Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human serum albumin (HSA) is one of the key components in human blood that may influence drug distribution. As such, it is important to know the affinity of any drug for albumin. Previously, Photofrin, a mixture of monomeric, dimeric and oligomeric porphyrins, has been subjected to HSA binding studies. However, due to its complex nature, binding studies on Photofrin or other hematoporphyrin derivatives with HSA are inconclusive. In this report, the binding properties of some components (dimers and trimers) of Photofrin and the relationship between murine photosensitizing efficacy and those binding properties were investigated. The interaction of these porphyrins with HSA was investigated by direct ultrafiltration and fluorescent titration techniques with fluorescent probes such as dansyl-L-proline (DP), which is known to interact selectively with site II on HSA. Porphyrins also were tested for antitumor activity in a mouse model following intravenous administration and exposure to laser light. Together, the results suggest that the photosensitizers that were preferentially bound to site II of HSA were most effective at controlling murine tumor regrowth.
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PMID:Correlation between site II-specific human serum albumin (HSA) binding affinity and murine in vivo photosensitizing efficacy of some Photofrin components. 927 41

Albumin dominates the plasma proteins in man. Following our observation that albumin turnover in rodent tumors is markedly increased, we will present evidence that albumin can be employed as an efficient carrier for targeting cytostatic agents like methotrexate (MTX) into tumors. The considerable discrepancy in the molecular weight of MTX (454 Da) and albumin (about 67,000 Da) tempted researchers to load multiple drug molecules on one carrier molecule. It was supposed that the optimal therapeutic efficacy of MTX protein conjugates could be achieved by increasing the number of the molecules of MTX attached to the carrier. In this paper we will show that only loading rates of close to 1 mol of the cytostatic drug MTX/mol of albumin offer optimal conditions for targeting MTX-albumin conjugates into rodent tumors. Conjugates bearing 5, 7, 10 and 20 molecules of MTX on average showed considerable alterations in the HPLC profiles of the conjugates compared to albumin. Conjugates carrying 5-20 mol MTX, tagged with a residualizing radiolabel, were efficiently trapped by the liver before reaching the tumor. The tumor uptake rates of these conjugates declined dramatically with an increasing molecular load of the cytotoxic drug linked to albumin. Competition experiments with maleylated bovine serum albumin and fucoidan revealed that scavenger receptors present on the cells of the liver monocyte macrophage system were involved in this process. For further preclinical and clinical studies, we chose MTX-albumin conjugates, derivatized at a molar ratio of 1:1. These conjugates enjoy the same favorable tumor targeting properties like albumin, e.g. high tumor uptake rates, low liver uptake rates and a very long biological half-life.
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PMID:The loading rate determines tumor targeting properties of methotrexate-albumin conjugates in rats. 931 44

The value of macromolecular contrast agents (MMCM) for the characterization of benign and malignant breast tumors will be demonstrated in this review. Animal studies suggest a high potential of MMCM to increase the specificity of MR-mammography. The concept of tumor differentiation is based on the pathological hyperpermeability of microvessels in malignant tumors. MMCM show a leak into the interstitium of carcinomas, whereas they are confined to the intravascular space in benign tumors. Capabilities and limitations of the MMCM-prototype. Albumin-Gd-DTPA, for breast tumor characterization will be summarized and compared to the standard low molecular weight contrast agent Gd-DTPA. Initial experience with new MMCM, such as Dendrimers, Gd-DTPA-Polylysine and MS-325 will be outlined. The potential of "blood-pool"-iron oxides, such as AMI-227 for the evaluation of tumor microvascular permeabilities will be discussed.
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PMID:[Macromolecular contrast media for MR mammography. A new approach to characterizing breast tumors]. 942 19

Novel anti-neoplastic agents such as gene targeting vectors and encapsulated carriers are quite large (approximately 100-300 nm in diameter). An understanding of the functional size and physiological regulation of transvascular pathways is necessary to optimize delivery of these agents. Here we analyze the functional limits of transvascular transport and its modulation by the microenvironment. One human and five murine tumors including mammary and colorectal carcinomas, hepatoma, glioma, and sarcoma were implanted in the dorsal skin-fold chamber or cranial window, and the pore cutoff size, a functional measure of transvascular gap size, was determined. The microenvironment was modulated: (i) spatially, by growing tumors in subcutaneous or cranial locations and (ii) temporally, by inducing vascular regression in hormone-dependent tumors. Tumors grown subcutaneously exhibited a characteristic pore cutoff size ranging from 200 nm to 1.2 microm. This pore cutoff size was reduced in tumors grown in the cranium or in regressing tumors after hormone withdrawal. Vessels induced in basic fibroblast growth factor-containing gels had a pore cutoff size of 200 nm. Albumin permeability was independent of pore cutoff size. These results have three major implications for the delivery of therapeutic agents: (i) delivery may be less efficient in cranial tumors than in subcutaneous tumors, (ii) delivery may be reduced during tumor regression induced by hormonal ablation, and (iii) permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter.
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PMID:Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. 953 85

The intracellular accumulation of albumin has been observed in cytosols of benign and malignant human breast tumors and in mammary tumors of rodents induced by carcinogens. Additionally, cellular uptake of albumin has been detected in MCF-7 human breast cancer cells in culture. The clinical relevance of the albumin accumulation in human and rodent mammary tumors is not clear. In this study, we investigated the accumulation of albumin in an estrogen-induced and -dependent hamster kidney tumor model to understand the mechanisms and the role of hormones in this process. Protein accumulation patterns were examined by Western blot analyses in kidney homogenates of hamsters treated with 17beta-estradiol for various lengths of time and in kidney tumors which are induced with 100% incidence by this treatment for at least six months. Such analyses were also carried out in tissues of hamsters treated with the weakly carcinogenic estrogen 17alpha-ethinylestradiol (10% tumor incidence after nine months of treatment). Our data demonstrate the accumulation of albumin in kidney of hamsters treated with 17beta-estradiol but not with 17alpha-ethinylestradiol. Albumin accumulates specifically in the target organ of carcinogenesis, the kidney, however, with no increase in the serum concentrations or in the liver. Tumors do not develop in the livers of hamsters under these conditions of 17beta-estradiol treatment. This accumulation of albumin in hamster kidney may be the result of damage to the glomerulum which may be compromised by estradiol-induced toxicity and therefore unable to filter out excess albumin.
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PMID:Accumulation of albumin in renal cytosol of hamsters treated with estradiol and in estrogen-induced hamster kidney tumors. 977 4

A quantitative assay of albumin messenger RNA (mRNA) in blood samples was designed using the competitive reverse-transcription polymerase chain reaction, and the significance of measuring albumin mRNA levels in the blood of patients with hepatocellular carcinoma (HCC) in hepatic resection was evaluated. Albumin mRNA levels were measured in the following: (1) peripheral blood in 11 patients with HCC and 20 control subjects without liver disease, (2) blood in the portal and hepatic veins in five patients with HCC immediately after laparotomy, and (3) a perioperative series of peripheral blood in eight patients with HCC. Two patients with HCC whose albumin mRNA level in peripheral blood was markedly high were both at stage IVa. On the other hand, 20 control subjects showed negative or <5 x 10(3) transcripts/microgram RNA of albumin mRNA expression. Immediately after laparotomy, the albumin mRNA levels in the tumor-draining hepatic vein were greater than in the portal and non-tumor-draining hepatic veins in four of five patients with HCC. Albumin mRNA levels in peripheral blood showed a marked increase after mobilization and/or resection of the liver and, thereafter, gradually decreased at postoperative day 7 in all eight patients with HCC. A new method to measure the albumin mRNA levels in blood samples was developed, and high albumin mRNA levels in the peripheral blood of patients with advanced-stage HCC suggest the presence of HCC cells in the circulation. Increased levels in the tumor-draining hepatic vein could indicate the spontaneous release of tumor cells or nontumorous hepatocytes or an increased albumin transcription in activated blood mononuclear cells. An increase in the levels in peripheral blood during an operation is intermittent. Therefore, an increased albumin mRNA level in the tumor-draining vein suggests, but does not prove, that the increased albumin mRNA level reflects tumor cells entering the systemic circulation. This alone does not prove that the prognosis is worsened.
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PMID:Perioperative change in albumin messenger RNA levels in patients with hepatocellular carcinoma. 982 32

A prospective study was carried out in 207 patients with benign and neoplastic diseases of the digestive tract who were candidates for elective surgery, in order to evaluate the influence of the nutritional status and perioperative transfusions on the appearance of postoperative infections. All patients were subjected to a nutritional assessment study based on anthropometric parameters, analytical data, and cutaneous delayed hypersensitivity tests. With the aim of establishing a risk potential for postoperative infection based on the nutritional status of the patients, a multi-parametric index called Nutritional Septicemic Risk (NSR) was applied to all. NSR = 14.265 - 1.764 + Albumin - 1.472 x risk area The criteria that were considered to indicate Proteic Caloric Malnutrition (PCM) were the presence of a Usual Weight Percentage (UW%) lower than 90% and an albumin level lower than 3.5 g/dl. Transfusions were indicated at Hemoglobin levels lower than 10 g/dl and/or a Hematocrit lower than 30%. The perioperative transfusion was defined as that which took place within three weeks prior to the surgery, during the surgery itself, and that which took place during the first 48 hours postoperatively. The postoperative infections have qualitatively been evaluated as: infection of the surgical wound, intraabdominal abscess, and respiratory infection. A total of 80 patients (38.6%) showed some degree of malnutrition. With regard to the transfusions, 55 patients (26.6%) underwent a transfusion. The univariable study has identified the nutritional status as classified according to the NSR multi-parametric index, neoplastic disease, perioperative transfusion and a surgical intervention time greater than two hours, as being risk factors of infection. By means of the logistic regression study, the nutritional status (NSR score) and the perioperative transfusions have been identified as independent risk factors.
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PMID:[Modification of the nutritional septicemic risk (RSN) by means of perioperative transfusion]. 1050 58

Primary porcine hepatocytes (PPH) are currently used in research and therapeutic applications as the biological component of extracorporeal liver assist devices to overcome the shortage of human hepatocytes. However, their finite life span and typically rapid loss of functions limit their utility. An immortalized, nontumorigenic, highly differentiated porcine hepatocyte cell line was developed in our laboratory to resolve these disadvantages. PPH were transfected with simian virus 40 (SV40) T antigen under the control of the SV40 early promoter. From the established 69 clones, 23 clones displaying hepatocyte-like morphology were screened for diazepam metabolism. One clone, HepLiu D63, has been maintained in culture for > 2 years, through more than 60 passages and 240 divisions. Albumin protein, present in early passages, was lost at later passages, but albumin transcript still was detectable in later passages. Carbamoyl phosphate synthetase, a gateway enzyme of the urea cycle, was consistently detectable in HepLiu cells. Cytokeratin 18, a characteristic marker of primary hepatocytes, was detected by both immunofluorescent staining and Western blot in HepLiu cells. Furthermore, maintenance of P450 functions in HepLiu cells was evidenced by diazepam and 7-ethoxycoumarin metabolites measured by HPLC. Phase II conjugative function was measured as acetaminophen glucuronidation. P450 dealkylase was demonstrated microscopically by the conversion of a nonfluorescent substrate to a fluorescent product. Both Northern blot analysis and immunofluorescent staining showed SV40 T antigen expression in the nuclei of HepLiu cells. No tumor formation occurred when HepLiu cells were injected into severe combined immunodeficient (SCID) mice nor was the TAI (a tumor marker) mRNA expressed, even in later passages. This immortalized, nontumorigenic, highly functional cell line may provide a valuable tool for drug/toxicological studies, liver biologic regulation studies, and artificial liver support systems.
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PMID:Characterization and evaluation of detoxification functions of a nontumorigenic immortalized porcine hepatocyte cell line (HepLiu). 1044 35

p53 is a transcription factor that is activated by genotoxic stress and mediates cell cycle arrest and apoptosis. Here we demonstrate that infection of mouse liver with recombinant E1/E3-deleted adenovirus leads to p53 activation and simultaneously to the down-regulation of albumin gene expression. In vitro transcription assays indicate that transcriptional mechanisms mediated through the albumin promoter are responsible for reduced albumin mRNA levels during viral infection. Albumin expression is maintained in the liver by a combination of liver-enriched transcription factors such as CAAT enhancer-binding protein (C/EBP)alpha and C/EBPbeta. We show that p53 wild type and tumor-derived p53 mutations repress C/EBP-mediated transactivation of the albumin promoter. The binding of C/EBPalpha or -beta to its cognate sequence in the albumin promoter is not inhibited by p53 expression. Deletion analysis and domain swapping experiments show that repression of C/EBPbeta-mediated transactivation is dependent on the N-terminal domain of p53 and the transactivation domain, leucine zipper domain, and the inhibitory domain II (amino acids 163-191) of C/EBPbeta. Our results provide a molecular explanation for the p53-mediated down-regulation of liver-specific gene expression after viral infection. Additionally, as overexpression of p53 mutants is frequently found in undifferentiated hepatocellular carcinomas, the same mechanisms may contribute to the lack of liver-specific gene transcription in these tumors.
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PMID:p53 represses CAAT enhancer-binding protein (C/EBP)-dependent transcription of the albumin gene. A molecular mechanism involved in viral liver infection with implications for hepatocarcinogenesis. 1054 49

Albumin-based drug carrier systems have been developed in the field of chemotherapy to improve the passive tumor targeting properties of anti-cancer drugs. Usually, serum albumins of different species are used as carrier proteins, mostly of bovine (BSA), human (HSA) or rat (RSA) origin. The resulting albumin conjugates are often tested for anticancer activity in heterologous tumor models. No data is available whether the choice of the albumin species might influence the pharmacokinetics or the tumor uptake rates of the conjugates in vivo. Residualizingly ([111In]DTPA) radiolabeled RSA, BSA or HSA were administered to Walker-256 carcinoma-bearing rats. No significant difference was found in the absolute or the weight-adjusted tumor uptake rates of the three albumin tracers. The tumors were the major catabolic sites accumulating 14-18% of the injected dose (ID). Low hepatic uptake rates were determined for all albumins (below 100% ID). Minor differences were found for hepatic uptake in favor of the autologous RSA (5.8% ID) versus HSA (6.9%) and BSA (8.0%). These differences might have occurred during the commercial preparation or the radiolabeling of the different batches. In addition, there are structural differences between the three albumins, which might have contributed, despite high sequence homologies above 70% for RSA, HSA and BSA. These minor differences in the distribution patterns of RSA, HSA or BSA might not decisively influence the results of drug targeting experiments in rats. For further studies with albumin conjugates, HSA was chosen as drug carrier in rodent animal models when considering later human use. In rats or nude mice multiple injections of various HSA-drug conjugates were well tolerated without signs of allergy or anaphylaxis.
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PMID:Albumin-based drug carriers: comparison between serum albumins of different species on pharmacokinetics and tumor uptake of the conjugate. 1057 11


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