Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001418 (adenocarcinoma)
 68,496 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis and antitumor activity of a new series of E-3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones is described. Several compounds were active on the primary test (three human cell lines) and entered the second level (60 human cell lines). All of them were potent growth inhibitors with GI(50) ranging from -5.32 to -7.27. Four are now under review by BEC (Biological Evaluation Committee of the NCI). The most potent antitumor derivatives were also evaluated as cardiotonic agents (in view of a possible coanthracyclinic activity). In order to find a possible mechanism of action their effects on cell cycle progression in an adenocarcinoma cell line (HT29) were tested, evidencing that these molecules are able to block HT29 in mitosis. The introduction of new substituents in the indolinone moiety while maintaining the same chloroindole portion generated interesting derivatives. 3-(2-Chloro-5-methoxy-6-methyl-3-indolylmethylene)5-hydroxy-1,3-dihydroindol-2-one was the most active of the whole series. It was more potent than vincristine against seven of the nine tumors considered. Moreover it was selective towards some cell lines such as MDA-MB-435 (breast), OVCAR-3 (ovarian) and SK-MEL-28 (melanoma). Even the introduction of a benzyl ring at the nitrogen of the chloroindole portion, gave rise to potent compounds.
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PMID:Substituted E-3-(2-Chloro-3-indolylmethylene)1,3-dihydroindol-2-ones with antitumor activity. 1498 Jun 24

Nine new nitrogen mustard compounds derived from 2,6-difluoro-4-hydroxy- (3a-e) and 2,6-difluoro-4-amino- (4a-d) aniline were synthesized as potential prodrugs. They were designed to be activated to their corresponding 3,5-difluorophenol and -aniline (4)-nitrogen mustards by the enzyme carboxypeptidase G2 (CPG2) in gene-directed enzyme prodrug therapy (GDEPT) models. The compounds were tested for cytotoxicity in the MDA MB-361 breast adenocarcinoma. The cell line was engineered to express stably either CPG2 tethered to the cell surface stCPG2-(Q)3 or beta-galactosidase (beta-Gal) as control. The cytotoxicity differentials were calculated between CPG 2-expressing and -nonexpressing cells and yielded different results for the two series of prodrugs despite their structural similarities. While the phenol compounds are ineffective as prodrugs, their aniline counterparts exhibit outstanding activity in the tumor cell lines expressing CPG2. [3,5-Difluoro-4-[bis(2-chloroethyl)amino]phenyl]carbamoyl-l-glutamic acid gave a differential of >227 in MDA MB361 cells as compared with 19 exhibited by 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-l-glutamic acid, 1a, which has been in clinical trials.
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PMID:Significant differences in biological parameters between prodrugs cleavable by carboxypeptidase G2 that generate 3,5-difluoro-phenol and -aniline nitrogen mustards in gene-directed enzyme prodrug therapy systems. 1511 6

The gastric inflammatory response provoked by Helicobacter pylori (H. pylori) consists of infiltrations by neutrophils, lymphocytes, and macrophages, resulting in varying degrees of epithelial cell damage. H. pylori-associated inflammation not only activates various oxidant-producing enzymes such as NADPH oxidase and inducible nitric oxide synthase, but also lowers the antioxidant ascorbic acid in the stomach. Reactive oxygen metabolites and nitrogen metabolites generated by these enzymes react with each other to generate new or more potent reactive species. The specific types of cellular damage resulting from reactive oxygen metabolites include lipid peroxidation, protein oxidation, and oxidative DNA damage. All of these oxidative products can result in biochemical changes leading to cancer. A positive association has been demonstrated between H. pylori infection and gastric adenocarcinoma with increased oxidative stress. Therefore, appropriate treatment to reduce oxidative stress would be expected to prevent subsequent gastric carcinogenesis through lessening of H. pylori-associated inflammation. This review will provide evidence that antiinflammatory regimens can decrease the development of tumors and the amelioration of gastric inflammation might lead to chemoprevention strategies by the attenuation of oxidative stress.
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PMID:Amelioration of oxidative stress with ensuing inflammation contributes to chemoprevention of H. pylori-associated gastric carcinogenesis. 1513 Feb 81

In the Western world at least, most upper gastrointestinal cancers now arise from the mucosa near to the oesophagogastric junction. Research into the mechanism of the development of adenocarcinoma at the oesophagogastric junction has mainly focused on the noxious effects of acid and bile. There is however an alternative concept for explaining the location of adenocarcinomas: the cancers are occurring at the anatomical site where saliva encounters acidic gastric juice and their interaction generates reactive nitrogen species which are potentially mutagenic and carcinogenic. At present, it is unclear whether the active nitrite chemistry is exerting detrimental effects on the surrounding tissue but it is important to investigate this possibility as it could reveal new ways of preventing and treating the high prevalence of disease occurring at this anatomical site.
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PMID:When saliva meets acid: chemical warfare at the oesophagogastric junction. 1559 95

Poly-[N-(2-hydroxyethyl)-L-glutamine] (PHEG) and poly(ethylene glycol) (PEG)-grafted PHEG conjugates of N,N-di(2-chloroethyl)-4-phenylenediamine mustard (PDM) were synthetised. A collagenase-sensitive oligopeptide spacer was selected to link the cytotoxic agent PDM onto the polymeric carrier. First, the oligopeptide-drug conjugate, L-pro-L-leu-gly-L-pro-gly-PDM, was prepared. In a second step, the low molecular weight PDM derivative and PEG-NH(2) were coupled to a N,N-disuccinimidylcarbonate activated PHEG. Dynamic laser light scattering measurements indicated the formation of aggregates. The presence of human serum albumin had no significant effect on the diameter of the conjugates. The hydrolytic stability of the conjugates was investigated in buffer solutions. The conjugates showed an improved stability compared to the parent nitrogen mustard. The enzymatic degradation studies of the polymeric conjugates were performed in the presence of collagenase type IV (Clostridiopeptidase A; EC 3.4.24.3), cathepsin B (EC 3.4.22.1), cathepsin D (EC 3.4.23.5) and tritosomes. Only the bacterial collagenase type IV was able to cleave the spacer releasing free PDM and its peptidyl derivative, gly-L-pro-gly-PDM. The in vitro cytotoxicity of the conjugates was evaluated against HT1080 fibrosarcoma cells and MDA adenocarcinoma cells. All conjugates showed low toxicity towards these cell lines.
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PMID:Synthesis and in vitro evaluation of macromolecular antitumour derivatives based on phenylenediamine mustard. 1566 87

Clinical and experimental studies provide evidence that the plasminogen activation system plays a pivotal role in the pathogenesis of tumor growth and metastatic spread. The aim of the present study was to evaluate plasminogen activator inhibitor type I (PAI-1) in plasma and tumor extracts in patients with non-small cell lung cancer (NSCLC). The study group consisted of 146 patients (18 females, 128 males), aged 33-76 years with squamous cell carcinoma (107), adenocarcinoma (19), and mixed type of lung carcinoma (20) in pTNM stage I (72), stage II (30) and stage III (44) and 50 healthy volunteers as a control group (15 females, 35 males) aged 25-69 years. Blood for analysis was collected in the morning, 1-2 days before operation. Lung cancer and normal lung tissue specimens were obtained during surgery and homogenized in liquid nitrogen. The tissue extracts and plasma were assayed for concentration of PAI-1 with ELISA method. Significantly higher plasma level of PAI-1 was observed in patients with lung cancer than in control group. Concentration of PAI-1 in tumor tissues was significantly higher compared to normal lung tissue and was irrelevant from plasma level. Positive correlation between tumor level of PAI-1 and stage of lung cancer was noticed. Therefore it can be assumed that PAI-1 has an influence on the lung cancer progression.
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PMID:[Plasminogen activator inhibitor type 1 (PAI-1) in blood and tissue extracts of patients with non-small cell lung cancer]. 1602 96

Patients on hemodialysis (HD) who undergo surgery represent a high risk group requiring careful perioperative management to avoid electrolyte imbalance and hemodynamic instability. The aim of the study was to analyze the postoperative outcome in terms of complications and survival of a group of patients on HD who had undergone pulmonary resection for non-small cell lung cancer (NSCLC). Six patients on HD underwent seven pulmonary resections at our institution from 1998 to 2003. The underlying kidney disease was nephrosclerosis in two patients and glomerulonephritis in four. The mean levels of blood urea nitrogen and serum creatinine were 107 +/- 11.5 mg/dl and 7.9 +/- 0.64 mg/dl, respectively. The mean preoperative PO2 and FEV1 were 77.6 +/- 2.4 mmHg and 2.4 +/- 0.16 liters, respectively. The histologic diagnosis was squamous cell carcinoma in four cases and adenocarcinoma in three. One patient underwent two lung resections in 4 years for two primary lung cancers. Five patients underwent lobectomy, one underwent a wedge resection, and in one case pneumonectomy was performed after neoadjuvant chemotherapy. There was no operative mortality. Postoperatively, atrial fibrillation occurred in two patients associated with sputum retention in both, and two other patients had hyperkalemia (complication rate 57%). One patient died of cardiac complications 27 months after surgery. The remaining five patients are currently alive with no evidence of disease. Patients on HD who undergo lung resection have a high rate of postoperative complications. Although the underlying disease influences long-term survival, radical lung resection in NSCLC patients is recommended in selected cases. Careful metabolic, hematologic, and pharmaceutical management is mandatory during the perioperative period.
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PMID:Pulmonary resection for non-small-cell lung cancer in patients on hemodialysis: clinical outcome and long-term results. 1622 51

Porphyrazines (pzs), or tetraazaporphyrins, can be viewed as porphyrinic macrocycles in which the porphyrin meso (CH) groups are replaced by nitrogen atoms; as such, it can be anticipated that pzs would show similar biocompatibility and biodistribution to those of porphyrins. However, distinctive chemical and physical features of the pzs differentiate them from either the porphyrins or phthalocyanines, in particular making them excellent candidates as optical imaging/therapeutic agents. The novelty of the pzs requires that we first determine how specific structures selectively alter biological function, leading to the development of "rules" that will be used to predict future biologically functional pzs. In the first of these studies, we present here a correlation of pz charge with biocompatibility for a suite of three pzs-neutral, negative, and positive. Confocal fluorescence microscopy and proliferation/viability measurements disclose that the three pzs differ in their toxicity, uptake, and localization in A549 human lung adenocarcinoma cells and WI-38 VA13 normal cells. Interestingly, the negatively charged pz exhibits selective dark toxicity in pulmonary adenocarcinoma cells.
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PMID:Charge dependence of cellular uptake and selective antitumor activity of porphyrazines. 1636 94

A female golden retriever was referred to assess a history of a palpable abdominal mass. A serum chemistry analysis revealed elevated concentrations of blood urea nitrogen, creatinine, calcium, and parathyroid hormone-related protein (PTH-rP). Exploratory laparotomy revealed an ovoid mass within the right ovary. This mass was removed surgically by performing an ovariohysterectomy. The right ovarian mass was diagnosed as a serous papillary adenocarcinoma. Following surgery, the dog recovered, and the serum calcium and PTH-rP concentrations decreased. Therefore, concentrations of PTH-rP and calcium might be associated with serous papillary adenocarcinomas. Serial evaluation of the serum PTH-rP and calcium was useful for evaluating the prognosis.
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PMID:Canine ovarian serous papillary adenocarcinoma with neoplastic hypercalcemia. 1701 69

The quantitative understanding of the role of sugar phosphates in regulating tumor energetic metabolism at the proteomic and genomic level is a prerequisite for an efficient rational design in combined drug chemotherapy. Therefore, it is necessary to determine accurately the concentration of the main sugar phosphate pools at the lower concentrations present in the often-limited volume of tumor cell samples. Taking as an example the human adenocarcinoma cell line HT29, we here report a fast and reliable quantitative method based on the use of liquid nitrogen, a weak acid extraction, and liquid chromatography-electrospray ionization tandem mass spectrometry to quantify simultaneously the intracellular concentration of sugar phosphate pools. The method was set up using standard addition curves. Thus, it is possible to identify and quantify hexose phosphate, pentose phosphate, and triose phosphate pools up to 0.02-0.10 ng x microL(-1), depending on the analyte. The method developed was here used for the quantitative study of changes in phosphorylated carbohydrates of central carbon metabolism when high or low glucose concentration conditions are induced in vitro in the HT29 human colon adenocarcinoma cell line.
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PMID:Quantification of intracellular phosphorylated carbohydrates in HT29 human colon adenocarcinoma cell line using liquid chromatography-electrospray ionization tandem mass spectrometry. 1752 95


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