Potential antitumor agents. 59. Structure-activity relationships for 2-phenylbenzimidazole-4-carboxamides, a new class of "minimal" DNA-intercalating agents which may not act via topoisomerase II

A series of substituted 2-phenylbenzimidazole-4-carboxamides has been synthesized and evaluated for in vitro and in vivo antitumor activity. These compounds represent the logical conclusion to our search for "minimal" DNA-intercalating agents with the lowest possible DNA-binding constants. Such "2-1" tricyclic chromophores, of lower aromaticity than the structurally similar 2-phenylquinolines, have the lowest DNA binding affinity yet seen in the broad series of tricyclic carboxamide intercalating agents. Despite very low in vitro cytotoxicities, several of the compounds had moderate levels of in vivo antileukemic effects. However, the most interesting aspect of their biological activity was the lack of cross-resistance shown to an amsacrine-resistant P388 cell line, suggesting that these compounds may not express their cytotoxicity via interaction with topoisomerase II.     

Tyrosine kinase inhibitors. 15. 4-(Phenylamino)quinazoline and 4-(phenylamino)pyrido[d]pyrimidine acrylamides as irreversible inhibitors of the ATP binding site of the epidermal growth factor receptor.

A series of 6- and 7-acrylamide derivatives of the 4-(phenylamino)quinazoline and -pyridopyrimidine classes of epidermal growth factor receptor (EGFR) inhibitors were prepared from the corresponding amino compounds by reaction with either acryloyl chloride/base or acrylic acid/1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. All of the 6-acrylamides, but only the parent quinazoline 7-acrylamide, were irreversible inhibitors of the isolated enzyme, confirming that the former are better-positioned, when bound to the enzyme, to react with the critical cysteine-773. Quinazoline, pyrido[3,4-d]pyrimidine, and pyrido[3,2-d]pyrimidine 6-acrylamides were all irreversible inhibitors and showed similar high potencies in the enzyme assay (likely due to titration of the available enzyme). However the pyrido[3,2-d]pyrimidine analogues were 2-6-fold less potent than the others in a cellular autophosphorylation assay for EGFR in A431 cells. The quinazolines were generally less potent overall toward inhibition of heregulin-stimulated autophosphorylation of erbB2 (in MDA-MB-453-cells), whereas the pyridopyrimidines were equipotent. Selected compounds were evaluated in A431 epidermoid and H125 non-small-cell lung cancer human tumor xenografts. The compounds showed better activity when given orally than intraperitoneally. All showed significant tumor growth inhibition (stasis) over a dose range. The poor aqueous solubility of the compounds was a drawback, requiring formulation as fine particulate emulsions.     

Efficacy and safety evaluation of human reovirus type 3 in immunocompetent animals: racine and nonhuman primates.

PURPOSE: Human reovirus type 3 has been proposed to kill cancer cells with an activated Ras signaling pathway. The purpose of this study was to investigate the efficacy of reovirus in immunocompetent glioma animal models and safety/toxicity in immunocompetent animals, including nonhuman primates. EXPERIMENTAL DESIGN: Racine glioma cells 9L and RG2 were implanted s.c. or intracranially in Fisher 344 rats with or without reovirus antibodies, followed by treatment of reovirus. To study whether reovirus kills contralateral tumors in the brain and to determine viral distribution, we established an in situ dual tumor model followed by reovirus intratumoral inoculation only into the ipsilateral tumor. To evaluate neurotoxicity/safety of reovirus, Cynomolgus monkeys and immunocompetent rats were given intracranially with reovirus, and pathological examination and/or behavioral studies were done. Viral shedding and clinical biochemistry were systematically studied in monkeys. RESULTS: Intratumorally given reovirus significantly suppressed the growth of both s.c. and intracranially tumors and significantly prolonged survival. The presence of reovirus-neutralizing antibodies did not abort the reovirus' antitumor effect. Reovirus inhibited glioma growth intracranially in the ipsilateral but not the contralateral tumors; viral load in ipsilateral tumors was 15 to 330-fold higher than the contralateral tumors. No encephalitis or behavioral abnormalities were found in monkeys and rats given reovirus intracranially. No treatment-related clinical biochemistry changes or diffuse histopathological abnormality were found in monkeys inoculated intracranially with Good Manufacturing Practice prepared reovirus. Microscopic changes were confined to the region of viral inoculation and were dose related, suggesting reovirus intracranially was well tolerated in nonhuman primates. CONCLUSIONS: These data show the efficacy and safety of reovirus when it is used in the treatment of gliomas in immunocompetent hosts. Inoculation of reovirus into the brain of nonhuman primates did not produce significant toxicities.     

Prevalence and factors associated with anthropometric failure,vitamin A and iron deficiency among adolescents in a Nigerian urban community

BackgroundUnder nutrition is a problem of severe magnitude in low income countries like Nigeria. Adolescent school children might also be vulnerable. The dearth of data hinders planning of school health and nutrition programmes for school children.ObjectiveTo determine the prevalence of stunting, thinness; vitamin A and iron deficiencies among adolescent students in Nsukka urban, Nigeria and to determine factors that are associated with these nutritional problems.MethodsA total of 400 participants were randomly selected from 717 students aged 12 – 18 years in 3 randomly selected secondary schools. Questionnaires, anthropometric measurements, and blood analyses were the data collection methods employed.ResultsThe prevalence of stunting was 33.3% and thinness 31.0%. Neither overweight nor obesity was observed. While 64.0% were anaemic; 44.0% had vitamin A deficiency (VAD). A total of 48.0% had both anaemia and stunting, 42% had VAD + thinness; while 40% had anaemia + VAD. Household income was a predictor of vitamin A status. Children from medium/high income households had higher odds of having VAD than those from low income households (AOR=0.14; 95% CI=0.031, 0.607; P=0.009). Household income (AOR=0.12; 95% CI=0.021, 0.671; P=0.016), and age (AOR=0.09; 95% CI=0.014, 0.587; P=0.012) were independent determinants of height-for-age status.ConclusionAmong urban adolescent students in Nigeria, stunting, thinness, anaemia and VAD were problems of public health significance. Age and household monthly income played major roles.     

缺血预处理程序中心肌环磷酸腺苷含量及环磷酸腺苷依赖蛋白激酶活性的变化

目的:制备大鼠在体缺血再灌注模型,观察缺血预处理程序中心肌环磷酸腺苷含量及环磷酸腺苷依赖蛋白激酶活性的变化。方法:实验于2005-03/2006-10在解放军沈阳军区总医院医学实验动物中心和全军心血管研究所实验室完成。实验分组:选用健康雌性SD大鼠36只,根据预适应程序分为第1,2,3次缺血,第1,2,3次再灌注,每一时间点6只大鼠。实验过程:用手术套管法造成左冠状动脉主干缺血及再灌注。所有实验动物在实验程序结束后,取出心脏迅速置液氮保存备用。实验评估:用放射免疫法测环磷酸腺苷水平,生化法测环磷酸腺苷依赖蛋白激酶活性变化。结果:36只大鼠均进入结果分析。①环磷酸腺苷含量:第1次再灌注组低于第1次缺血组[(0.325±0.015),(0.395±0.024)pmol/g,t=6.06,P<0.001],第2次再灌注组低于第2次缺血组[(0.523±0.017),(0.708±0.067)pmol/g,t=6.56,P<0.001],第3次再灌注组低于第3次缺血组[(0.567±0.031),(0.712±0.038)pmol/g,t=7.24,P<0.001]。②环磷酸腺苷依赖蛋白激酶活性:第1次再灌注组低于第1次缺血组[(10.115±1.000),(16.351±0.849)pkat/g,t=11.12,P<0.001],第2次再灌注组低于第2次缺血组[(11.877±2.213),(14.869±0.619)pkat/g,t=3.31,P<0.01],第3次再灌注组低于第3次缺血组[(11.745±0.987),(14.766±0.329)pkat/g,t=7.09,P<0.001]。③缺血预处理程序中心肌环磷酸腺苷含量及环磷酸腺苷依赖蛋白激酶活性随缺血及再灌注呈周期性波动。在5min缺血预处理时表现为明显增高,而在间隔的再灌注程序中恰呈相反改变,有明显下降的趋势。结论:环磷酸腺苷及环磷酸腺苷依赖蛋白激酶的周期性波动变化可能是激发心肌缺血预处理的机制之一,环磷酸腺苷可能在预处理保护作用中起一些作用。     

How often are nonenhancing supratentorial gliomas malignant? A population study

The presence of contrast enhancement in a brain tumor is often regarded as a sign of malignancy. The authors identified 314 patients with malignant and low-grade supratentorial glial neoplasms in an unselected population, 58 of which lacked contrast enhancement on preoperative neuroimaging. Nonenhancing gliomas were malignant in approximately one third of cases, especially in older patients. Histologic confirmation of the diagnosis is therefore important in all patients suspected of harboring a primary glial neoplasm.     

Exchange transfusion in neutropenic septicemic neonates: effect on granulocyte functions

Depletion neutropenia caused by overwhelming bacterial infection is associated with fatal outcome and is an objective indicator of the severity of sepsis. Studies on controlled evaluation of exchange transfusion in the management of severe neonatal sepsis have not considered neutropenia as an inclusion critcrion, and randomized, controlled trials on evaluation of ncutrophil functions after exchange transfusion are scarce. This prompted us to carry out the present study. Septicemic neonates were enrolled if they had neutropenia and were randomized to undergo exchange transfusion (study group, n = 20) or not (controls, n= 10). Granulocyte functions were assessed using the nitro blue tetrazolium (NBT) reduction test and the staphylococcicidal index. Blood was drawn for granulocyte function tests once from controls and donors, and before, immediately after and 6 h after exchange transfusion in the study group. Mortality was 35% in the study group and 70% in controls. Gram-negative organisms accounted for 80%, in the study group and 90% in controls. Mean total leukocyte count and neutrophil count increased significantly immediately after exchange transfusion and 6 h later. Absolute band count decreased significantly immediately after exchange transfusion and incrcased 6 h later. NBT reduction in septicemic neonates in the study group, as wclras in controls. was significantly decreascd as compared to donor cells. NBT reduction improved significantly immediately after exchange transfusion and 6 h later. The valucs of the perccntage of viable staphylococci recovered from neutrophils also improved significantly immediately after exchange transfusion and 6 h later. We conclude that exchange transfusion with fresh whole blood in severe neonatal septicemia with neutropenia improves survival, increases the neutrophil count and cnhances neutrophil function.