Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Targeted Therapy”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 505 records · Page 28Linked to original sources
PubMed2002

Volume-targeted therapy of increased intracranial pressure: the Lund concept unifies surgical and non-surgical treatments.

Opinions differ widely on the various treatment protocols for sustained increase in intracranial pressure (ICP). This review focuses on the physiological volume regulation of the intracranial compartments. Based on these mechanisms we describe a protocol called 'volume-targeted' ('Lund concept') for treatment of increased ICP. The driving force for transcapillary fluid exchange is determined by the balance between effective transcapillary hydrostatic and osmotic pressures. 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 (5500 mmHg) on both sides of the BBB. This contrasts to most other capillary regions where the osmotic pressure is mainly derived from the plasma proteins (approximately 25 mmHg). Accordingly, the level of the cerebral perfusion pressure (CPP) is of less importance under physiological conditions. In addition cerebral intracapillary hydrostatic pressure (and cerebral blood flow) is physiologically tightly autoregulated, and variations in systemic blood pressure are generally not transmitted to these capillaries. 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: (1) Reduction of stress response and cerebral energy metabolism; (2) reduction of capillary hydrostatic pressure; (3) maintenance of colloid osmotic pressure and control of fluid balance; and (4) 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 favorable.

Animals↗
PubMed2005

Targeted therapy for haematological malignancies: clinical update from the American Society of Hematology, 2004.

Recent advances in the treatment and management of haematological malignancies are due in large part to an improved understanding of the basic biology that drives tumour cell growth and survival. This improved understanding has led to the clinical study and approval of a number of different targeted agents across a number of different haematological tumours. This review of clinical data covers some of the exciting clinical advances that were reported at the recent American Society of Hematology meeting in San Diego, USA. This paper focuses on three important areas of biological research that has yielded clinical trials that have affected clinical outcomes. The areas covered include proteasome inhibition and myeloma, tyrosine kinase inhibitors that are directed at the BCR-ABL fusion protein and chronic myeloid leukaemia/acute lymphoblastic leukaemia, and FLT3 inhibitors and acute myeloid leukaemia acute lymphoblastic leukaemia therapy.

Animals↗
PubMed2001

Targeted therapies for high-risk acute myeloid leukemia.

Approximately half of children with acute myeloid leukemia (AML) can be cured with contemporary chemotherapy regimens; however, various forms of drug resistance pose considerable obstacles for curing the remaining patients. Recent advances in immunology, cytogenetics, and cellular and molecular biology have provided new insights into fundamental biological differences between leukemic myeloid blasts and their normal counterparts. This article focuses on new technologies involving: (1) antibody- or growth factor-mediated targeting of antigens or growth factor receptors found on AML blasts and restricted sub-groups of normal cells, (2) pharmacologic targeting of the pathologic t(15;17) translocation of acute promyelocytic leukemia with all-trans retinoic acid, (3) pharmacologic and immunologic targeting of mutant RAS oncogenes and related aberrant signaling in AML blasts, and (4) targeting of pathological signaling of the Bcr-Abl oncoprotein and c-kit tyrosine kinase in myeloid leukemias. These advances herald an exciting new era of AML-specific therapies.

ATP-Binding Cassette Transporters↗
PubMed2006

Targeted therapy in colorectal cancer.

Advances in chemotherapeutic agents have led to improved outcomes for patients with metastatic colorectal cancer (CRC). Chemotherapies, however, are limited by their toxicities and lack of specificity. Aberrations in the regulation and expression of growth factors have been implicated in the development of CRC, and this understanding has led to the development of targeted agents. In 2004, two novel agents, bevacizumab and cetuximab, were approved by the US Food and Drug Administration for the treatment of metastatic CRC. Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor, and cetuximab, a human-mouse chimeric monoclonal antibody to the epidermal growth factor receptor, have changed the field dramatically. Bevacizumab appears to augment the efficacy of combination chemotherapy regimens for the treatment of metastatic CRC in both the first- and second-line settings, and the role of bevacizumab as part of adjuvant treatment is the subject of ongoing trials. However, because of the increased incidence of serious arterial thromboembolic events, gastrointestinal perforations, bleeding complications, and hypertension associated with bevacizumab, this agent is probably not indicated in all circumstances. Combination treatment with cetuximab and irinotecan appears appropriate in patients with advanced CRC who have failed irinotecan. Patients who are unable to receive additional irinotecan may be treated with cetuximab monotherapy. Positive epidermal growth factor receptor status by immunohistochemistry of a tumor specimen is presently mandated to determine candidacy for this therapy, although this assay appears to be suboptimal and newer assessment techniques to determine suitability for therapy must be developed. Phase III trials should shed light on the role of cetuximab in the first-line metastatic and adjuvant settings. Multitargeted strategies in CRC combining chemotherapy with bevacizumab and cetuximab are currently being explored. Further advances in the treatment of CRC are expected through continued scientific investigation and well-designed clinical trials.

Antibodies, Monoclonal↗
PubMed1994

Preclinical models for the evaluation of targeted therapies of metastatic disease.

It has been estimated that approx 60-70% of cancer patients harbor overt or subclinical metastases at diagnosis, and it is the eradication of such systemic disease that largely determines survival. Preclinical tumor model systems employed to evaluate potential new treatment strategies should aim to represent the process and patterns of metastasis of their clinical counterparts as closely as possible. Severe combined immune-deficient (SCID) and nu/nu mice have been extensively used as hosts for the growth of human tumor cell lines and in some cases fresh tumor material. However, in most instances the resulting neoplasms fail to metastasize, and the aberrant immune systems of such animals has limited their use mainly to passive therapies of localized disease. Recently, the development of specially selected tumor variants and the use of appropriate orthotopic sites for implantation has provided several models in which dissemination can be demonstrated. Where the gene coding for a potential target antigen has been cloned, and where its overexpression or mutation is associated with malignancy (e.g., c-erbB-2, H-ras), transgenic mice may yield tumors that will develop in these immunocompetent hosts. In some cases such tumors exhibit metastasis. A third approach is to transfect human genes of interest into appropriate rodent tumors expressing the desired metastatic phenotype. These various approaches are compared with particular reference to mammary carcinoma biology.

Animals↗
PubMed2006

The urokinase plasminogen activator receptor as a gene therapy target for cancer.

Urokinase plasminogen activator (uPA) and/or its receptor (uPAR) are essential for metastasis, and overexpression of these molecules is strongly correlated with poor prognosis in a variety of malignant tumours. Impairment of uPA and/or uPAR function, or inhibition of the expression of these components, impedes the metastatic potential of many tumours. Several approaches have been employed to target uPAR with the aim of disrupting its ligand-independent action or interaction with uPA, including the more recent antigene technology. This review discusses the in vivo use of antigene approaches for downregulating uPAR as a potential therapy for cancer. Preclinical studies are advancing towards the translational phase, provided that established orthotopic tumours, which mimic clinical progression and presentation, are treated using clinically acceptable modes of nucleic acid delivery.

Animals↗
PubMed2002

Gene therapy targeting monocyte chemoattractant protein-1 for vascular disease.

Monocyte chemoattractant protein-1 (MCP-1) has been shown to play an essential role in the pathogenesis of arteriosclerosis and other vascular diseases, such as restenosis after arterial injury, by recruiting monocytes into the arterial wall. We devised a new strategy for anti-MCP-1 gene therapy against arteriosclerosis by transfecting an amino-terminal deletion mutant (7ND), which lacks the amino-terminal amino acids 2 to 8 of the human MCP-1 gene, into a remote organ (skeletal muscles). Intramuscular transduction with the mutant MCP-1 gene suppressed inflammatory and proliferative changes and arteriosclerosis formation induced by the chronic inhibition of nitric oxide synthesis in rats. 7ND gene transfection also inhibited the initiation, progression, and destabilization of atherosclerosis in Apolipoprotein E-knockout mice. Moreover, the strategy reduced restenosis after balloon injury in rabbits, rats, and monkeys, or neointimal formation after stent implantation in monkeys. This new strategy may be a useful and feasible gene therapy against atherosclerosis and restenosis after angioplasty.

Animals↗
PubMed2006

Regulation of apoptosis and proliferation in Ewing's sarcoma--opportunities for targeted therapy.

The Ewing's sarcoma family of tumors are malignant tumors of bone and soft tissue which occur predominantely in children and adolescents. Whereas cure rates for patients with localized tumors are around 70%, survival rates for patients with metastases or relapse are poor in spite of intensive chemo- and radiation therapy, demonstrating a clear need for new, more effective therapies. Insights into the biology of the tumors of the Ewing's sarcoma family with identification of the EWS/ETS gene rearrangement as the key event in malignant transformation and its influence on the regulation of various pathways involved in proliferation, differentiation and apoptosis has led to the identification of potential targets for the development of new molecular therapeutics. This review will focus on the regulation of major pathways of proliferation and apoptosis in tumors of the Ewing's sarcoma family and point out how modulation of these pathways might be of potential use for future therapy.

Apoptosis↗
PubMed2005

Zidovudine: a targeted therapy for endemic Burkitt's lymphoma.

BACKGROUND: Although cyclophosphamide based regimens can produce remission rates approaching 60 to 80% in endemic Burkitts lymphoma, relapses and refractory disease are fairly common in developing countries, due to advanced stage disease and cost-constraints in the implementation of optimal chemotherapeutic protocols. OBJECTIVE: To evaluate an affordable, tolerable and targeted approach to chemotherapy for endemic Burkitt's lymphoma as would be desirable in resource poor settings such as Africa. METHOD: We present data and review pertinent literature that indicates that the antiviral agent Zidovudine specifically targets this tumour through a unique and novel mechanism. DATA SOURCE: Our original studies, publications original and review articles searched in Pubmed indexed for Medline. DATA EXTRACTION: A systematic review to identify studies relating to Zidovudine, EBV+ and Burkitt's lymphoma, indicating antiviral agents zidovudine targeting BL in a unique and novel mechanisms. DATA SYNTHESIS: Our data and a qualitative assessment of the relevant literature was undertaken, given the heterogenicity of the study types making it inappropriate to pool results across studies. CONCLUSION: Our data suggests that the incorporation of Zidovudine into Burkitt's regimens may enhance tumour kill and abbreviate the duration of treatment necessary for this disease. Furthermore, the addition of the widely available and inexpensive agent hydroxyurea, markedly potentiates the tumorcidal activity of Zidovudine in Epstein Barr virus positive Burkitt's lymphomas. We recommend that further clinical studies in patients afflicted with this disease are needed to clearly define this potential use of Zidovudine.

Africa↗
PubMed2003

Combination of epidermal growth factor receptor targeted therapy with radiation therapy for malignant gliomas.

Glioblastoma multiforme (GBM) are extremely aggressive brain tumors characterized by resistance to standard treatment modalities including surgery, radiation therapy and chemotherapy. While radiation therapy is the standard treatment after surgical resection, these tumors invariably recur and are associated with a uniformly dismal prognosis. Cytotoxic chemotherapy has failed to improve on the modest gains conferred by radiation therapy. Our understanding of the molecular events driving gliomagenesis has led to the recognition of frequent alterations in the epidermal growth factor receptor (EGFR) pathway, leading to increased aggressiveness and a poorer prognosis. Based on the importance of EGFR in the development of malignancy in multiple tumor types, several classes of novel therapeutic agents have been developed that specifically target EGFR. This review outlines the relevance of normal and aberrant EGFR signaling in the biology of gliomas, the strategies for inhibiting EGFR activity and the rationale for combining EGFR inhibitors with radiation therapy in the treatment of GBM.

Animals↗
PubMed1997

Allergic contact dermatitis: understanding the immune response and potential for targeted therapy using cytokines.

Allergic contact dermatitis is the most common job-related disease of the western world. The only available treatments are avoidance of contact with the allergen and the use of potent corticosteroids. Recently, the role of cytokines in the pathogenesis of this disease has been studied and, besides defining the key molecules and basic cellular immune responses responsible for disease development, these studies might help to develop new therapeutic strategies to target cytokines and thereby try to alter or abrogate ongoing immune reactions.

Animals↗
PubMed2005

Gene therapy targeting the Tie2 function ameliorates collagen-induced arthritis and protects against bone destruction.

OBJECTIVE: In a previous study, we demonstrated that Tie2 regulates angiogenesis in arthritis. The current study was performed to determine whether systemic delivery of a soluble Tie2 receptor (ExTek) using an adenoviral vector (AdExTek) as a Tie2 inhibitor affects arthritis development and progression in an animal model. METHODS: We used a collagen-induced arthritis (CIA) mouse model to study the outcome of treatment with either AdExTek or a control vector. The onset, incidence, and severity of arthritis were quantified. Immunohistologic analysis of endothelium obtained from the paws was performed. Bone destruction in paws was analyzed using phase-contrast radiography. RESULTS: The data showed that systemic delivery of ExTek before disease development significantly inhibited the onset, incidence, and severity of arthritis. When AdExTek was given after disease onset, the severity of disease in mice treated with AdExTek was significantly lower than that in the control group at 35 days postimmunization, which correlated with significantly diminished angiogenesis in mouse paws. Strikingly, AdExTek treatment protected bone from erosion in the CIA model and reduced levels of RANKL. No differences in collagen-specific antibodies were detected between these 2 groups. CONCLUSION: We demonstrated that blocking Tie2 receptor activation inhibits angiogenesis and arthritis development and protects against bone destruction in a CIA mouse model. These findings identify Tie2 as a therapeutic target for arthritis treatment and imply that interventions designed to target the Tie2 pathway could be clinically beneficial.

Adenoviridae↗
PubMed2005

[EGFR/HER1 inhibition: an example of new targeted therapies in non-small cell lung cancer].

BACKGROUND: Lung cancer is one of the most common forms of cancer in western industrialized countries. Patients with advanced non-small cell lung cancer (NSCLC) have a poor prognosis and suffer many tumor-associated symptoms. Unfortunately, approximately 70% of patients with NSCLC present themselves with advanced poor-prognosis stage III and IV disease. In advanced disease, treatment is palliative and symptom-oriented. New less Adenotoxic drugs are urgently needed. One of the targets of new agents is the human epidermal growth factor receptor (EGFR/HER1), and agents targeting this receptor include erlotinib, gefitinib and cetuximab. CLINICAL STUDIES: Erlotinib, gefitinib and cetuximab have been investigated in different clinical studies and provided objective responses and symptom relief. A benefit in survival could only be observed in second- and third-line therapy with erlotinib. All new agents have been generally well tolerated. Erlotinib was recently approved in the USA and Europe for second- and third-line treatment of patients with locally advanced or metastatic NSCLC. CONCLUSION: Anti-EGFR has shown promising antitumor activity in NSCLC with a mild toxicity profile. However, some clinical issues such as screening for potentially responsive patients and optimal combination with other drugs should be the aim of future studies.

Antibodies, Monoclonal↗
PubMed2006

B-cell targeted therapies in rheumatoid arthritis and systemic lupus erythematosus.

B cells appear to have a central role in the immunopathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE); both autoantibody production and B-cell anomalies are characteristic of these diseases. With the recent availability of biologic agents that can deplete B cells or block their function in vivo, it has become possible to target B cells therapeutically. Evidence strongly suggests that novel B-cell targeting agents are effective. In addition, the mechanistic specificity of B-cell targeted approaches, combined with the ability to test them in large randomized controlled trials, will provide an unprecedented opportunity to study the precise roles of B cells in the immunopathogenesis of RA and SLE. The largest volume of information is available for rituximab, a chimeric monoclonal antibody that depletes B cells by binding to the CD20 cell-surface antigen. Information from multiple investigator-sponsored trials and from off-label use suggests efficacy of this antibody in RA, SLE, and other autoimmune syndromes. Randomized controlled trials have also provided solid evidence for the efficacy of rituximab in RA and are ongoing in SLE. Other therapeutic agents supported by controlled data include cytotoxic T-lymphocyte-associated protein 4 immunoglobulin and antibodies against the interleukin-6 receptor and the B-cell survival molecule BLyS. Additional agents and targets are in earlier stages of development. The concerns about infectious complications have so far not proven to be justified. We can reasonably expect important advances in the understanding and treatment of RA and SLE in the next 5-10 years, as B-cell targeting methods become more widespread and sophisticated.

Animals↗
PubMed2001

Epidermal growth factor receptor as a genetic therapy target for carcinoma cell radiosensitization.

BACKGROUND: Exposure of human cancer cells to ionizing radiation activates the epidermal growth factor receptor (EGFR), which, in turn, mediates a cytoprotective response that reduces the cells' sensitivity to ionizing radiation. Overexpression of a dominant-negative EGFR mutant, EGFR-CD533, disrupts the cytoprotective response by preventing radiation-induced activation of the receptor and its downstream effectors. To investigate whether gene therapy with EGFR-CD533 has the potential to increase tumor cell radiosensitivity, we introduced an adenoviral vector containing EGFR-CD533 into xenograft tumors in nude mice and evaluated the tumor response to ionizing radiation. METHODS: Xenograft tumors established from the human mammary carcinoma cell line MDA-MB-231 were transduced via infusion with the adenoviral vector Ad-EGFR-CD533 or a control vector containing the beta-galactosidase gene, Ad-LacZ. The transduced tumors were then exposed to radiation in the therapeutic dose range, and radiation-induced EGFR activation was assessed by examining the tyrosine phosphorylation of immunoprecipitated EGFR. Radiosensitization was determined in vitro by colony-formation assays. All statistical tests were two-sided. RESULTS: The transduction efficiency of MDA-MB-231 tumors by Ad-LacZ was 44%. Expression of EGFR-CD533 in tumors reduced radiation-induced EGFR activation by 2.94-fold (95% confidence interval [CI] = 2.23 to 4.14). The radiosensitivity of Ad-EGFR-CD533-transduced tumors was statistically significantly higher (46%; P<.001) than that of Ad-LacZ-transduced tumors, yielding a dose-enhancement ratio of 1.85 (95% CI = 1.54 to 2.51). CONCLUSIONS: Transduction of MDA-MB-231 xenograft tumors with Ad-EGFR-CD533 conferred a dominant-negative EGFR phenotype and induced tumor radiosensitization. Therefore, disruption of EGFR function through overexpression of EGFR-CD533 may hold promise as a gene therapeutic approach to enhance the sensitivity of tumor cells to ionizing radiation.

Animals↗
PubMed2002

Advanced NSCLC: from cytotoxic systemic chemotherapy to molecularly targeted therapy.

Approximately a third of non-small cell lung cancer patients present with disseminated disease at the time of diagnosis. For these patients, as well as those with recurrent disease, chemotherapy remains the mainstay of treatment. For several decades, researchers have attempted different combinations of drugs in search for the 'best' chemotherapy regimen. Despite the emergence of newer, 'third-generation' cytotoxic agents, success is still modest at best. Fortunately, new insights in tumor biology, leading to the design of molecularly targeted drugs, are opening a new era in cancer treatment. These novel agents target molecular pathways specifically found in cancer cells, thus maximizing the antitumor effect while minimizing toxicities on normal cells.

Alkyl and Aryl Transferases↗