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 937 records · Page 52Linked to original sources
PubMedDate not supplied

Synthesis and in vitro testing of J591 antibody-dendrimer conjugates for targeted prostate cancer therapy.

Targeted therapeutics using antibodies are an attractive option over conventional cancer chemotherapeutics due to their potential to deliver a therapeutic specifically to cancer tissue without damaging normal tissue. However, there are known problems with immunoconjugates such as decreased immunoreactivity and poor solubility. Using dendrimers as carriers for these agents has the potential to resolve these issues. We synthesized J591 anti-PSMA (prostate specific membrane antigen) antibody dendrimer conjugates containing fluorophores on the dendrimer. The in vitro studies of these conjugates show that they specifically bind to cells expressing PSMA. Confocal microscopy experiments document the binding and internalization of these conjugates. This research encourages the further study of antibody-dendrimer-drug conjugates for use in targeted therapeutics.

Antibodies, Monoclonal↗
PubMed2002

Clinical developments for treating ARDS.

Acute respiratory distress syndrome (ARDS), is characterised by capillary permeability and pulmonary oedema formation and may complicate a variety of medical and surgical illnesses. As a self-perpetuating state of inflammatory derangement, acute lung injury (ALI)/ARDS is manifest clinically as rapid development of radiographic infiltrates, severe hypoxaemia and reduced lung compliance. Over the years, researchers have made significant progress in elucidating the pathophysiology of this complex syndrome. Therapies targeting specific pathophysiologic steps in the development or persistence of this syndrome are in various stages of laboratory and clinical testing. Results to date have shown nitric oxide (NO) to improve oxygenation in the majority of patients but fail to improve mortality. Surfactant replacement has had limited success in adults, but new formulations and delivery methods may prove beneficial. Several inflammatory mediator-targeted therapies have progressed successfully through early clinical evaluation. Among these, neutrophil elastase inhibitors have shown the most promise and are currently undergoing Phase III trials. Other mediator-targeted therapies, such as prostaglandin E1, IL-10 and platelet activating factor antagonists, have not been found efficacious in large clinical trials of ARDS. However, these therapies, along with coagulation modulators, may have a favourable impact on ARDS by improving outcomes in sepsis, the greatest risk factor for developing this condition. In the interim, supportive care through improvements in mechanical ventilation are beneficial, while specific fluid balance and nutrition strategies may prove advantageous.

Acetylcysteine↗
PubMed2004

The triglyceride-high-density lipoprotein axis: an important target of therapy?

Coronary heart disease is the single largest cause of morbidity and mortality in the United States. The link between elevated low-density lipoprotein cholesterol (LDL-C) levels and coronary heart disease (CHD) has been clearly established. However, triglycerides (TG) are increasingly believed to be independently associated with CHD, while high-density lipoprotein cholesterol (HDL-C) is inversely associated with CHD risk. High TG and low HDL often occur together, often with normal levels of LDL-C, and can be described as abnormalities of the TG-HDL axis. This lipid abnormality is a fundamental characteristic of patients with the metabolic syndrome, a condition strongly associated with the development of both type 2 diabetes and CHD. Patients with high TG and low HDL-C should be aggressively treated with therapeutic lifestyle changes. For high-risk patients, lipid-modifying therapy that specifically addresses the TG-HDL axis should also be considered. Current pharmacologic treatment options for such patients include statins, fibrates, niacin, fish oils, and combinations thereof. Several new pharmacologic approaches to treating the TG-HDL axis are currently being investigated. More clinical trial data is needed to test the hypothesis that pharmacologic therapy targeting the TG-HDL axis reduces atherosclerosis and cardiovascular events.

Cholesterol, HDL↗
PubMed2001

Antibody constructs for radioimmunodiagnosis and treatment of human pancreatic cancer.

Pancreatic cancer (PC) is a common disease that is seldom cured. Current approaches to the treatment of PC are not effective because the non-specific nature of both chemotherapy and external beam radiation results in toxicity to normal tissue. Monoclonal antibodies (MAbs) can be used as selective carriers for delivering radionuclides, toxins, or cytotoxic drugs to malignant cell populations. Therefore, MAb-technology has led to a significant amount of research in targeted therapy. Targeted therapy would generally allow the concentration of cytotoxic agents in tumors and would markedly lessen the toxicity to normal tissues, which limits the dosage and effectiveness of systemically administered drugs. A variety of MAbs are being pre-clinically evaluated for the diagnosis and treatment of PC. Novel recombinant antibody constructs hold a promising future in both the diagnosis and treatment of cancer. By genetic-engineering methods, several high affinity antibody fragments with optimum tumor targeting properties, such as higher functional affinity (divalent and multivalent scFvs) and blood residence time (good tumor localization with high radiolocalization index), have been generated. Animal models have permitted the in vivo assessment of these antibody-based reagents, therapeutic/diagnostic radionuclide, radiolabeling conditions, and efficacy of administration regimes. For PC, immunoscintigraphy using MAbs has taken new strides. The use of MAbs and their fragments for radioimmunoguided surgery and therapy of PC has shown encouraging results at preclinical levels and warrants further attention.

Adenocarcinoma↗
PubMed2006

Imatinib-refractory gastrointestinal stromal tumors: the clinical problem and therapeutic strategies.

Treatment of gastrointestinal stromal tumor (GIST) is a paradigm for targeted therapy. These mesenchymal tumors are refractory to standard chemotherapy and radiation therapy. Targeted therapy has successfully exploited the oncologic drivers of GIST--the tyrosine kinases, KIT, and the platelet-derived growth factor receptor. Therapy with imatinib has dramatically altered the natural history of patients with advanced GIST. However, patients are developing resistance to imatinib and thus presenting with a major clinical challenge. Alternative approaches to imatinib-refractory disease are needed. Newer approaches using biologic data regarding the mechanisms of resistance are being tested alone or in combination with imatinib and are the focus of this review. Effective novel agents for imatinib-refractory GIST used as single agents or in combination with imatinib will likely become future regimens to be tested in first-line metastatic disease and in the adjuvant setting.

Antineoplastic Agents↗
PubMed2005

Homozygous deletion of the MTAP gene in invasive adenocarcinoma of the pancreas and in periampullary cancer: a potential new target for therapy.

Methylthioadenosine phosphorylase (MTAP) plays an important role in the salvage pathway for the synthesis of adenosine. Novel chemotherapeutic strategies exploiting the selective loss of MTAP function in cancers have been proposed. The MTAP gene, on chromosome 9p21, is frequently included within homozygous deletions of the p16INK4A/ CDKN2A gene. Biallelic deletions of the p16INK4A/CDKN2A gene are found in 40% of pancreatic cancers, suggesting that the MTAP gene may be frequently inactivated in pancreatic cancer and that selected patients with pancreatic cancer may benefit from therapies targeting this loss. We immunolabeled six xenografted pancreatic cancers with known MTAP and p16INK4A/CDKN2A gene status and found that immunolabeling mirrored gene status. Loss of expression of both MTAP and p16 was observed only in those pancreatic cancers with homozygous deletions that encompassed both the MTAP and p16INK4A/CDKN2A genes. We then immunolabeled a series of 320 microarrayed infiltrating pancreatic adenocarcinomas, 35 biliary adenocarcinomas, 54 ampullary cancers, and 35 noninvasive intraductal papillary mucinous neoplasms. Immunolabeling for MTAP was lost in 91 of the 300 (30%) evaluable pancreatic cancers, 9 of 54 (17%) ampullary cancers, 4 of 33 (12%) biliary cancers, and in 1 of 35 (3%) IPMNs. All neoplasms with loss of MTAP labeling also demonstrated loss of p16 labeling. These results suggest that MTAP expression is lost in approximately 30% of infiltrating pancreatic cancers and in a lower percentage of other periampullary neoplasms, that this loss is the result of homozygous deletions encompassing both the MTAP and p16INK4A/CDKN2A genes. Thus, pancreatic cancer is a promising cancer type in which to explore novel chemotherapeutic strategies to exploit the selective loss of MTAP function.

Adenocarcinoma↗
PubMed2002

Translation initiation in cancer: a novel target for therapy.

Translation initiation is regulated in response to nutrient availability and mitogenic stimulation and is coupled with cell cycle progression and cell growth. Several alterations in translational control occur in cancer. Variant mRNA sequences can alter the translational efficiency of individual mRNA molecules, which in turn play a role in cancer biology. Changes in the expression or availability of components of the translational machinery and in the activation of translation through signal transduction pathways can lead to more global changes, such as an increase in the overall rate of protein synthesis and translational activation of the mRNA molecules involved in cell growth and proliferation. We review the basic principles of translational control, the alterations encountered in cancer, and selected therapies targeting translation initiation to help elucidate new therapeutic avenues.

Animals↗
PubMed2003

[Target-based therapy against gastrointestinal stromal tumors--from molecular diagnosis to molecular target therapy].

Gastrointestinal stromal tumors (GIST) are composed of KIT-positive mesenchymal-origin spindle- or polygonal-shaped tumor cells in the gastrointestinal tract without immunoreactivity for desmin and S-100. The gain-of-function mutations in the c-kit gene (90%) or platelet-derived growth factor receptor alpha (PDGF-R alpha) gene (5%) are now considered to be causative for GIST. STI571 (Glivec), a molecule designed to selectively inhibit Bcr-Abl, KIT, and PDGF-R activity, shows high response rate and efficacy for non-resectable and/or relapsed GIST (PR 60%). Its serious adverse effects (more than Grade 3) were infrequent, thus, tolerability and safety are good. Glivec is the first successful case of molecular target therapy for solid tumors. However, new resistance against this new generation of drug is going to appear and becomes an urgent problem.

Antineoplastic Agents↗
PubMed2005

Treatment modalities for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, accounting for approximately 5 to 10% of all cancers. It is estimated to cause approximately 1 million deaths annually. Currently, no adjuvant or palliative treatment modalities have been conclusively shown to prolong survival in HCC. Despite the high mortality and frequency of this cancer, surgical resection is an option for only a small proportion of patients, less than 18%. Liver cirrhosis is the most common cause of HCC and necessitates the preservation as much liver as possible, resulting in local ablation, intra-arterial and systemic treatments being major therapeutic modalities. Through better understanding of the molecular basis of hepatocarcinogenesis, new preventative and treatment modalities have recently emerged. This article reviews the current treatment options and new therapeutic advances for HCC including antiangiogenesis therapy, targeted therapy and antisense gene targeting. Future clinical trials and research will help to evaluate and improve both systemic and targeted molecular therapies for this complex disease.

Animals↗
PubMed2002

Treatment planning for molecular targeted radionuclide therapy.

Molecular targeted radionuclide therapy promises to expand the usefulness of radiation to successfully treat widespread cancer. The unique properties of radioactive tags make it possible to plan treatments by predicting the radiation absorbed dose to both tumors and normal organs, using a pre-treatment test dose of radiopharmaceutical. This requires a combination of quantitative, high-resolution, radiation-detection hardware and computerized dose-estimation software, and would ideally include biological dose-response data in order to translate radiation absorbed dose into biological effects. Data derived from conventional (external beam) radiation therapy suggests that accurate assessment of the radiation absorbed dose in dose-limiting normal organs could substantially improve the observed clinical response for current agents used in a myeloablative regimen, enabling higher levels of tumor control at lower tumor-to-normal tissue therapeutic indices. Treatment planning based on current radiation detection and simulations technology is sufficient to impact on clinical response. The incorporation of new imaging methods, combined with patient-specific radiation transport simulations, promises to provide unprecedented levels of resolution and quantitative accuracy, which are likely to increase the impact of treatment planning in targeted radionuclide therapy.

Antigens, Neoplasm↗
PubMed1998

Antibodies for targeted gene therapy: extracellular gene targeting and intracellular expression.

Antibody genes of human origin and human antibodies directed against human proteins have become widely available in recent years. These are valuable reagents for gene therapy applications, in which the use of human proteins and genes allows for increased therapeutic benefit. Engineered human antibodies can be used in gene therapy both as a component of a gene delivery system and as a therapeutic gene. As the targeting moiety of a gene delivery system, the antibody should meet certain criteria that have been previously determined from other clinical applications of antibodies. These include bioavailability, specificity for the target cell, and rapid clearance. In addition, if repeat delivery of therapeutic genes is going to be needed, then gene delivery vectors should be non-immunogenic to allow repeated administration. The use of human antibodies in this application should therefore be superior to approaches which use rodent-derived antibodies. Another application of antibodies in gene therapy is the use of antibodies expressed inside the cell (intrabodies) as therapeutic agents. The power of the immune system to rearrange a limited set of genes to create recognition sites for any known molecule is well documented. The ability to harness this information and use these highly specific binding molecules as medicines to inhibit an unwanted cellular function is a promising advance in the field of molecular medicine, and in particular, in the field of intracellular immunization.

Journal Article↗
PubMed2005

Targeted cancer therapies.

The term "targeted cancer therapies" refers to treatment strategies designed to inhibit the product of an oncogene involved in the process of neoplastic transformation. Different categories of targeted therapies can be identified: 1) Therapies directed at oncogenes that are directly involved in the initiation of neoplastic transformation: the use of imatinib for the treatment of CML or GIST is the classical model in this subgroup. Single agent targeted therapies generally produce high response rates in this situation. 2) Therapies directed at oncogenes involved at a later stage of neoplastic transformation. These oncogenes contribute to tumor progression but not necessarily to the onset of malignant transformation. The use of trastuzumab for HER2-amplified breast adenocarcinoma is the classical model in this subgroup. These treatments are associated with low response rates when used as single agent therapy, whereas generally displaying a synergistic or additive effect with classical chemotherapy in models currently available. In contrast, when these targeted therapies are applied to tumor models where the targeted gene is present but not directly involved in the process of malignant transformation, no antitumor efficacy is generally observed. Recently, the identification of HER1 mutations in subsets of lung carcinoma as a predictive factor for response to gefitinib and erlotinib provided an example of how the empiric use of a targeted treatment may enable to identify new nosological entities. The present paper reviews examples of targeted cancer therapies and their results.

Angiogenesis Inhibitors↗
PubMedDate not supplied

[Role of meta-analysis in the definition of target population in therapy].

The efficacy of a drug is a quantitative concept rather than a qualitative one. This quantity is expressed by several efficacy indices. None of them meet all the requirements. However, that of absolute benefit is especially suitable for the patients because it tells them the exact gain they can expect from taking the treatment. The absolute benefit varies according to patients' profiles because it interacts with some components of these profiles. In theory, such interactions can be used to predict the size of the absolute benefit for each patient, as well to describe better than with the current tools the therapy target population. We explain why meta-analysis and effect models are means of improving the prediction of the size of the effect and the definition of the therapy target population.

Drug Therapy↗
PubMed2003

Targeting strategies in cancer gene therapy.

Targeting to the tumor tissues can improve the therapeutic effect of gene transfer by preventing damage of healthy tissues and decreasing the risk of germ line transduction. Although targeting seems not important for intratumoral gene delivery, it becomes crucial when systemic gene transfer is performed. Targeted gene therapy of malignancies can be achieved through targeted gene delivery or targeted gene transcription. Recent advances in targeted delivery include the successful use of bifunctional crosslinkers to target adenoviral and retroviral vectors, inserting short targeting peptides and larger polypeptide-binding domains into the coat proteins of a number of different viral vectors, and replication-competent vectors which have been shown to be promise as anti-cancer agents. Some other non-viral therapeutic agents, including receptor-mediated DNA or liposome-DNA complex, and bacteria vehicles have also been developed. Some of these delivery systems are currently in clinical trials. For targeted and regulable gene transcription, tissue or tumor specific promoters and some manual regulatory systems are used to regulate therapeutic gene expression. Antisense oligonucleotides, some ribozyme and DNAzyme molecules are developed to inactivate genes that are essential to the development of many tumors.

Drug Delivery Systems↗
PubMed2002

Estimation and implications of random errors in whole-body dosimetry for targeted radionuclide therapy.

For targeted radionuclide therapy, the level of activity to be administered is often determined from whole-body dosimetry performed on a pre-therapy tracer study. The largest potential source of error in this method is due to inconsistent or inaccurate activity retention measurements. The main aim of this study was to develop a simple method to quantify the uncertainty in the absorbed dose due to these inaccuracies. A secondary aim was to assess the effect of error propagation from the results of the tracer study to predictive absorbed dose estimates for the therapy as a result of using different radionuclides for each. Standard error analysis was applied to the MIRD schema for absorbed dose calculations. An equation was derived to describe the uncertainty in the absorbed dose estimate due solely to random errors in activity-time data, requiring only these data as input. Two illustrative examples are given. It is also shown that any errors present in the dosimetry calculations following the tracer study will propagate to errors in predictions made for the therapy study according to the ratio of the respective effective half-lives. If the therapy isotope has a much longer physical half-life than the tracer isotope (as is the case, for example, when using 123I as a tracer for 131I therapy) the propagation of errors can be significant. The equations derived provide a simple means to estimate two potentially large sources of error in whole-body absorbed dose calculations.

Computer Simulation↗
PubMed2000

Current and future antifungal therapy: new targets for antifungal therapy.

Invasive fungal infections will continue to cause major complications in immunocompromized patients. At the moment, the expansion of antifungal drug research has occurred because there is a critical need for new antifungal agents to treat these life-threatening invasive fungal infections. The overview of the development of antifungal therapy which is provided here demonstrates the increased interest in this very special area of infectious diseases. Although we now have some newer and less toxic antifungal agents that are currently available for clinical use, their clinical efficacy in some invasive fungal infections, such as aspergillosis and fusariosis, is not very good. Intense efforts in antifungal drug discovery are urgently needed to develop more promising and effective antifungal agents for use in the clinical arena.

Antifungal Agents↗
PubMed1983

[Need for therapy and target groups for therapy in nursing homes].

The staff of 16 nursing homes with a total 472 residents evaluated possibilities to change the residents life situations by therapeutic activities. A statistical estimate of groups in need of therapy in a very broad sense is put forth. Younger residents (age 59 and below) need therapy most often. Significant differences in characterizing residents are to be found according to the degree of being "bedridden" (= hours out of bed per day). The less time residents are out of bed and the more dependent on help they are the lower the chances of estimated ameliorations. What is essential: need or the chance of amelioration? For about 1/4 of the residents more affiliation and activities are considered necessary. Facilitating independency is a central therapeutic goal. With some groups large differences between factual and possible independency are found. Staff expects amelioration of residents most often by therapy. This point of view may be partly result from the limited chances perceived to exert influence on residents.

Activities of Daily Living↗