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At least 541 records · Page 30Linked to original sources
PubMed2003

Volume-targeted therapy of increased intracranial pressure.

Fluid exchange across the intact blood-brain barrier (BBB) is counteracted by the low permeability to crystalloids (mainly Na+ and Cl-) combined with the high osmotic pressure (5,700 mm Hg) on both sides of the BBB. If the BBB is disrupted transcapillary water transport will be determined by the differences in hydrostatic and colloid osmotic pressure between the intra- and extracapillary compartments. Under these pathological conditions pressure autoregulation of cerebral blood flow is likely to be impaired and intracapillary hydrostatic pressure will depend on variations in systemic blood pressure. The volume targeted "Lund concept" can be summarized under four headings: A. Reduction of stress response and cerebral energy metabolism: B. Reduction of capillary hydrostatic pressure; C. Maintenance of colloid osmotic pressure and control of fluid balance: D. Reduction of cerebral blood volume. The efficacy of the protocol has been evaluated in experimental and clinical studies regarding the physiological and biochemical (utilizing intracerebral microdialysis) effects and the clinical experiences have been favourable.

Blood Pressure↗
PubMed2006

B cell targeted therapies in autoimmune diseases.

In addition to rheumatoid arthritis (RA), B cells are likely to play a significant role in the development of other autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE), myositis, and vasculitis. Small-vessel vasculitis subtypes may be immune complex-mediated (cryoglobulinemia) or antineutrophil cytoplasmic antibody (ANCA)-associated; ANCA may be involved in the pathogenesis of vasculitis. In SLE, both antibody-associated and antibody-independent processes are almost certainly involved. B cell activity and autoantibody production are increased, while patients often have reduced peripheral B cells and abnormal B cell profiles. B lymphocyte stimulator (BLyS) protein regulates B cell activation and differentiation. For these reasons, B cells and the molecules that activate them are potential therapeutic targets in these diseases. Recent clinical trial data from small studies of rituximab (RTX) in SLE suggest that treatment improved clinical variables and measures of disease activity in patients, including those with central nervous system SLE. With retreatment, patients whose B cells were successfully depleted continued to show improvement in clinical and laboratory variables. Preliminary data suggest that treatment with RTX may be effective in ANCA-associated vasculitis. In addition a recent study showed significant benefit with myositis. Although these studies contain small cohorts of patients, they demonstrate that B cell-modulating therapies show promise in treatment of a variety of autoimmune diseases.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2005

Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by genetic and acquired abnormalities that suppress apoptosis and enhance cell proliferation in the vascular wall, including downregulation of the bone morphogenetic protein axis and voltage-gated K+ (Kv) channels. Survivin is an "inhibitor of apoptosis" protein, previously thought to be expressed primarily in cancer cells. We found that survivin was expressed in the pulmonary arteries (PAs) of 6 patients with PAH and rats with monocrotaline-induced PAH, but not in the PAs of 3 patients and rats without PAH. Gene therapy with inhalation of an adenovirus carrying a phosphorylation-deficient survivin mutant with dominant-negative properties reversed established monocrotaline-induced PAH and prolonged survival by 25%. The survivin mutant lowered pulmonary vascular resistance, RV hypertrophy, and PA medial hypertrophy. Both in vitro and in vivo, inhibition of survivin induced PA smooth muscle cell apoptosis, decreased proliferation, depolarized mitochondria, caused efflux of cytochrome c in the cytoplasm and translocation of apoptosis-inducing factor into the nucleus, and increased Kv channel current; the opposite effects were observed with gene transfer of WT survivin, both in vivo and in vitro. Inhibition of the inappropriate expression of survivin that accompanies human and experimental PAH is a novel therapeutic strategy that acts by inducing vascular mitochondria-dependent apoptosis.

Adenoviridae↗
PubMed1995

Targeted therapy of carcinomas using BR96 sFv-PE40, a single-chain immunotoxin that binds to the Le(y) antigen.

Monoclonal antibody BR96 recognizes a Le(y)-related carbohydrate antigen expressed on a wide range of carcinomas. Immunotoxins composed of BR96 and a binding defective form of Pseudomonas exotoxin A were constructed both as chemical conjugates and as fusion proteins. While both forms of BR96 immunotoxin were equally cytotoxic to human carcinoma cell lines in vitro, the fusion protein form, BR96 sFv-PE40, was > 10-fold more active in vivo as an antitumor agent. BR96 sFv-PE40 was used to target established human tumor xenografts in both mice and in rats. The rat which displays the Le(y) antigen on the same normal tissues as humans appears to be an appropriate model for the preclinical evaluation of this immunotoxin. Complete regressions of lung, breast and bladder carcinomas were obtained in these models upon administration of well-tolerated doses of BR96 sFv-PE40. The clinical limitations of BR96 sFv-PE40, as well as other immunotoxins, depend on the management and/or prevention of neutralizing anti-immunotoxin antibodies and the onset of toxicities, specifically vascular leak syndrome.

ADP Ribose Transferases↗
PubMed1999

Immunopharmacology: anti-inflammatory therapy targeting transcription factors.

Immunopharmacology is one of the most dynamic areas in pharmacology encompassing classical immunosuppressive drugs which reveal completely new clues concerning their mode of action as well as novel molecular biology approaches for treating inflammatory and autoimmune diseases, infections and cancer. This article focuses on transcription factors that regulate cell activities involved in immune and inflammatory cell responses and how traditional anti-inflammatory compounds such as glucocorticoids, cyclosporins, tacrolismus and salicylates interfere with the activation cascades triggering the transcription factors. Moreover, promising new initiatives for selective therapeutics including recombinant anti-inflammatory cytokines and proinflammatory cytokine antagonists, and gene therapy will be presented.

Anti-Inflammatory Agents↗
PubMed2003

Radiation sensitizers and targeted therapies.

Chemotherapeutic agents that are highly responsive to ionizing radiation and enhance the effectiveness of radiation treatment are termed radiation sensitizers. Radiation sensitizers act in a number of ways to make cancer cells more susceptible to death by radiation than surrounding normal cells, and several such compounds are now available for the treatment of solid tumors. This review discusses the biology that underlies chemotherapy and radiation interactions for one radiosensitizer--gemcitabine (Gemzar). It also provides a brief assessment of how to modify treatment regimens for various cancers to maximize the radiosensitization potential of gemcitabine in order to further increase efficacy. Newer molecularly targeted agents and their antitumor potential as monotherapy or in combination with radiation are also reviewed.

Deoxycytidine↗
PubMed2004

[Cell cycle-targeted therapy].

BACKGROUND: The cell cycle defines sequential molecular processes that ensure orderly cell division. The progression throughout the cell cycle is governed by cyclin-dependent kinases, each of which is enzymatically active solely upon binding to its specific cyclin. The cell cycle harbours two checkpoints, or surveillance posts, which are activated when DNA is damaged. The response to the DNA damage involves a temporary cell cycle arrest, mediated by cell cycle inhibitors or other enzyme proteins, ultimately leading to the outcome of cell survival if the DNA is properly repaired, or cell death. The cell cycle checkpoints may also be biological targets for new therapeutic strategies in cancer intervention. MATERIAL AND METHODS: We compared the effect of ionising radiation on tumour cells with intact or defective functions of the cell cycle checkpoint that governs cell division. RESULTS: The tumour cells responded to radiation-induced DNA damage by cell cycle arrest that required intact checkpoint function. This defence response was overridden upon treatment of the tumour cells with a checkpoint signalling inhibitor. INTERPRETATION: Several pharmacological compounds designed to experimentally target the cell cycle are currently in the pipeline for testing in early-phase clinical trials and may have therapeutic potential as radiosensitizers.

Cell Cycle↗
PubMed2006

Targeted therapy in advanced non-small cell lung cancer (NSCLC): where do we stand?

Cytotoxic chemotherapy has helped improve the outcomes in patients with advanced non-small cell lung cancer (NSCLC), but we seem to have reached a plateau with respect to the benefit obtained. Also, a large subset of elderly patients and those with a poor performance status cannot tolerate these drugs at recommended doses. There is a growing need to incorporate newer drugs with different mechanisms of action and better safety profile. The epidermal growth factor receptor family (EGFR) and vascular endothelial growth factor (VEGF) have been identified as potential targets and agents acting specifically against these targets have been developed with the hope of improving outcomes. Although recent data with the small molecule EGFR tyrosine kinase inhibitors have been disappointing, there have been instances of dramatic responses thereby raising questions about the ideal patient to whom these drugs should be administered. Cetuximab, the anti-EGFR antibody has shown promising results. Bevacizumab, the anti-VEGF antibody was the first drug to demonstrate a survival benefit in first line treatment when added to chemotherapy. This review will briefly discuss the important trials using these targeted agents in advanced NSCLC.

Angiogenesis Inhibitors↗
PubMed1999

Tetracycline therapy targets intracellular bacteria in the filarial nematode Litomosoides sigmodontis and results in filarial infertility.

Intracellular bacteria have been described in several species of filarial nematodes, but their relationships with, and effects on, their nematode hosts have not previously been elucidated. In this study, intracellular bacteria were observed in tissues of the rodent parasite Litomosoides sigmodontis by transmission electron microscopy and by immunohistochemistry using antiendobacterial heat shock protein-60 antisera. Molecular phylogenetic analysis of the bacterial 16S ribosomal RNA gene, isolated by PCR, showed a close relationship to the rickettsial Wolbachia endobacteria of arthropods and to other filarial intracellular bacteria. The impact of tetracycline therapy of infected rodents on L. sigmodontis development was analyzed in order to understand the role(s) these bacteria might play in filarial biology. Tetracycline therapy, when initiated with L. sigmodontis infection, eliminated the bacteria and resulted in filarial growth retardation and infertility. If initiated after microfilarial development, treatment reduced filarial fertility. Treatment with antibiotics not affecting rickettsial bacteria did not inhibit filarial development. Acanthocheilonema viteae filariae were shown to lack intracellular bacteria and to be insensitive to tetracycline. These results suggest a mutualistic interaction between the intracellular bacteria and the filarial nematode. Investigation of such a mutualism in endobacteria-containing human filariae is warranted for a potential chemotherapeutic exploitation.

Animals↗
PubMedDate not supplied

Cancer genetics of sporadic colorectal cancer: BRAF and PI3KCA mutations, their impact on signaling and novel targeted therapies.

Novel activating mutations in sporadic colorectal cancer (CRC) have recently been identified on major kinase encoding genes such as BRAF and PI3KCA. The presence of these activating point mutations, including the well characterized KRAS oncogene mutations, represent up to 75% of cases in CRC. These genes, that have been implicated in the adenoma-carcinoma transition, cause deregulation and constitutive activation of the MAP AKT/kinase pathways, rendering growth advantages to colon tumor cells. This review focuses on the key genetic alterations underlying the cumulative effect of multiple mutations within the colon cancer cell. Moreover, the currently available and alternative treatment approaches that may target these different genetic alterations are discussed, such as the novel BRAF inhibitor. Identification of novel mutations as well as differential gene expression analyzed by microarray reveal potential targets for combined therapeutic protocols which will result in personalized treatments in the near future.

Animals↗
PubMed2006

Developing target therapy against oncogenic tyrosine kinase in myeloid maliganacies.

Myeloid malignancies are frequently associated with translocations and mutations of tyrosine kinase genes. Fusion genes involving ABL, ARG, PDGFRs, JAK2, SYK, TRKC, and FGFRs, and gain-of-function mutations of FLT3, KIT and JAK2 have been detected at various rates in myeloproliferative disease and acute myeloid leukemia. Furthermore, abnormal overexpression of tyrosine kinases such as FLT3 has also been reported. These gene products are constitutively activated and potentially transform hematopoietic cells by augmentation of proliferation and enhanced viability. Since the fusion or mutation of tyrosine kinase is a primary and central event in chronic myeloproliferative diseases, targeting the kinase activity has been thought to be an ideal intervention to treat these diseases. The clinical success of imatinib for chronic myeloid leukemia has made this idea a reality, and has accelerated the development of new tyrosine kinase inhibitors (TKIs). Challenging studies with TKIs have also been reported for acute myeloid leukemia. This review will focus on recent trials of TKIs against oncogenic tyrosine kinases (ABL, PDGFRs, FLT3 and KIT) in myeloid malignancies.

Antineoplastic Agents↗
PubMedDate not supplied

VEGF-targeted therapy: therapeutic potential and recent advances.

After over 30 years of theorizing, the use of angiogenesis inhibitors as anticancer therapy has finally moved from the realm of research to reality. Normal adult vasculature is generally quiescent in nature, with endothelial cells dividing approximately every 10 years. In contrast, the growth of tumors requires constant vascular growth and remodeling in order for solid tumors to grow beyond 1-2 mm(3) in size. Vascular endothelial growth factor (VEGF) and its receptors are key regulators of the process of angiogenesis, which makes them attractive therapeutic targets. A multitude of VEGF-targeted inhibitory agents are currently being investigated for the treatment of cancer. This review article focuses on recent developments in the use of angiogenesis inhibitors for the treatment of breast, lung, and colorectal cancers.

Angiogenesis Inhibitors↗
PubMed2004

Targeted therapies in the treatment of colorectal cancer: what managed care needs to know.

OBJECTIVE: This review is designed to explore the disease, its current treatment, the expanding field of antiangiogenic treatments, and the implications of these advances for the managed care patient. DATA SOURCES: This article is based, in part, on presentations given by the authors in a continuing education symposium presented during the Academy of Managed Care Pharmacy.s 16th Annual Meeting and Showcase, April 1, 2004, in San Francisco. CONCLUSIONS: Colorectal cancer (CRC) is the third most common cancer in the United States, and the second-leading non.gender-specific cause of cancer deaths. If the cancer is caught soon enough (before node involvement and metastasis occur), there is a strong chance of survival; however, only slightly more than one third of cases are detected that soon. Emerging treatments that target only the cancer cells are increasing the length of survival for those who are diagnosed at later stages of the disease.

Antibodies, Monoclonal↗
PubMed2002

Gemcitabine and targeted therapy in metastatic breast cancer.

Gemcitabine, a new cytotoxic nucleoside analog, has demonstrable single-agent antitumor activity in metastatic breast cancer. Recently, nearly 20 phase II clinical trials of gemcitabine alone or as part of combination therapy have confirmed its role in this disease. As a single agent, gemcitabine leads to response rates ranging from 16% to 37% in either first-line and/or refractory settings. Combined with platinum, taxanes, vinorelbine, and anthracyclines as doublets or triplets, response rates in the range of 50% to 80% have been reported in small phase II clinical trials. The relatively mild toxicity profile of gemcitabine makes it an attractive agent to evaluate in combination with targeted drugs such as trastuzumab, tyrosine kinase inhibitors, and angiogenesis inhibitors, among others. In this review we summarize current available data of gemcitabine in the management of metastatic breast cancer, and provide a perspective of gemcitabine in future clinical research for management of this disease.

Antimetabolites, Antineoplastic↗
PubMed2006

[The plasma cell myeloma--molecular pathogenesis and target therapies].

The cells of the malignant clone of plasmacell myeloma have cytogenetic aberrations in a substantial number of cases. Many of these abnormal karyotypes are predictive for an unfavorable outcome. Gene mutations and abnormal gene expression, particularly of oncogenes and tumor suppressor genes, are often observed in myeloma cells. The cross talk between the myeloma cells and the bone marrow microenvironment plays an important role for growth and survival of the tumor cells. As a consequence of this cell-to-cell-interaction, several cytokines are secreted. The intracellular signaling, evoked by these cytokines, leads to continuous growth and proliferation and inhibition of apoptosis. Since these molecular pathways have been defined, many new targets for therapeutical interventions become obvious. Some molecules, directed against cytokines, are under early clinical investigation. Medicaments intervening in the cross talk between the myeloma cell and the bone marrow stroma as Thalidomide, Lenalidomide or Bortezomib are already available. Many of the myeloma patients suffer from bone disease. Some new drugs inhibiting the differentiation and activation of osteoclasts are evaluated in clinical trials. These molecules will be an important contribution against the painful bone disease of plasmacell myeloma.

Aged↗
PubMed2003

Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal.

Recent progress in the development of molecular cancer therapeutics has revealed new types of antitumor drugs, such as Herceptin, Gleevec, and Iressa, as potent therapeutics for specific tumors. Our work has focused on molecular cancer therapeutics, mainly in the areas of drug resistance, apoptosis and apoptosis resistance, and survival-signaling, which is related to drug resistance. In this review, we describe our research on molecular cancer therapeutics, including molecular mechanisms and therapeutic approaches. Resistance to chemotherapeutic drugs is a principal problem in the treatment of cancer. P-Glycoprotein (P-gp), encoded by the MDR1 gene, is a multidrug transporter and has a major role in multidrug resistance (MDR). Targeting of P-gp by small-molecular compounds and/or antibodies is an effective strategy to overcome MDR in cancer, especially hematologic malignancies. Several P-gp inhibitors have been developed and are currently under clinical phased studies. In addition to the multidrug transporter proteins, cancer cells have several drug resistance mechanisms. Solid tumors are often placed under stress conditions, such as glucose starvation and hypoxia. These conditions result in topo II poison resistance that is due to proteasome-mediated degradation of DNA topoisomerases. Proteasome inhibitors effectively prevent this stress-induced drug resistance. Glyoxalase I, which is often elevated in drug- and apoptosis-resistant cancers, offers another possibility for overcoming drug resistance. It plays a role in detoxification of methylglioxal, a side product of glycolysis, which is highly reactive with DNA and proteins. Inhibitors of glyoxalase I selectively kill drug-resistant tumors that express glyoxalase I. Finally, the susceptibility of tumor cells to apoptosis induced by antitumor drugs appears to depend on the balance between pro-apoptotic and survival (anti-apoptotic) signals. PI3K-Akt is an important survival signal pathway, that has been shown to be the target of various antitumor drugs, including UCN-01 and geldanamycin, new anticancer drugs under clinical evaluation. Our present studies provide novel targets for future effective molecular cancer therapeutics.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2026

RHAMM drives formation of polyploid cancer cells and confers resistance to ER-targeted therapy in breast cancer.

Endocrine resistance in ER+ breast cancer remains a major clinical challenge. Here, we identify RHAMM as a key driver of resistance by orchestrating polyploid cancer cell (PCC) formation. Single-cell transcriptomics uncovered a G2/M-enriched, RHAMM+ subpopulation in endocrine-resistant tumors. Mechanistically, RHAMM binds Septin9/10 to promote aberrant cytoskeleton polymerization, activating YAP independent of Hippo signaling, which induces cytokinesis failure and facilitates PCC generation. Concurrently, RHAMM destabilizes p21 mRNA, enabling cell cycle progression despite genomic instability. The RHAMM-p21 axis serves as a bypass mechanism supporting polyploidization. Upon endocrine treatment, RHAMM is transcriptionally up-regulated by Slug. Clinically, RHAMMhigh signatures are enriched in metastatic and recurrent ER+ tumors and correlate with poor prognosis, highlighting its therapeutic relevance. Importantly, targeting RHAMM or YAP abrogates PCC formation and restores fulvestrant sensitivity. These findings reveal RHAMM-mediated polyploidization as an adaptive mechanism underlying endocrine resistance, suggesting the therapeutic potential of targeting the RHAMM-YAP axis.

Humans↗
PubMed2003

Advances in targeted therapy for chronic myeloid leukemia.

Despite the lack of long-term survival data, the impressive results obtained with imatinib mesylate (Gleevec) therapy and the lack of serious adverse events have significantly altered the management of patients with chronic myeloid leukemia. Nevertheless, a large proportion of patients with more advanced disease will develop resistance to imatinib mesylate monotherapy. To prevent the development of resistance, an understanding of the pathophysiology of chronic myeloid leukemia, including the signaling pathways that are activated by the BCR-ABL fusion protein, and the mechanisms of resistance to imatinib are required. This review summarizes the pathogenesis of chronic myeloid leukemia and the potential therapeutic impact of small molecule inhibitors that target pathways critical to the growth or survival of the leukemic cells in patients with chronic myeloid leukemia.

Animals↗