Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With the FDA approval of Rituximab in 1998 for the treatment of lymphoma, and Trastuzumab in 1999 for the treatment of breast cancer, monoclonal antibodies were officially added to the therapeutic armamentarium against malignancy. Most of the side effects associated with these agents are due to antigen-antibody interactions on specific cells and tissues. One of the most predictable side effects of these products is a constellation of various systemic effects including flu-like symptoms such as headache, fever, sweats, skin rash, shortness of breath, hypotension, nausea, and asthenia that occurs with the first infusion of such products. Rarely severe hypotension, bronchospasm, and hypoxia and even death have occurred. The pathophysiology of these reactions appears to be secondary to the release of cytokines as the antibodies bind do circulating antigen-expressing cells that are then removed in the reticuloendothelial system of the lungs, spleen and liver. In patients with large numbers of antigen-dense cells that have a high mitotic index, such as prolymphocytic leukemia, mantle cell lymphoma, or lymphosarcoma cell leukemia, there is a risk of true tumor lysis syndrome. One should be particularly cautious when treating patients with high numbers of circulating antigen-expressing cells in the setting of underlying cardiovascular or respiratory disease.
 ...
PMID:Infusion reactions associated with the therapeutic use of monoclonal antibodies in the treatment of malignancy. 1085 89

HER2 (neu, erbB-2), a receptor related to the human epidermal growth factor receptor, has now become more important as a predictive marker of treatment response. While the value and direction of the treatment/HER2 interaction may vary, depending on the agents, dose, or schedule of drug administration, there is little disagreement that HER2 testing is an important part of breast cancer evaluation. In 1998, trastuzumab (Herceptin) was approved for the treatment of HER2-positive metastatic breast cancer patients by the Food and Drug Administration of the USA. Patients with abnormal HER2 in their breast cancer cells (generally 2 or 3+ with the HercepTest, overexpression by other immunohistochemical assays or amplification by fluorescence in situ hybridization [FISH] assay) have demonstrated the greatest response to trastuzumab treatment. It is unclear which test (method, reagent, cut-off points, etc.) is best to use to evaluate HER2 for this purpose because parallel testing of the same cancers from patients who received trastuzumab has only recently been initiated and the data are limited. It is widely believed that breast cancers without HER2 alterations will not be responsive to trastuzumab, although a clinical trial to test this specific hypothesis has not been initiated. There are also concerns that clonal heterogeneity for HER2 within a tumor, or between primary and metastatic cancer foci, may affect treatment response; yet we do not currently evaluate these parameters. Consensus regarding the best methods, reagents, or cut-off points to define HER2 status for determining trastuzumab responsivity has not yet been reached. HER2 testing for other prognostic or predictive purposes, e.g. to determine whether patients are likely to respond to other agents, such as dose-intensive doxorubicin, may be less. Data from the Cancer and Leukemia Group B trial 8541 (companion 8869) suggest that, with proper controls in high-volume laboratories, many of the available methods produce comparable results.
 ...
PMID:HER2--a discussion of testing approaches in the USA. 1152 14

This article focuses on the recent dramatic advances in the applications of monoclonal antibody therapy to hematopoietic and neoplastic disease. The increase in the understanding of the role of growth factors and their receptors in the pathogenesis of malignancy and other undesirable hematological events taken in conjunction with the ability to produce humanized chimeric monoclonal antibodies to these targets is providing a new perspective for the treatment of leukemia, lymphoma and breast cancer, autoimmune disease and for prevention of ischemic complications. Dr. Waldmann describes approaches targeting the Her2/neu and the II-2/IL-15 receptor systems. The Her2/neu receptor is overexpressed in select breast, ovarian, gastric and pancreatic neoplasms. The use of trastuzumab (Herceptin) in the treatment of patients with breast cancer whose tumors overexpress this receptor are reviewed. The IL-2 receptor (Tac) is expressed on select malignant cells (adult T cell leukemia, hairy cell leukemia) and activated T cells involved in autoimmune disease and organ rejection. Humanized anti-Tac alone (daclizumab, Zenapax) or armed with toxins or radionuclides have been used successfully in the treatment of leukemia. Dr. Levy updates the experience with rituximab targeting CD20 on B cell lymphomas and reviews the antibodies to CD3, CD22, CD33, CD52, HLA-DR beta chain and HLA-D currently in or proposed for clinical trials, including radiolabelled antibodies. In the last section, Dr. Coller reviews the therapeutic results achieved with abciximab (ReoPro), an antagonist of platelet receptor GPIIbIIIa for the prevention of restenosis in percutaneous coronary interventions and the treatment of unstable angina. The mechanism of action, pharmacology and safety and efficacy of abciximab are reviewed.
 ...
PMID:Emerging Therapies: Spectrum of Applications of Monoclonal Antibody Therapy. 1170 53

The long-term effort in investigating chemical methods to eliminate only cancer cells has improved our knowledge and has led to the development of new drugs. The targets for cancer treatment may be large polymeric molecules such as DNA or microtubules as well as regulatory pathways for tumor development and cell survival preservation or tyrosine kinase activity. Examples of new agents are: trastuzumab (Herceptin), a humanized monoclonal antibody that blocks the HER-2/neu proto-oncogene in combination with cytotoxic agents, is used in a percentage of breast cancer patients; signal transduction inhibitor of abl tyrosine kinase STI 571 (Glivec) has been shown to be an active treatment for chronic myeloid leukemia and GISTs; epidermal growth factor receptors in certain tumors have been targeted with agents such as C225 (Cetuximab) and ZD 1839 (IRESSA); an adenosine deaminase analogue of deoxyadenosine, Cladribine (2-chloro-2 deoxy-adenosine) has shown high effectiveness in hairy-cell leukemia and the multitargeted antifolate (Premetrexed) and several vaccines have been studied and are in clinical trials for resistant cancers. These new drug developments represent a promising field for future cancer management.
 ...
PMID:Molecular characterization as a target for cancer therapy in relation to orphan status disorders (Review). 1237 30

The Cancer and Leukemia Group B (CALGB) Genitourinary Committee has developed a broad range of clinical trials across most stages of bladder cancer. Recurrence rates of superficial bladder cancer after transurethral resection range from 50-70%. Although adjuvant bacillus Calmette-Guerin reduces the risk of disease recurrence or progression, only 30% of patients have long-term disease-free survival. Because the development of novel secondline agents is needed, the CALGB is evaluating the utility of intravesicle gemcitabine as well as an oral proapoptotic agent (CP-461). In patients with locally advanced disease with an increased risk of disease recurrence after cystectomy, a randomized trial of conventional chemotherapy versus sequential dose-dense therapy is under development. The gemcitabine/cisplatin combination has become a commonly used regimen for the treatment of advanced transitional cell carcinoma (TCC). The CALGB is undertaking a Phase II study that incorporates a fixed dose rate gemcitabine infusion in this regimen, together with a selective epidermal growth factor receptor tyrosine kinase inhibitor, Iressa (Astra Zeneca, Wilmington, DE). In patients with renal insufficiency, a regimen of carboplatin, gemcitabine, and Iressa is planned. Novel agents, including arsenic trioxide and trastuzumab (Herceptin; Genentech, Inc., South San Francisco, CA), are being evaluated as secondline therapy in patients with advanced TCC who have disease progression after frontline therapy.
 ...
PMID:Overview of bladder cancer trials in the Cancer and Leukemia Group B. 1267 1

The fusion of a murine B cell and a myeloma cell generates a hybridoma that produces monoclonal antibody (mAb). These murine mAb induce the HAMA (human anti-mouse antibodies) response. Murine mAb have been modified by genetic engineering, producing molecules with a higher proportion of human protein. At present, chimeric, humanized and fully human mAb are available. mAb block interactions between target molecules and their ligands or trigger the lyses of mAb-coated tumor cells. Numerous mAb have been developed using the recombinant DNA technology and several are available in the market. Trastuzumab, against HER2/neu, is useful in breast cancer; rituximab, against CD20 in B lymphocytes is useful in lymphoma; alemtuzumah, against CD52 is used in lymphoma and leukemia; daclizumab and basiliximab block the IL-2 receptor interaction and reduce acute rejection in kidney transplantation; abciximab, an antagonist of GPIIb/IIIa platelet receptor, is used in patients undergoing acute coronary syndromes. In autoimmunity diseases, blocking tumor necrosis factor by infliximab and adalimumab has demonstrated excellent results. Thus, infliximab is useful in the treatment of rheumatoid arthritis (RA), Crohn's disease and ulcerative colitis while adalimumab is the first fully human mAb available for RA. Infliximab and adalimumab reduce signs and symptoms in RA and they also interfere with progression of joint damage. Finally, the direct benefits of antagonist treatment can occur at the expense of a major adverse effect in some other biological function.
 ...
PMID:[New immunological weapons for medicine in the 21st Century: biological therapy based on the use of the latest generation monoclonal antibodies]. 1502 9

Current treatments for cancer (surgery, radiation and chemotherapy) are successful for early stage localised disease but have severe side effects. New treatments are needed to increase the cure rate and life expectancy of patients. With the discovery of oncogenes, tumour suppressor genes and an understanding of their role in the development of the malignant disease, a new era of therapy has begun. Cancer is a manifestation of deregulated signalling pathways that mediate cell growth and programmed cell death. Protein kinases are essential elements in these signalling pathways. In the US, Novartis launched Gleevec (imantinib, STI-571) in May 2001 as the first anticancer drug whose mechanism of action is kinase inhibition. In Phase I trials, 23/24 patients with chronic myelogenous leukaemia (CML) had complete remissions and the drug is relatively non-toxic. Herceptin (trastuzumab) is a monoclonal antibody (mAb) against a member of the growth factor receptor family (HER-2/neu) that was launched in 1998 by Genentech for the treatment of breast cancer. Trastuzumab has an excellent antitumour profile, particularly when used in combination with doxorubicin and paclitaxol. These drugs are pioneering the treatment of cancer based on the molecular understanding of the disease. Numerous drugs that target growth factor receptors and their signalling pathways are in advanced clinical trials. Herein, antibodies against receptors and small molecule inhibitors of kinases in signalling pathways will be summarised. Inter-disciplinary preclinical studies have identified chemicals that target specific kinases. We believe that clinical studies of these agents will yield new anticancer agents that target specific diseases and that are less toxic than current agents.
 ...
PMID:Drugs targeted against protein kinases. 1598 28

Since 1997, nine humanized antibodies received the approval of the FDA to be used as drugs for the treatment of various diseases including transplant rejections, metastatic breast and colon cancers, leukaemia, non-Hodgkin lymphomas, allergic conditions or multiple sclerosis. This review describes techniques used to engineer these antibodies and presents the recent evolutions of these techniques : SDRs grafting or << abbreviated >> CDRs grafting. Based on the illustrative examples of several antibodies, Mylotarg, Herceptin or Xolair, the therapeutic effectiveness of humanized antibodies are underlined and, with the example of Tysabri, the sometimes dramatic adverse effects associated with their clinical use is stressed. In a second part, this review presents some future and realistic avenues to improve the effectiveness of the humanized antibodies, to decrease their immunogenicity and to reduce their cost.
 ...
PMID:[Humanized antibodies as therapeutics]. 1632 46

The rapidly evolving insights into the protective and modulatory function of neuregulin-1 (NRG-1) in the adult heart are discussed in this review. The actions of NRG-1 in the adult heart have begun to be elucidated following the unexpected clinical observation that trastuzumab can cause ventricular dysfunction and increases the risk of cardiomyopathy induced by anthracyclines. Trastuzumab is an inhibitory antibody against the NRG receptor erythroblastic leukemia viral oncogene homolog 2 (ErbB2) and is used in the treatment of breast cancer. In vitro studies have demonstrated that NRG-1 promotes growth and survival of isolated cardiomyocytes. Ventricular dysfunction following anti-ErbB2 treatment was initially explained by a loss of ErbB2-dependent cell survival pathways in the heart. However, in vivo studies in genetically modified mice did not uniformly confirm this finding. More recent studies have revealed that NRG-1 counterbalances the adrenergic inotropic response of the adult myocardium through an obligatory interaction with the muscarinic cholinergic system. In addition, it was demonstrated that cardiac NRG-1 synthesis and release from the cardiac endothelium, the principal source of NRG-1 in the heart, is dynamically controlled by neurohormonal and biomechanical stimuli, allowing adaptive tuning of ErbB signaling during cardiovascular stress. Cardiac NRG-1 is beginning to emerge as a cardioprotective factor implicated in the physiological regulation of myocardial performance and sympathovagal balances. Cardiac NRG-1/ErbB signaling has implications for the treatment of both cancer and heart failure. As novel ErbB inhibitors are currently being tested in broader oncological indications, there is a need to better understand their cardiovascular side effects. It is possible that pharmacological activation of ErbB signaling is an indirect, beneficial effect of the drugs currently used in heart failure, and this could be a promising therapeutic approach for prevention or reversal of myocardial dysfunction. Heart Fail Monit 2008;5(4):119-24.
 ...
PMID:Neuregulin-1 and its potential role in the control of cardiac function. 1827 95

Anthracycline-based regimens became the standard of care for early breast cancer patients based on the survival advantage they provide over nonanthracycline-containing regimens. The addition of taxanes, and subsequently trastuzumab in HER2-overexpressing patients, to anthracyclines further improved their efficacy in several studies involving high-risk early breast cancer patients. Concern over toxicity initially surfaced after anthracyclines were reported to carry an increased risk of cardiotoxicity and secondary leukemia. Trastuzumab has since been shown to compound the risk of cardiotoxicity in patients who have received an anthracycline. This has led to the development of regimens featuring a taxane without an anthracycline; these protocols vary in design and have different toxicity and efficacy profiles. Ongoing investigations are centered on the optimization of nonanthracycline regimens, prospective exploration of molecular markers to identify populations of patients who will derive maximal benefit from anthracycline-based chemotherapy, and the identification of less cardiotoxic formulations of existing anthracycline agents. Perhaps most importantly, a rapidly growing understanding of the biological heterogeneity of breast cancer is likely to lead to an individualized standard of care guided by particular patient and tumor characteristics.
 ...
PMID:Do anthracyclines still have a role in adjuvant chemotherapy of breast cancer? 2117 37


1 2 Next >>