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At least 163 records · Page 9Linked to original sources
PubMed1992

[Targeting therapy with adriamycin-monoclonal antibody (HAb18) conjugate in nude mice with human hepatocellular carcinoma xenografts].

Adriamycin (ADM) was linked covalently to the murine monoclonal antibody (McAb) HAb18 against human hepatocellular carcinoma via a dextran T-40 bridge. The molar ratio of HAb18: DEX: ADM was 1:2.4:56 in the conjugate. It was confirmed by immunochemical staining and ELISA that the antigen binding capacity of HAb18 in the conjugate was well preserved. In vitro study indicated that the conjugate cytotoxicity to tumor target cell lines was selective. The radio-immunoimaging and distribution of the conjugate labelled with 125I in the nude mice bearing human hepatocellular carcinoma showed that 125I-HAb 18-DEX-ADM conjugate was localized in the tumor site. The HAb18-DEX-ADM targeting therapy in nude mice bearing human hepatocellular carcinoma showed the following results: decreased tumor size and partly necrosed cancer tissue in contrast to the rapidly growing tumor in the control group (P < 0.05). Our study suggested that targeting therapy with HAb18-DEX-ADM conjugate may be useful in the treatment of patients with hepatocellular carcinoma.

Animals↗
PubMed2005

Gastrointestinal stromal tumors and the evolution of targeted therapy.

Gastrointestinal stromal tumors (GISTs) historically have differed from other soft-tissue sarcomas in demonstrating a particularly grim prognosis. GISTs have an extraordinarily high rate of recurrence after surgical resection and are highly resistant to radiation and standard chemotherapy. The discovery that constitutive activation of the c-kit gene drives malignant behavior in GISTs exposed a weakness that was soon exploited through the application of the novel targeted therapy imatinib, a small-molecule tyrosine kinase inhibitor of Bcr-Abl, KIT, and the platelet-derived growth factor receptor-alpha and -beta. Imatinib had shown unparalleled results in patients with advanced chronic myelogenous leukemia (remission rates approaching 98%), and the first GIST patients treated with imatinib demonstrated dramatic response rates unseen with other therapeutic modalities. Thousands of patients worldwide with advanced GIST have been treated with imatinib, with the demonstration of significant response rates, prolongation of survival, and improvement in quality of life. Studies of imatinib in both the neoadjuvant and adjuvant settings are now being conducted to evaluate whether low rates of cure with surgical resection alone can be improved. Additionally, multiple new targeted agents are being tested in patients with imatinib-resistant GIST. The gains that have been made in the treatment of GIST through the use of imatinib have helped to open the door to a new era of development of targeted therapeutic agents in oncology. Whether this new era of targeted therapy will provide the same advances in more common malignancies will be determined only through the ongoing application and development of clinical trials.

Benzamides↗
PubMed2006

From radiotherapy to Targeted therapy: 20 years in the management of non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Before 1980, radiotherapy was considered the only real recourse in advanced disease. In 1995, a landmark meta-analysis of trials conducted in the 1980s and early 1990s demonstrated a survival benefit with platinum-based chemotherapy. Newer chemotherapy agents and improved supportive care measures have allowed more patients to benefit from chemotherapy with reduced toxicity. Concurrent platinum-based chemotherapy and radiotherapy has improved the survival in stage III disease, and recently chemotherapy has also demonstrated improved survival in resected early-stage disease. The majority of patients still present with advanced unresectable disease for whom the prognosis remains poor, but for key subpopulations the outlook has improved markedly since the emergence of targeted therapies directed against the epidermal growth factor receptor and vascular endothelial growth factor receptor pathways. Patient selection and the incorporation of targeted therapies with cytotoxic chemotherapy are the focus of many ongoing studies, and there is an abundance of new agents undergoing clinical trials. Together, these developments have moved us away from the nihilism of 20 years ago into an era of unprecedented optimism in taking on the many remaining challenges of managing NSCLC in the 21st century.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Biologic therapy for psoriasis: an update on the tumor necrosis factor inhibitors infliximab, etanercept, and adalimumab, and the T-cell-targeted therapies efalizumab and alefacept.

Psoriasis is a chronic skin disorder that affects approximately 2% of the US and European population. Over the last several years, one of the major focuses in psoriasis research has been the development of biologic therapies for this disease. The aim of these therapies is to provide selective, immunologically directed intervention with fewer side effects than traditional therapies. The goal of this article is to update the progress of the tumor necrosis inhibitors which are available, or under investigation, for clinical use in psoriasis: infliximab, etanercept, and adalimumab, as well as the T-cell-targeted therapies efalizumab and alefacept (Table 1).

Adalimumab↗
PubMed2004

Imatinib as a paradigm of targeted therapies.

Imatinib (Gleevec) exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. This article reviews the identification of the BCR-ABL tyrosine kinase as a therapeutic target in chronic myeloid leukemia and the steps in the development of an agent to specifically inactivate this abnormality. The clinical trials results are reviewed along with a description of resistance mechanisms. As imatinib also inhibits the tyrosine kinase activity of KIT and the platelet-derived growth factor receptors, the extension of imatinib to malignancies driven by these kinases will be described. Issues related to clinical trials of molecularly targeted agents are discussed, including patient and dose selection. Last, the translation of this paradigm to other malignancies is explored.

Animals↗
PubMed2005

Targeted therapy in renal cell carcinoma.

Hypoxia-regulated genes such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are both important for tumour progression in renal cell carcinoma (RCC). Drugs that block these and other pathways have been examined in Phase I and II clinical trials in patients with advanced or metastatic RCC. Results from a randomised study of an anti-VEGF antibody demonstrate a delay in the time to disease progression, suggesting a biological effect and change in the natural history of the disease. Results using small-molecule inhibitors of VEGF, FLT3, KIT and platelet-derived growth factor receptor tyrosine kinases, such as sunitinib, show a 40% objective response rate. Results from a Phase III clinical trial with sorafenib, an inhibitor of multiple tyrosine kinases, show only a 2% response rate; however, a statistically significant improvement in progression-free survival was observed. Objective responses have also been noted using an inhibitor of the mammalian target of rapamycin. Conversely, EGF receptor inhibitors, proteosome inhibitors, microtubule stabilising agents, cell-cycle inhibitors and imatinib were also examined with few objective responses. Ultimately, identifying the predictive factors for responsiveness to these targeted therapies may improve the clinical benefit; for example, RCC with biallelic mutations in the von Hippel-Lindau gene would have higher levels of hypoxia-inducible factor-1alpha, and may be more responsive to inhibitors of angiogenesis. Phase III studies comparing the combinations of targeted therapy could lead to a new standard of care for RCC.

Animals↗
PubMed2006

Genetics, gene expression, and targeted therapies in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) represents the most common leukemia among adults in the Western countries. CLL is a remarkably diverse disorder following an extremely variable clinical course. Some patients have an indolent disease that may never require treatment. In others a progressive clinical course is rapidly fatal. CLL affects mainly elderly individuals, but about a third of patients are less than 60 years of age at diagnosis. Traditionally, the therapeutic procedures were aimed at palliation, but over the recent years highly effective and potentially curative approaches such as combined antibody-chemotherapy and autologous or allogeneic stem cell transplantation have been developed. In parallel there has been progress in the understanding of pathogenesis and outcome prediction. The cornerstones to estimate prognosis are the clinical staging systems of Rai and Binet. To refine outcome prediction for individual patients there has been intensive work on biological factors of potential prognostic relevance. Among these, the genetic characteristics of the CLL cells that can be divided into genomic aberrations and the mutation status of the variable segments of immunoglobulin-heavy chain genes (VH) have attained considerable importance. In addition, data on gene expression of CLL cells are accumulating which further characterize the CLL subgroups. In this context, the expression of ZAP-70 has been recognized a useful surrogate marker to predict the VH mutation status and outcome of CLL patients. At present, targeted therapies are focused on humanized antibodies that bind proteins expressed on the surface of CLL cells. The most prominent agents of these are the anti-CD52 antibody alemtuzumab and the anti-CD20 antibody rituximab, which are currently being tested in clinical trials. To identify CLL-specific gene expression products as candidates for targeted therapies will be an important part of CLL research in the next years.

Animals↗
PubMed2006

Targeted therapies in gynecologic cancers.

With the rapid development of high-throughput techniques for identifying novel specific molecular targets in human cancer over the past few years, attention to targeted cancer therapy has dramatically increased. The term "targeted cancer therapy" refers to a new generation of drugs designed to interfere with a specific molecular target that is believed to play a critical role in tumor growth or progression, is not expressed significantly in normal cells, and is correlated with clinical outcome. There has been a rapid increase in the identification of targets that have potential therapeutic application. The clinical success of the small-molecule kinase inhibitor imatinib mesylate in chronic myeloid leukemia and gastrointestinal stromal tumors has accelerated the development of a new era of molecular targeted cancer therapy. The number of agents under preclinical and clinical investigation has grown accordingly. This emphasis on molecular biology and genetics has also resulted in significant changes in the treatment of gynecologic cancers. Several promising drugs targeting tyrosine kinases (EGFR and Her-2/Neu), mTOR, Raf kinase, proteasome, and histone deacetylases, as well as drugs affecting apoptosis and mitosis, are under development for clinical application. However, some clinical trials of p53 gene therapies and farnesyl transferase inhibitors have had limited success. In this review, we will focus on potential novel targets in gynecologic cancer and the development of targeted therapy and its clinical applications in gynecologic cancer.

Angiogenesis Inhibitors↗
PubMed2006

Recent advances in targeted therapies for colorectal cancer.

BACKGROUND: Recent advances in the molecular biology and genetics of colorectal cancer have led to the identification of potential therapeutic targets such as epidermal growth factor receptor, vascular endothelial growth factor and endothelial receptors. OBJECTIVE: This review will examine the major therapeutic advances along with the preclinical basis justifying their combination with conventional therapeutic tools. This review will also critically consider current possibilities offered to identify responding patients. DATA SOURCES: Preclinical and primary clinical trial results published in peer-review journals. The authors examined the relevance and subsequent inclusion of the data. CONCLUSIONS: Cetuximab and bevacizumab provide new benefits in terms of the response rate and survival. There remain, however, important questions concerning, for instance, optimal combinations between conventional cytotoxic agents and targeted therapies and also between targeted drugs themselves. These new targeted treatments are costly and in this context the question of the identification of the right drug for the right patient is particularly relevant. Adequate tools in predicting the efficacy of targeted treatments are still needed.

Angiogenesis Inhibitors↗
PubMed1987

Selective immunosuppression with anti-interleukin 2 receptor-targeted therapy: helper and suppressor cell activity in rat recipients of cardiac allografts.

(LEW X BN)F1 cardiac allografts are rejected within 8 days in unmodified LEW rats. ART18, a mouse anti-rat IgG1 monoclonal antibody which binds specifically in vitro to the interleukin 2 receptor (IL 2R) molecule expressed primarily on activated T cells, prolongs allograft survival in a dose-dependent fashion to ca. 3 weeks (p less than 0.001) after being administered for 10 days after transplantation. This effect was related to the specificity of the antibody for IL 2R, as therapy with ART62 (a monoclonal antibody recognizing MHC class I antigen but not binding the rat IL 2R) was ineffectual. Suppressor activity was detected in spleen cells of ART18-treated grafted hosts: in vivo, splenic T suppressor/cytotoxic fraction adoptively transferred into normal LEW improved donor-specific but not third-party test graft survival (17 days, vs. 8 days, respectively, p less than 0.001); in vitro, mixed lymphocyte reaction was profoundly but nonspecifically inhibited (less than 5% of test mixed lymphocyte reaction, p less than 0.001 as compared to acutely rejecting controls). In contrast, splenic T helper (Th) cells from ART18-treated hosts were functionally depressed, as noted by their passive transfer into immunologically anergic B recipients of cardiac allografts (rejection in ca. 40 days, vs. ca. 13 days after transfer of Th from specifically sensitized rats). ART18 treatment also resulted in diminished elaboration of IL 2 as compared to normal (p less than 0.005) or acutely rejecting hosts (p less than 0.001); however, a remarkable increase in the production of IL 3 occurred (p less than 0.001). These results demonstrate that IL 2R-targeted therapy of immunocompetent graft recipients produces a selective immune defect in which donor-specific T suppressor cells are spared, but Th cells attenuated or destroyed. Decreased elaboration of IL2 concomitantly augments the release of IL 3, a lymphokine which might play a role in suppressor effect in vivo. In addition, IL 2R-targeted therapy of the immunodeficient graft recipients abrogates the capacity of alloactivated T cells to re-establish acute immune responsiveness.

Animals↗
PubMed2006

Her-2 targeted therapy: beyond breast cancer and trastuzumab.

Her-2 is a validated therapeutic target in breast cancer. The two critical questions that remain regarding Her-2 targeting concern 1) the relevance of Her-2 inhibition in other malignancies and 2) the ability of novel agents to achieve greater Her-2 inhibition than trastuzumab. The contribution of cell signaling effects and immunologic mechanisms to the effect of trastuzumab in vivo remains poorly understood. Thus, the preclinical data that support the greater efficacy of novel Her-2 antibodies or small molecule tyrosine kinase inhibitors remain to be validated in clinical trials. In this review, we discuss the evidence from recent trastuzumab clinical trials as a point of departure for consideration of novel Her-2 targeted therapies. Preliminary results from early clinical trials suggest that Her-2 tyrosine kinase inhibitors may extend the population for which this strategy offers therapeutic effect.

Antibodies, Monoclonal↗
PubMedDate not supplied

Photodynamic therapy targeted to pathogens.

Photodynamic therapy (PDT) employs a non-toxic dye termed a photosensitizer (PS) together with low intensity visible light, which, in the presence of oxygen, produce cytotoxic species. PS can be targeted to its destination cell or tissue and, in addition, the irradiation can be spatially confined to the lesion giving PDT the advantage of dual selectivity. This promising approach can be used for various applications including microbial inactivation and the treatment of infections. Resistance to PDT has not been shown and multiantibiotic-resistant strains are as easily killed as naive strains. It is known that Gram (+) bacteria are more sensitive to PDT as compared to Gram (-) species. However, the use of cationic PS or agents that increase the permeability of the outer membrane allows for the effective killing of Gram (-) organisms. Some PS have an innate positive charge, but our approach is to link PS to a cationic molecular vehicle such as poly-L-lysine. This modification dramatically increases PS binding to and penetrating through the negatively charged bacterial permeability barrier. Due to focused light delivery the use of PDT is possible only for localized infections. Nonetheless numerous diseases can be treated. Selectivity of the PS for microbes over host cells, accurate delivery of the PS into the infected area, and PDT dose adjustment help minimize side effects and give PDT an advantage over conventional therapy. There are only a few reports about the use of antimicrobial PDT in animal models and clinical trials. We have used genetically modified bioluminescent bacteria to follow the effect of PDT in infected wounds, burns, and soft tissue infections in mice. Not only were bacteria infecting wounds, burns, and abscesses killed, but mice were saved from death due to sepsis and wound healing was improved.

Animals↗
PubMed2004

Reversing resistance to targeted therapy.

The development of molecular targeted anticancer drugs is rapidly changing cancer therapeutics. However, drug resistance to these novel agents remains a real clinical concern. Reports now indicate that resistance to many of these molecular targeted agents--including hormone therapies, trastuzumab, imatinib, and gefitinib--occurs via common resistance mechanisms. These include 1) inadequate target blockade due to sub-optimal drug delivery; 2) altered target expression at the DNA (gene amplification), mRNA or protein level; 3) an altered target such as a mutated kinase domain; 4) modified target regulating proteins (e.g. altered expression of co-activators and/or co-repressors for nuclear steroid hormone receptors); 5) signalling by alternative proteins (functional redundancy) or different signalling pathways. It is envisioned that the molecular evaluation of clinical anticancer drug resistance, which requires the detailed study of pharmacokinetics, pharmacogenetics and pharmacodynamics, will allow the development of rational reversal strategies and improved patient outcome.

Antibodies, Monoclonal↗
PubMed2000

[Targeting therapy using a monoclonal antibody against tumor vascular endothelium].

Recent studies have revealed that the targeting therapy using monoclonal antibody against tumor associated antigens did not have a clinically satisfactory effect due to various physiological characters of tumor. We propose a novel approach targeting tumor vascular endothelium to solve the inefficiency of common tumor missile therapy. In this study, the tissue distribution of anti-tumor vascular endothelium monoclonal antibody (TES-23) produced by immunizing with plasma membrane vesicles obtained from isolated rat tumor-derived endothelial cells (TECs) was assessed in various tumor-bearing animals. Radiolabeled TES-23 dramatically accumulated in KMT-17 fibrosarcoma, a source of isolated TECs after intravenous injection. In Meth-A fibrosarcoma, Colon-26 adenocarcinoma in BALB/c mice and HT-1080 human tumor tissue in nude mice, radioactivities of 125I-TES-23 were also up to fifty times higher than those of control antibody with little distribution to normal tissues. Furthermore, immunostaining of human tissue sections showed specific binding of TES-23 on endothelium in esophagus and colon cancers. These results indicate that tumor vascular endothelial cells express a common antigen in different tumor types of various animal species. In order to clarify the efficacy of TES-23 as a drug carrier, an immunoconjugate, composed of TES-23 and neocarzinostatin, was tested for its antitumor effect in vivo. The immunoconjugate (TES-23-NCS) caused a marked regression of the tumor, KMT-17 in rats and Meth-A in mice. Thus, from a clinical view, TES-23 would be a novel drug carrier because of its high specificity to tumor vascular endothelium and its application to many types of cancer.

Animals↗
PubMed2006

Targeted therapy for metastatic renal cell carcinoma.

The discovery of a relationship for the VHL tumor suppressor gene, hypoxia inducible factor-1 alpha, and vascular endothelial growth factor in the growth of clear-cell renal cell carcinoma (RCC) has identified a pathway for novel targeted therapy. This study evaluated the impact of these agents on metastatic RCC (mRCC), and highlights recent phase II and III trials. A systematic review examined the clinical data for novel targeted agents in mRCC, with a focus on randomized phase II and III trials of the novel targeted agents sunitinib, temsirolimus, sorafenib, and bevacizumab. Several agents, including the small-molecule targeted inhibitors sunitinib, temsirolimus, sorafenib, and the monoclonal antibody bevacizumab, have demonstrated antitumor activity in randomized trials. Superior activity was found with sunitinib and temsirolimus versus cytokines in first-line therapy. Improved progression-free survival was reported with sorafenib and bevacizumab given second-line compared with placebo. Targeted therapies show promising activity in this disease, and they have been changing patient management. Sunitinib and sorafenib were recently approved by the US Food and Drug Administration for treatment of mRCC, These drugs are currently included in clinical practice.

Angiogenesis Inhibitors↗
PubMed2003

The new generation of targeted therapies for breast cancer.

Traditional therapies for breast cancer have generally relied upon the targeting of rapidly proliferating cells by inhibiting DNA replication or cell division. Although this strategy has been effective, its innate lack of selectivity for tumor cells has resulted in diminishing returns, approaching the limits of acceptable toxicity. A growing understanding of the molecular events that mediate tumor growth and metastases has led to the development of rationally designed targeted therapeutics that offer the dual hope of maximizing efficacy and minimizing toxicity to normal tissue. Promising strategies include the inhibition of growth factor receptor and signal transduction pathways, prevention of tumor angiogenesis, modulation of apoptosis, and inhibition of histone deacetylation. This article reviews the development of several novel targeted therapies that may be efficacious in the treatment of patients with breast cancer and highlights the challenges and opportunities associated with these agents.

Angiogenesis Inhibitors↗
PubMed2005

Prospects for targeted therapy of synovial sarcoma.

Synovial sarcoma is a distinct tumor with unique promise for targeted therapy. It has a diagnostic translocation and a potentially informative fusion protein. It has moderate chemosensitivity, with about 50% response rates to regimens containing ifosfamide and doxorubicin. Therapeutic advances are unlikely to occur by continuing to lump synovial sarcomas in trials with other soft tissue sarcomas and adjusting traditional agents; rather, attention should be turned toward prospective molecular targets and investigation or development of novel agents to exploit them. The SYT-SSX fusion protein that results from the X,18 translocation is an appealing target, as are the proteins overexpressed in synovial sarcoma: bcl-2, EGFR, and HER-2/neu.

Drug Delivery Systems↗