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) nanoparticles represent a promising tool for targeted drug delivery to tumor cells. The coupling of the antibody trastuzumab to nanoparticles uses the capability of human epidermal growth factor receptor 2 (HER2)-positive cells to incorporate agents linked to HER2. In our present study, we developed targeted nanoparticles loaded with antisense oligonucleotides (ASOs) against polo-like kinase 1 (Plk1). We evaluated the receptor-mediated uptake into HER2-positive and -negative breast cancer and murine cell lines. We performed quantitative real-time PCR and Western blot analyses to monitor the impact on Plk1 expression in HER2-positive breast cancer cells. Antibody-conjugated nanoparticles showed a specific targeting to HER2-overexpressing cells with cellular uptake by receptor-mediated endocytosis and a release into HER2-positive BT-474 cells. We observed a significant reduction of Plk1 mRNA and protein expression and increased activation of Caspase 3/7. Thus, this is the first report about ASO-loaded HSA nanoparticles, where an impact on gene expression could be observed. The data provide the basis for the further development of carrier systems for Plk1-specific ASOs to reduce off-target effects evoked by systemically administered ASOs and to achieve a better penetration into primary and metastatic target cells. Treatment of tumors using trastuzumab-conjugated ASO-loaded HSA nanoparticles could be a promising approach to reach this goal.
Neoplasia 2008 Mar
PMID:Downregulation of Plk1 expression by receptor-mediated uptake of antisense oligonucleotide-loaded nanoparticles. 1832 67

Despite advances in treatment of patients with metastatic breast cancer (MBC), prognosis remains poor and median survival is 2-3 years. Resistance to antineoplastics mediated by many factors, potentially including overexpression of drug efflux proteins or altered beta-tubulin isotype expression limits the effectiveness of MBC chemotherapy. Capecitabine, approved for anthracycline- and taxane-resistant MBC, has produced modest responses, highlighting the need for more effective treatments for MBC resistant to multiple chemotherapeutic agents. Agents with potential to reverse drug resistance have not proven effective. Albumin-bound paclitaxel is a formulation that may enhance delivery to tumor tissues. Conversely, ixabepilone, an epothilone analog, has been reported to have lower susceptibility to at least some mechanisms of tumor resistance and clinical activity in resistant/refractory MBC. The topoisomerase-I inhibitor irinotecan also has low cross-resistance with other antineoplastics, and has shown some activity against refractory MBC. Development of new agents and identification of genetic biomarkers in translational studies promise to improve management of patients with resistant/refractory breast cancer.
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PMID:Impact, mechanisms, and novel chemotherapy strategies for overcoming resistance to anthracyclines and taxanes in metastatic breast cancer. 1844 2

Many chemotherapeutic and biologic agents used for advanced breast cancer exhibit activity alone or in combination, but the small number of randomized trials, coupled with the significant heterogeneity of patient and tumor characteristics, have precluded the development of standardized, evidence-based approaches to therapy for advanced disease. This expert faculty roundtable discussion focused on chemotherapy regimens used in pretreated patients. Given the increasing data on taxanes in this setting, a specific need was identified that led to the theme of standard and novel taxanes in this discussion. Numerous factors can predict response and long-term outcome: tumor characteristics like hormone and HER2 receptor status and grade and clinical characteristics like age, functional status, disease-free interval, previous adjuvant therapy, and sites or burden of metastatic disease. The choice of therapeutic agents or combinations, therefore, relies not only on randomized or phase II trial results but also on patient context in relation to these variables. After anthracycline and taxane therapy, agents such as capecitabine, vinorelbine, gemcitabine, and platinum agents and combinations thereof can be active. Taxanes themselves also possess activity, with a dependency on a specific agent and schedule. Albumin-bound paclitaxel has demonstrated superiority to certain taxane agents and schedules and has demonstrated activity after taxane exposure. This discussion highlights basic paradigms by which standard taxanes and albumin-bound paclitaxel can be evaluated as possible therapeutic or investigative options, along with nontaxane agents, emerging biologic agents, and combinations.
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PMID:Novel taxane formulations in the treatment of breast cancer: a thought leader discussion and consensus roundtable. 1850 Oct 57

Albumin is playing an increasing role as a drug carrier in the clinical setting. Principally, three drug delivery technologies can be distinguished: coupling of low-molecular weight drugs to exogenous or endogenous albumin, conjugation with bioactive proteins and encapsulation of drugs into albumin nanoparticles. The accumulation of albumin in solid tumors forms the rationale for developing albumin-based drug delivery systems for tumor targeting. Clinically, a methotrexate-albumin conjugate, an albumin-binding prodrug of doxorubicin, i.e. the (6-maleimido)caproylhydrazone derivative of doxorubicin (DOXO-EMCH), and an albumin paclitaxel nanoparticle (Abraxane) have been evaluated clinically. Abraxane has been approved for treating metastatic breast cancer. An alternative strategy is to bind a therapeutic peptide or protein covalently or physically to albumin to enhance its stability and half-life. This approach has been applied to peptides with antinociceptive, antidiabetes, antitumor or antiviral activity: Levemir, a myristic acid derivative of insulin that binds to the fatty acid binding sites of circulating albumin, has been approved for the treatment of diabetes. Furthermore, Albuferon, a fusion protein of albumin and interferon, is currently being assessed in phase III clinical trials for the treatment of hepatitis C and could become an alternative to pegylated interferon. This review gives an account of the different drug delivery systems which make use of albumin as a drug carrier with a focus on those systems that have reached an advanced stage of preclinical evaluation or that have entered clinical trials.
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PMID:Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. 1858 81

The study included 20 patients with carcinoma of the pharynx and larynx. The incidence of metastases was compared between sentinel lymph nodes and the rest of lymph nodes in resected material. Patient inclusion criteria were primary tumor verified as squamous cell carcinoma by preoperative histopathology and negative clinical neck finding (cN0). Human serum albumin radiocolloid labeled with radioactive technetium-99m 0.5 mCi (18 MBq) was used. In two patients (with tumors of the hypopharynx and glottis), lymph nodes were not preoperatively visualized by scintigraphy. A total of 32 lymph nodes (range 0-4), were visualized. All nodes were found in regions II-IV, mostly in region II. In three patients, sentinel lymph nodes were detected bilaterally. Twenty six selective neck resections were performed (bilateral in six patients). A total of 319 (mean 12) lymph nodes were isolated in resected material, 7 of them were positive, all ipsilateral. A positive definitive histopathology finding was recorded in five patients. Three patients had one positive lymph node each (pN1), all sentinel lymph nodes. In one patient, positive sentinel lymph node histopathology was associated with tumor lesions detected in other lymph nodes (pN2b). One patient had false negative result. Study results confirmed the lymphatic drainage of the upper aerodigestive tract and metastasizing area from tumors of this localization are constant and predictable.
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PMID:[Sentinel lymphadenectomy in squamous cell carcinoma of the pharynx and larynx]. 1859 61

Diagnostic medicine has seen significant changes during the past decade. The emergence of proteomics and genomics has significantly increased our understanding of disease. These fields have also revealed the vast array of proteins that are expressed in various disease processes, such as cancer. Measurement of these unique proteins expressed in certain diseases may offer diagnostic clues or allow patient prognosis to be assessed. Another approach is to measure the effects that these ligands have on the structure and function of albumin. Albumin is known to play an important role in modulating the serum concentrations of various proteins produced by tumor cells. In this review, we introduce the reader to the technique of spin labeling followed by electron paramagnetic resonance spectroscopy. This method is a powerful tool for evaluating the structural and functional changes that can occur to albumin following the binding of various ligands. We describe the utility of this technique for the diagnosis of cancer and sepsis, as well as some other novel potential applications.
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PMID:Application of spin label electron paramagnetic resonance in the diagnosis and prognosis of cancer and sepsis. 1878 41

For future cell-based therapies for liver diseases, the shortage of cell sources must be resolved. Immortalized human hepatocytes are expected to be among the new sources. In addition to telomerase activation by the introduction of human telomerase reverse transcriptase (hTERT), inactivation of the p16/RB pathway and/ or p53 by E6/E7 of human papillomavirus type 16 (HPV16) has been shown to be useful for efficient immortalization of several human cell types. Here we report the immortalization of human hepatocytes by the introduction of HPV16 E6/E7 and hTERT. Human adult hepatocytes were lentivirally transduced with HPV16 E6/E7 and hTERT. Two human immortalized hepatocyte cell lines were established and were named HHE6E7T-1 and HHE6E7T-2. Those cells proliferated in culture beyond 200 population doublings (PDs). Albumin synthesis and expression of liver-enriched genes were confirmed, but gradually decreased as passages progressed. Karyotype analysis showed that HHE6E7T-1 cells remained near diploid but that HHE6E7T-2 cells showed severe aneuploidy at 150 PDs. Subcutaneous injection of these cells into severe combined immunodeficiency (SCID) mice did not induce tumor development. Intrasplenic transplantation of dedifferentiated HHE6E7T-1 cells over 200 PDs significantly improved the survival of acetaminophen-induced acute liver failure SCID mice. In conclusion, we successfully established immortalized human hepatocytes that retain the characteristics of differentiated hepatocytes. We also showed the reduction of hepatocyte-specific functions in long-term culture. However, the results of intrasplenic transplantation to SCID mice with acetaminophen-induced acute liver failure showed the possibility of HHE6E7T-1 serving as a cell source for hepatocyte transplantation.
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PMID:Establishment of immortalized human hepatocytes by introduction of HPV16 E6/E7 and hTERT as cell sources for liver cell-based therapy. 1917 44

Rat small hepatocytes (SHs) are committed progenitor cells that can differentiate into mature hepatocytes and can selectively proliferate in serum-free medium when they are cultured on hyaluronic acid (HA)-coated dishes. In this study we examined the separation of human SHs from adult human livers. We obtained liver tissues from the resected liver of 16 patients who underwent hepatic resections. Extracted liver specimens were clearly separate from the tumor regions with sufficient margins. Hepatic cells were isolated using the modified method of two-step collagenase perfusion. A low-speed centrifugation was performed and cells in the supernatant were finally cultured on HA-coated dishes in serum-free DMEM/F12 medium including nicotinamide, EGF, and HGF. Small-sized hepatocytes selectively proliferated to form colonies and many colonies continued growing for more than 3 weeks. The average number of cells in a colony was 38.6 +/- 18.0, 79.0 +/- 54.0, and 101.5 +/- 115.7 at day 7, 14, and 21, respectively. About 0.04% of plated cells could form an SH colony. Immunocytochemistry showed that the cells forming a colony were positive for albumin, transferrin, keratin 8, and CD44. The results of RT-PCR showed that colony-forming cells expressed albumin, transferrin, alpha1-antitrypsin, fibrinogen, glutamine synthetase, many cytochrome P450s, and liver-enriched transcription factors (HNF3alpha, HNF4alpha, C/EBPalpha, and C/EBPbeta). Furthermore, the cells expressed not only the genes of hepatic differentiated functions but also those of both hepatic stem cell marker (Thy1.1, EpCAM, AFP) and SH marker (CD44, D6.1A, BRI3). Albumin secretion into culture medium was also observed. Our results demonstrate the existence of hepatocyte progenitor cells in human adult livers, and the cells can grow in a serum-free medium on HA-coated dishes. Human SHs may be a useful source for cell transplantation as well as pharmaceutical and toxicological investigations.
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PMID:Proliferation of hepatocyte progenitor cells isolated from adult human livers in serum-free medium. 1918 Dec 16

Acute phase proteins (APPs) are proteins whose concentrations in serum change after any inflammatory stimulus or tissue damage. The aim of the current study was to evaluate 3 positive APPs (C-reactive protein, serum amyloid A, and haptoglobin) and 1 negative APP (albumin) in female dogs with mammary neoplasia. Acute phase proteins were studied in 70 female dogs aged 8-12 years in the following groups: healthy (n = 10); mammary tumors in stages I (n = 19), II (n = 5), III (n = 6), IV (n = 5), and V (n = 7); and with mammary neoplasia plus a concomitant disease (n = 18). In animals with mammary neoplasia, significant increases of positive APPs were only detected in those that had metastasis or a neoplasm with a diameter greater than 5 cm and ulceration. Dogs with mammary neoplasia and a concomitant disease also had high C-reactive protein concentrations. Albumin concentration was decreased in animals with metastasis and with a concomitant disease. The results of the present study indicate that the acute phase response could be stimulated in female dogs with mammary gland tumors because of different factors, such as metastasis, large size of the primary mass, and ulceration or secondary inflammation of the neoplasm.
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PMID:Serum acute phase protein concentrations in female dogs with mammary tumors. 1928

The high tumor uptake of ultrasmall near-infrared quantum dots (QDs) attributed to the enhanced permeability and retention effect is reported. InAs/InP/ZnSe QDs coated by mercaptopropionic acid (MPA) exhibit an emission wavelength of about 800 nm (QD800-MPA) with very small hydrodynamic diameter (<10 nm). Using 22B and LS174T tumor xenograft models, in vivo and ex vivo imaging studies show that QD800-MPA is highly accumulated in the tumor area, which is very promising for tumor detection in living mice. The ex vivo elemental analysis (Indium) using inductively coupled plasma (ICP) spectrometry confirm the tumor uptake of QDs. The ICP data are consistent with the in vivo and ex vivo fluorescence imaging. Human serum albumin (HSA)-coated QD800-MPA nanoparticles (QD800-MPA-HSA) show reduced localization in mononuclear phagocytic system-related organs over QD800-MPA plausibly due to the low uptake of QD800-MPA-HSA in macrophage cells. QD800-MPA-HSA may have great potential for in vivo fluorescence imaging.
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PMID:Ultrasmall near-infrared non-cadmium quantum dots for in vivo tumor imaging. 1991 92


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