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Rationing scarce drugs has some questioning fairness and ethics.
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Rights row clouds malaria breakthrough.
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A commercial debut for DNA technology.
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California university sues the genetic engineers.
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Therapy of allergic bronchial asthma with omalizumab - an anti-IgE monoclonal antibody.
The immunoglobulin E (IgE) antibody plays a central role in the allergic immune responses, such as those which characterise allergic bronchial asthma. The ability to reduce circulating IgE by using anti-IgE antibodies represents a novel therapeutic approach for IgE-mediated allergic diseases. Omalizumab (rhuMAb-E25/Xolair Genentech, USA/Tanox, Inc., USA/Novartis Pharma AG, Switzerland) is a non-anaphylactogen humanised murine monoclonal antibody which binds to circulating IgE. Therapeutic use of an anti-IgE antibody in the treatment of asthma was first suggested in preliminary studies in which omalizumab demonstrated efficacy in attenuating both the early- and late-phase bronchial responses to inhaled allergens in atopic subjects. Treatment with omalizumab has demonstrated both a significant beneficial effect on a number of measures, and a favourable safety profile. It reduces the frequency of asthma exacerbations and the need for inhaled corticosteroids (ICSs), and improves asthma symptoms, lung function and quality of life. The anti-IgE approach to asthma treatment has a number of further potential advantages, such as the treatment of other concomitant atopic diseases (allergic conjunctivitis and rhinitis, atopic dermatitis and food allergy), regardless of the type of allergic sensitisation (seasonal or perennial). On the basis of several studies, omalizumab is likely to provide a new strategy for treating atopic asthma.
A cancer drug shows promise, at a price that many can't pay.
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Genentech caps cost of cancer drug for some patients.
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Human growth hormone--orphan with a silver spoon.
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Anti-IgE therapy of asthma.
There is a strong association between serum levels of immunoglobulin E (IgE) and asthma development. Allergen binds to IgE on basophils and mast cells, leading to cell degranulation and release of inflammatory mediators. A humanized antibody to IgE that reduces circulating free IgE, omalizumab (Genentech Inc/Novartis AG/Tanox Inc), inhibits the early- and late-phase response to allergen. In clinical trials of moderate-to-severe asthma, omalizumab allowed a reduction in oral and inhaled corticosteroids while improving peakflows and reducing exacerbations, particularly in patients at high risk of serious asthma-related morbidity. Omalizumab is a useful addition to the treatment armamentarium for patients with moderate-to-severe asthma.
Biological therapy for psoriasis: an overview of infliximab, etanercept, 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 foci in psoriasis research has been the development of biological therapies for this disease. The aim of these therapies is to provide selective, immunologically directed intervention with fewer side effects than traditional therapies. This article will review the progress of four biological agents that are available or under investigation for clinical use: infliximab (Centocor Inc), etanercept (Amgen Inc/Wyeth), efalizumab (Genentech Inc/XOMA Ltd/Serono SA) and alefacept.
Docetaxel (Taxotere) plus trastuzumab (Herceptin) in breast cancer.
The rationale for the combined use of docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ) and trastuzumab (Herceptin; Genentech, South San Francisco, CA) in HER2/neu-overexpressing breast cancer patients are several-fold. Docetaxel is a highly active chemotherapeutic agent in metastatic breast cancer. Response rates, time to progression, and survival are improved when trastuzumab is combined with chemotherapy. Finally, preclinical findings demonstrate synergistic cytotoxic activity when docetaxel and trastuzumab are combined. In addition, their different mechanisms of action and a nonoverlapping toxicity profile suggest the potential for a highly useful combination while minimizing potential cardiotoxicity. An ongoing pilot phase II evaluation is being conducted with every-3-week docetaxel plus weekly trastuzumab. Preliminary findings suggest an active and well-tolerated regimen. Efficacy data indicate an encouraging overall major response rate of 45% in first- and second-line metastatic breast cancer patients. Preliminary results from a second phase II trial of weekly docetaxel and trastuzumab have been reported. In 14 patients treated to date, grade (3/4) toxicities are infrequent. An overall response rate of 54% is reported thus far with 26 cycles (156 weeks) of therapy delivered. The preliminary data for the docetaxel and trastuzumab combinations look favorable from both a safety and an efficacy perspective. The lack of cardiac function changes despite frequent cardiac monitoring is promising. For the adjuvant therapy of HER2/neu-overexpressing breast cancer, the high level of efficacy of docetaxel and the need to identify nonanthracycline agents for combined use with trastuzumab place a high emphasis on the potential utility of docetaxel and trastuzumab-based regimens.
HER2 regulatory control of angiopoietin-2 in breast cancer.
BACKGROUND: HER2 overexpression is a marker of aggressive breast cancer. Tumors that overexpress HER2 induce endothelial cell retraction and endothelial destabilization. Because angiopoietin-2 (Ang-2) also destabilizes microvessels, we postulated that HER2 signaling upregulates Ang-2 as a mechanism of angioinvasion. METHODS: We tested human breast cancers and breast cancer cell lines for coexpression of HER2 and Ang-2 with Northern blot, reverse transcriptase-polymerase chain reaction, and enzyme-linked immunosorbent assay. Further, we manipulated HER2 signaling with 100 ng/mL MAbHu HER2 (Herceptin; Genentech, San Francisco, Calif) and Heregulin beta1 (100 ng/mL; R&D Systems, Inc, Minneapolis, Minn) to test for HER2 regulation of Ang-2 production. RESULTS: Three of 4 breast cancer cell lines expressed HER2 protein and Ang-2 mRNA. HER cells, a stably transfected cell line that overexpresses HER2 6-fold, showed a 430% increase in Ang-2 mRNA compared to parental MCF-7 cells. Heregulin beta1 stimulation of HER2 signaling in MCF-7 cells increased Ang-2 by 20% (P <.05). HER2 signaling blockade with 100 ng/mL Herceptin reduced Ang-2 mRNA 90% (P <.001). Five of 11 cancers expressed both HER2 and Ang-2; 2 cancers expressed only Ang-2. CONCLUSIONS: We conclude that human breast cancers express Ang-2. HER2 signaling appears to regulate Ang-2 expression, although other signaling pathways may also regulate Ang-2. Ang-2 may be a therapeutic target in these cancers and may define which patients would benefit from Herceptin therapy.
The platinum agents: a role in breast cancer treatment?
Metastatic breast cancer is a partially chemotherapy-sensitive neoplasm. Most chemotherapy groups have activity in this disease, and the most active single drugs are the taxanes, especially docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ), and the anthracyclines. The alkylating agents, antimetabolites, and vinca alkaloids are also widely used. The platinum coordination complexes, which are widely used in oncology, are also active in metastatic breast cancer, but the availability of other drugs that are less toxic and easier to administer has resulted in their having a strictly limited use in this setting. Cisplatin appears to be somewhat more active than carboplatin, but direct comparative studies are lacking. The identification of the prominent activity of the taxanes has led to the investigation of wholly novel non-anthracycline-containing combination regimens, and platinum/taxane doublets appear to be particularly active. More recently, reports that trastuzumab (Herceptin, Genentech, South San Francisco, CA), a novel monoclonal antibody directed against the protein product of the HER2/(neu) oncogene, has a powerful synergistic interaction with docetaxel and with platinum agents have prompted evaluation of the triplet docetaxel/platinum/trastuzumab in the therapy of metastatic breast cancer.
Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials.
The discovery of the HER2/neu proto-oncogene and its role in the pathogenesis of breast cancer tumors, and the development of the anti-HER2 monoclonal antibody, trastuzumab (Herceptin; Genentech, South San Francisco, CA), directed against the HER2 receptor represent major milestones in the research developments in breast cancer, making trastuzumab the first monoclonal antibody available for treatment of this disease. Clinical trials in HER2-positive patients have demonstrated that the combined use of targeted therapy with trastuzumab in conjunction with cytotoxic chemotherapy is associated with improved time to disease progression and overall survival. Unfortunately, findings also demonstrate an increased risk for cardiotoxicity when trastuzumab is combined with anthracyclines. For HER2/neu-overexpressing breast cancer patients, the adjuvant use of trastuzumab will become paramount; therefore, it must be evaluated in a randomized controlled trial. There is disagreement regarding the design of such a trial, largely because of the ubiquitous use of anthracyclines in the adjuvant setting and the opposing necessity of avoiding anthracycline plus trastuzumab combinations. Combination index values for various chemotherapeutic drugs in combination with trastuzumab demonstrate dramatic synergistic interactions with the platinum agents and with docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ). The greatest level of synergy has been demonstrated with the triple-drug combination of docetaxel, platinum, and trastuzumab in which synergy is demonstrated, even at low doses. The adjuvant trial design for the Breast Cancer International Research Group uses a control arm of doxorubicin/cyclophosphamide for four cycles followed by docetaxel for four cycles and the second arm contains the addition of trastuzumab to the taxane sequence. The third arm, a non-anthracycline-containing regimen, contains docetaxel, a platinum agent (either cisplatin or carboplatin), and trastuzumab. The rationale for the selection of this three-drug regimen is based on the biology of the system and preclinical and clinical findings that demonstrate a high potential for clinical synergy.