoing coronary artery bypass grafting without cardiopulmonary bypass died in this study. CONCLUSIONS: Although the incidence of major complications was high, patients with Child-Pugh class A cirrhosis tolerated cardiac surgery satisfactorily. Patients with more advanced cirrhosis, however, may not be suitable for elective cardiac operations with cardiopulmonary bypass. Although our results are not conclusive, coronary artery bypass grafting without cardiopulmonary bypass can be an alternative therapeutic strategy for patients with advanced cirrhosis requiring surgical revascularization.     

ZTTA,a Prolyl Endopeptidase Inhibitor,Potentiates the Arginine-Vasopressin-Induced Incorporation of [14C]Leucine in Rat Amygdaloid and Cortical Slices

Pharmaceutical Research -     

Consumption of a high-fat diet containing lard during the growth period in rats predisposes them to favorably respond to the diet in later life

To investigate whether preferential fat intake by adult rats could be linked to fat-feeding of rats during the growth period, this paper describes the next two studies. Three groups of 4-wk-old male rats in study 1 received one of three diets: control diet (CTD), low-fat high-carbohydrate diet (LFD), and high-fat low-carbohydrate diet (HFD). After 6 wk (dietary treatment period), 6 rats in each of the groups were sacrificed and the remaining rats were placed on a self-selection regimen of fat-protein diet (FPD) and carbohydrate-protein diet (CPD) for 3 wk (self-selection period). After the dietary treatment period, liver weight and plasma insulin concentration of the LFD group and perirenal fat tissue weight and plasma triacylglycerol and leptin concentrations of the HFD group were higher than those of the CTD group. Although no significant difference in fat energy ratio (F ratio) of combination diets self-selected by the three groups was observed, the F ratios of the combination diets were higher than that of the CTD. After the self-selection period, liver weight and plasma insulin concentration of the LFD group and plasma triacylglycerol concentrations of the HFD group decreased. These data suggested that the dietary selection pattern of the rats was associated with a reduced basal plasma insulin concentration. Three groups of rats in study 2 were placed on a self-selection regimen of the LFD and the HFD after being fed one of three diets (LFD, CTD and HFD) for 6 wk. Although the F ratio of the combination diet consumed by the CTD and the LFD groups was similar to that of the combination diet consumed by rats in study 1, the F ratio of the combination diet consumed by the HFD group was higher than that of other groups. These findings suggest that consumption of the fatty food during the growth period predisposed them to favorably respond to the diet that had become familiar to them in later life.