Cancer chemotherapy by liposomal 6-[12-(dimethylamino)ethyl]aminol-3-hydroxy-7H-indeno[2,1-clquinolin-7-one dihydrochloride (TAS-103), a novel anti-cancer agent

A novel anti-tumor agent, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103), effectively inhibits both topoisomerase I and II activities. To enhance anti-tumor efficacy and to reduce the side effects of the agent, liposomalization of TAS-103 was performed. TAS-103 was effectively entrapped in liposomes by a remote-loading method, and was stable at 4 degrees C and in the presence of 50% serum. To evaluate the anti-tumor efficacy of liposomal TAS-103, the growth inhibition against Lewis lung carcinoma cells in vitro and the therapeutic efficacy against solid tumor-bearing mice in vivo were examined. Liposomal TAS-103 showed strong cytotoxic effect against Lewis lung carcinoma cells in a dose dependent manner and effectively suppressed solid tumor growth accompanying longer survival time of tumor-bearing mice in comparison with the mice treated with free TAS-103. These results suggest that liposomal TAS-103 is useful for cancer therapy.     

Antimicrobial activities of clarithromycin, gatifloxacin and sitafloxacin, in combination with various antimycobacterial drugs against extracellular and intramacrophage Mycobacterium avium complex

We studied the activities of clarithromycin and fluoroquinolones (gatifloxacin, sitafloxacin, levofloxacin) in combination with other antimycobacterial drugs against extracellular and intramacrophage Mycobacterium avium complex (MAC). Clarithromycin potentiated the activities of rifampicin and rifalazil against both extracellular and intramacrophage MAC. In contrast, all the test quinolones exhibited antagonistic effects against extracellular MAC when combined with either clarithromycin or rifamycins. Such an antagonism was not observed for the activity of these combinations against intramacrophage MAC. Combined effects were observed with combinations of these fluoroquinolones with either ethambutol or streptomycin. Similar profiles were seen for the activities of two-drug combinations of clarithromycin or fluoroquinolones with other drugs against intramacrophage MAC isolated from pulmonary and disseminated MAC infections.     

Severe and selective deficiency of interferon-gamma-producing invariant natural killer T cells in patients with myelodysplastic syndromes

Here we show that patients with myelodysplastic syndromes (MDS) have a severe deficiency of glycolipid reactive Valpha24+/Vbeta11+ natural killer T (NKT) cells, but not NK cells or CD4+ or CD8+ T cells. Neither the blood nor marrow of MDS patients had detectable interferon-gamma-producing NKT cells in response to the NKT ligand, alpha-galactosyl ceramide, although influenza-virus-specific effector T-cell function was preserved. This severe and selective deficiency of an important immune regulatory cell may contribute to the pathogenesis of MDS.     

Protective effect of a new nonpeptidyl mimetic of SOD,M40401, against focal cerebral ischemia in the rat

We tested the neuroprotective effects of M40401, a new, low molecular weight (511.4 Da) maganese superoxide dismutase mimetic, against 90 min of middle cerebral artery occlusion (MCAO) in male Wistar rats. Animals received a single injection of vehicle (n=8), 1 mg/kg (n=6), or 3 mg/kg (n=7) 30 min before MCAO. Total lesion volume was reduced only in the group receiving 3 mg/kg M40401 (163.5+/-18.7 versus 43.4+/-7.0 mm(3), for vehicle and M40401, respectively; P<0.05), with almost complete reduction of lesion volume in the cortex but little protection in the basal ganglia. Neurological score was also improved in this group. The dose of 1 mg/kg M40401 had smaller and inconsistent effects on lesion parameters. Administration of a single dose of 3 mg/kg M40401 at 60 min of MCAO or at the end of MCAO (90 min) failed to significantly reduce lesion volume. A single dose of M40401 plus prolonged infusion into the post-MCAO period also failed to decrease lesion volume significantly. These data indicate that M40401 protects cerebral tissue from ischemic insult when administered before MCAO, probably by limiting damage mediated by detrimental actions of superoxide anion.     

Lipopolysaccharide pretreatment attenuates myocardial infarct size: A possible mechanism involving heat shock protein 70-inhibitory kappaBalpha complex and attenuation of nuclear factor kappaB

OBJECTIVE: Lipopolysaccharide pretreatment is known to reduce myocardial infarct size, but the mechanism has not been elucidated. We hypothesized that heat shock protein 70, induced by lipopolysaccharide pretreatment, formed complexes with inhibitory kappaBalpha, thereby inhibiting degradation and attenuating activation of nuclear factor kappaB and cellular injury in rat myocardium. METHODS: Fifteen Sprague-Dawley rats were given saline solution (control group) or lipopolysaccharide. After 48 hours, 5 hearts in each group were excised without ischemia for examination of heat shock protein 70 and inhibitory kappaBalpha levels and detection of heat shock protein 70-inhibitory kappaBalpha complexes. Myocardium from the remaining 10 rats in each group was exposed to 30 minutes of ischemia and 30 minutes of reperfusion (n = 5) to evaluate nuclear factor kappaB activity or to 24 hours of reperfusion (n = 5) to evaluate infarct size. RESULTS: Infarct size was reduced in the lipopolysaccharide group (P <.05). Nuclear factor kappaB was activated in the control ischemia group and attenuated in the lipopolysaccharide group (P <.05). Heat shock protein 70 levels were increased in the lipopolysaccharide group (P <.05), but inhibitory kappaBalpha levels were similar in both groups. Heat shock protein 70-inhibitory kappaBalpha complexes were detected only in the lipopolysaccharide group. Colocalization of the 2 proteins was observed in the lipopolysaccharide group. CONCLUSIONS: Heat shock protein 70, induced by lipopolysaccharide pretreatment, forms complexes with inhibitory kappaBalpha and attenuates activation of nuclear factor kappaB and myocardial infarct size. Our results suggest that attenuation of nuclear factor kappaB through a mechanism forming heat shock protein 70-inhibitory kappaBalpha complexes might protect the myocardium from ischemia-reperfusion injury.     

Solute-free versus electrolyte-free water clearance in the analysis of osmoregulation

Reduced bone mineral density (BMD) and an increased risk of vertebral fracture have been reported in calcium-stone-forming (CSF) patients presenting with idiopathic hypercalciuria. We investigated the association between BsmI vitamin D receptor (VDR) polymorphism and BMD in 68 hypercalciuric CSF patients (35 males and 33 premenopausal females, mean age +/- SD = 39 +/- 10 years). BMD was measured at lumbar spine (L2-L4) and femur neck sites using dual energy X-ray absorptiometry. A 72-hour dietary record and a 24-hour urine sample were obtained from each patient to determine calcium intake and excretion. The allelic frequency found for the sample as a whole was 16% BB, 44% Bb and 40% bb. Mean BMD values did not significantly differ among BB, Bb and bb patients at L2-L4 (1.162 +/- 0.10, 1.133 +/- 0.11 and 1.194 +/- 0.19 g/cm2, mean +/- SD, respectively) or at neck sites (0.920 +/- 0.11, 0.931 +/- 0.15 and 0.982 +/- 0.15 g/cm2, respectively). Calcium intake and excretion were also not significantly different among the three genotypes. Patients were then divided into two groups, normal BMD, T-score > or =-1 (n = 34) and low BMD, T-score <-1 (n = 34), to further evaluate the allele influence on previous bone loss. Despite a trend for a higher mean BMD at spine or neck sites for patients with one or two b alleles when compared to BB patients, the difference did not reach statistical significance. The distribution of BB, Bb and bb genotypes in the low-bone-mass group (15, 47 and 38%, respectively) was similar to that in the normal-bone-mass group (18, 41 and 14%, respectively). These data suggest that BsmI VDR polymorphism does not play an important role in the bone loss seen in hypercalciuric CSF patients.