Methionine aminopeptidase 2 inhibition is an effective treatment strategy for neuroblastoma in preclinical models. (41/211)

Tumor vascularity is correlated with an aggressive disease phenotype in neuroblastoma, suggesting that angiogenesis inhibitors may be a useful addition to current therapeutic strategies. We previously showed that the antiangiogenic compound TNP-470, an irreversible methionine aminopeptidase 2 (MetAP2) inhibitor, suppressed local and disseminated human neuroblastoma growth rates in murine models but had significant associated toxicity at the effective dose. We have recently shown that a novel, reversible MetAP2 inhibitor, A-357300, significantly inhibits CHP-134-derived neuroblastoma s.c. xenograft growth rate with a treatment-to-control (T/C) ratio at day 24 of 0.19 (P < 0.001) without toxicity. We now show that the combination of A-357300 with cyclophosphamide at the maximal tolerated dose sustained tumor regression with a T/C at day 48 of 0.16 (P < 0.001) in the CHP-134 xenograft model. A-357300 also significantly inhibited establishment and growth rate of hematogenous metastatic deposits following tail vein inoculation of CHP-134 cells and increased overall survival (P = 0.021). Lastly, A-357300 caused regression of established tumors in a genetically engineered murine model with progression-free survival in five of eight mice (P < 0.0001). There was no evidence of toxicity. These data show that MetAP2 may be an important molecular target for high-risk human neuroblastomas. We speculate that the growth inhibition may be through both tumor cell intrinsic and extrinsic (antiangiogenic) mechanisms. The potential for a wide therapeutic index may allow for treatment strategies that integrate MetAP2 inhibition with conventional cytotoxic compounds.  (+info)

Thirteen-week inhalation toxicity of p-dichlorobenzene in mice and rats. (42/211)

Subchronic inhalation toxicity of p-dichlorobenzene (p-DCB) was examined by exposing BDF1 mice and F344 rats of both sexes (6 h/d and 5 d/wk) to inhalation of 25, 55, 120, 270 or 600 ppm (v/v) p-DCB vapor for 13 wk. The exposure to p-DCB vapor retarded the growth rate in the male mice, and induced hepatotoxicity in the mice and rats of both sexes and renal and hematological toxicity in the male rats. Hepatotoxicity was characterized by increased liver weight, hepatocellular hypertrophy, and increased serum levels of total cholesterol. Liver necrosis and increased serum levels of AST and ALT were observed in the exposed mice, whereas these changes, which indicate hepatocellular death, did not occur in any of the exposed rats. p-DCB-induced renal lesions occurred only in the male rats. Hyaline droplets were observed in the proximal tubular epithelial cells, and were stained positively with anti-alpha2u-globulin, suggesting excessive accumulation of alpha2u-globulin in the epithelial cells. Granular casts were formed in the tubular lumen, resulting from the necrotic desquamation of the renal tubular epithelium. Papillary mineralization in the renal pelvis and increased serum levels of BUN and creatinine were noted. These renal changes indicated alpha2u-globulin nephropathy. Decreases in red blood cell counts, hemoglobin concentration, hematocrit and mean corpuscular volume and increased spleen weight occurred in the exposed male rats. The NOAEL was 120 ppm for the hepatic endpoint in mice and for the renal endpoint in rats. The maximum tolerated dose for a 2-yr bioassay inhalation study of rodent carcinogenicity was estimated to be 300 ppm, based on the present results.  (+info)

Novel potent human ether-a-go-go-related gene (hERG) potassium channel enhancers and their in vitro antiarrhythmic activity. (43/211)

A variety of drugs has been reported to cause acquired long QT syndrome through inhibition of the IKr channel. Screening compounds in early discovery and development stages against their ability to inhibit IKr or the hERG channel has therefore become an indispensable procedure in the pharmaceutical industry. In contrast to numerous hERG channel blockers discovered during screening, only (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl) -prop-2-ynyl]-piperidine-3-carboxylic acid (RPR260243) has been reported so far to enhance the hERG current. In this article, we describe several potent mechanistically distinct hERG channel enhancers. One example is PD-118057 (2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid) which produced average increases of 5.5 +/- 1.1, 44.8 +/- 3.1, and 111.1 +/- 21.7% in the peak tail hERG current at 1, 3, and 10 muM, respectively, in human embryonic kidney 293 cells. PD-118057 did not affect the voltage dependence and kinetics of gating parameters, nor did it require open conformation of the channel. In isolated guinea pig cardiomyocytes, PD-118057 showed no major effect on I(Na), I(Ca,L), I(K1), and I(Ks). PD-118057 shortened the action potential duration and QT interval in arterially perfused rabbit ventricular wedge preparation in a concentration-dependent manner. The presence of 3 muM PD-118057 prevented action potential duration and QT prolongation caused by dofetilide. "Early after-depolarizations" induced by dofetilide were also completely eliminated by 3 microM PD-118057. Although further investigation is warranted to evaluate the therapeutic value and safety profile of these compounds, our data support the notion that hERG activation by pharmaceuticals may offer a new approach in the treatment of delayed repolarization conditions, which may occur in patients with inherited or acquired long QT syndrome, congestive heart failure, and diabetes.  (+info)

Amino acids in positions 48, 52, and 73 differentiate the substrate specificities of the highly homologous chlorocatechol 1,2-dioxygenases CbnA and TcbC. (44/211)

Chlorocatechol 1,2-dioxygenase (CCD) is the first-step enzyme of the chlorocatechol ortho-cleavage pathway, which plays a central role in the degradation of various chloroaromatic compounds. Two CCDs, CbnA from the 3-chlorobenzoate-degrader Ralstonia eutropha NH9 and TcbC from the 1,2,4-trichlorobenzene-degrader Pseudomonas sp. strain P51, are highly homologous, having only 12 different amino acid residues out of identical lengths of 251 amino acids. But CbnA and TcbC are different in substrate specificities against dichlorocatechols, favoring 3,5-dichlorocatechol (3,5-DC) and 3,4-dichlorocatechol (3,4-DC), respectively. A study of chimeric mutants constructed from the two CCDs indicated that the N-terminal parts of the enzymes were responsible for the difference in the substrate specificities. Site-directed mutagenesis studies further identified the amino acid in position 48 (Leu in CbnA and Val in TcbC) as critical in differentiating the substrate specificities of the enzymes, which agreed well with molecular modeling of the two enzymes. Mutagenesis studies also demonstrated that Ile-73 of CbnA and Ala-52 of TcbC were important for their high levels of activity towards 3,5-DC and 3,4-DC, respectively. The importance of Ile-73 for 3,5-DC specificity determination was also shown with other CCDs such as TfdC from Burkholderia sp. NK8 and TfdC from Alcaligenes sp. CSV90 (identical to TfdC from R. eutropha JMP134), which convert 3,5-DC preferentially. Together with amino acid sequence comparisons indicating high conservation of Leu-48 and Ile-73 among CCDs, these results suggested that TcbC of strain P51 had diverged from other CCDs to be adapted to conversion of 3,4-DC.  (+info)

Enrichment and properties of an anaerobic mixed culture reductively dechlorinating 1,2,3-trichlorobenzene to 1,3-dichlorobenzene. (45/211)

Hexachlorobenzene (HCB), pentachlorobenzene (QCB), all three isomers of tetrachlorobenzene (TeCB), 1,2,3-trichlorobenzene (1,2,3-TCB), and 1,2,4-TCB were reductively dechlorinated by enrichment cultures in the presence of lactate, glucose, ethanol, or isopropanol as the electron donor. The enrichment cultures originated from percolation columns filled with Rhine River sediment in which dechlorination of TCBs and dichlorobenzenes (DCBs) occurred. A stable consortium obtained by transfer on lactate as the energy and carbon source in the presence of 1,2,3-TCB dechlorinated this isomer stoichiometrically to 1,3-DCB. Dechlorinating activity could only be maintained when an electron donor was added. Lactate, ethanol, and hydrogen appeared to be the best substrates. Optimal temperature and pH for dechlorination were 30 degrees C and 7.2, respectively. The specificity of the enrichment on lactate and 1,2,3-TCB was tested after approximately 60 transfers (after 2.5 years). HCB and QCB were stoichiometrically dechlorinated to 1,3,5-TCB and minor amounts of 1,2,4-TCB. 1,3,5-TCB was the sole product formed from 1,2,3,5-TeCB, while 1,2,3,4-TeCB and 1,2,4,5-TeCB were converted to 1,2,4-TCB. 1,2,4-TCB, 1,3,5-TCB, and the three isomers of DCB were not dechlorinated during 4 weeks of incubation. For further enrichment of the 1,2,3-TCB-dechlorinating bacteria, a two-liquid-phase (hexadecane-water) system was used with hydrogen as the electron donor and 1,2,3-TCB or CO2 as the electron acceptor. Methanogens and acetogens were the major substrate-competing (H2-CO2) microorganisms in the two-liquid-phase system. Inhibition of methanogenesis by 2-bromoethanesulfonic acid did not influence dechlorination, and acetogens which were isolated from the enrichment culture did not have dechlorinating activity.(ABSTRACT TRUNCATED AT 250 WORDS)  (+info)

Chlorobenzene degradation by bacteria isolated from contaminated groundwater. (46/211)

Bacterial isolates were obtained from groundwater and soils contaminated with chlorobenzene (CB). The isolates were tested to determine whether the natural community could remove the groundwater contaminants. These isolates were identified and characterized as to their ability to grow on CB and related aromatic compounds. The complete consortium could mineralize approximately 54% of the CB within 7 days, with no accumulation of 3-chlorocatechol. Metabolic pathways were evaluated for several isolates. One phenotype was characterized by the ability to degrade CB by the modified ortho pathway. One strain also degraded p-dichlorobenzene by using the same pathway. Isolates exhibiting a second phenotype degraded p-cresol, benzene, and phenol by the classical ortho pathway and accumulated 3-chlorocatechol when grown in the presence of CB. Strains of the third phenotype grew on complex media in the presence of CB but did not transform any of the aromatic compounds tested. The results suggest that the indigenous microbial community at the contaminated site would be able to degrade CB if provided with the appropriate conditions.  (+info)

Carcinogenicity and chronic toxicity in mice and rats exposed by inhalation to para-dichlorobenzene for two years. (47/211)

Carcinogenicity and chronic toxicity of para-dichlorobenzene (p-DCB) were examined by exposing 50 BDF1 mice and 50 F344 rats of both sexes by inhalation to p-DCB vapor at a target concentration of 0 (control), 20, 75 or 300 ppm for 6 hr/day, 5 days/week and 2 years. Incidences of hepatocellular carcinomas, hepatoblastomas and hepatic histiocytic sarcomas in the 300 ppm-exposed male mice, and hepatocellular adenomas and carcinomas and hepatoblastomas in the 300 ppm-exposed female mice were increased. An increase in the incidences of most of those liver tumors was dose-related. No increase in tumor incidence was found in any p-DCB-exposed rat of either sex. Centrilobular hypertrophy of hepatocytes and papillary mineralization and pelvic urothelial hyperplasia of the kidney were noted in the 300 ppm-exposed male rats. Treatment- and age-related increases in incidences of the eosinophilic globules of the respiratory and olfactory epithelia in female rats and incidences of the respiratory metaplasia of the nasal gland epithelium in mice and rats and the olfactory epithelium in mice were noted. The nasal lesion was the most sensitive endpoint of chronic inhalation toxicity. Induction of the mouse hepatocarcinogenicity and lack of the rat nephrocarcinogenicity found in the present study were compared with the mouse liver tumors and the rat renal tumors reported by the NTP gavage study, and discussed in light of the estimated p-DCB uptake into the body through the inhalation and the oral administration.  (+info)

Methodichlorophen as anti-tumor drug. (48/211)

Methodichlorophen was given to 26 patients with terminal malignant disease. Eight patients received adequate doses, and five of them showed objective evidence of tumour regression while three failed to respond. Those who responded included four out of five patients with lung cancer (three with squamous-cell carcinoma and one with oat-cell carcinoma) and a patient with hypernephroma. Two patients with testicular teratomas and one with acute myeloid leukemia failed to respond. The drug may be given safely by mouth to outpatients if certain precautions are taken.  (+info)