Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several recent publications have re-opened the question of whether HER2 status should be determined for all patients with newly diagnosed breast cancer. The barrier in the past to the use of HER2 has been the nonstandardization of HER2 status determination, which is the major caveat to its use today. Two test kits have been recently approved by the Food and Drug Administration for HER2 testing, one for determining HER2 amplification by fluorescence in situ hybridization and the other for measuring HER2 overexpression by immunohistochemistry. Neither of these tests, nor any of the other myriad tests used for HER2 determinations, has been validated in all the potential arenas for the use of HER2: refinement of estimates of prognosis of untreated low-risk patients, selection among treatment options for adjuvant therapy, and selection of patients for treatment with trastuzumab (Herceptin; Genentech, San Francisco, CA). The nonstandardization of testing has led to conflicting results and controversy as to the value of HER2 in evaluating breast cancer patient prognosis and the selection among therapeutic options. Thus, testing for HER2 is not yet routine for patients with newly diagnosed breast cancer, although it is of value for patients who develop metastatic disease and who need to know if they are candidates for trastuzumab.
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PMID:Should HER2 status be routinely measured for all breast cancer patients? 1048 3

Treatment of advanced breast cancer with autologous stem cell transplantation is limited by a high probability of disease relapse. In clinical trials, interleukin 2 (IL-2) alone can expand natural killer (NK) cells in vivo and increase their cytotoxic activity against breast cancer cell lines, but this increase is modest. Understanding the mechanisms that mediate NK cell lysis of breast cancer targets may lead to improvements of current immunotherapy strategies. NK cells from normal donors or patients receiving subcutaneous IL-2 were tested in cytotoxicity assays against five breast cancer cell lines. The role of adhesion molecules and antibodies that interact through Fc receptors on NK cells was explored. NK cell lysis of breast cancer targets is variable and is partially dependent on recognition through ICAM-1 and CD18. While blocking CD2 slightly decreased cytotoxicity, contrary to expectations, an antibody against CD58 (the ligand for CD2), failed to block killing and instead mediated an increased cytotoxicity that correlated with target density of CD58. The CD58 antibody-enhanced killing was dependent not only on FcRgammaIII but also on CD2 and ICAM-1/CD18. To further elucidate the mechanism of this CD58 antibody-dependent cellular cytotoxicity (ADCC), another antibody was tested. Trastuzumab (Herceptin), a humanized antibody against HER2/neu, mediated potent ADCC against all the HER2/neu positive breast cancer targets. Unlike CD58 antibody-mediated ADCC, Herceptin ADCC was minimally affected by blocking antibodies to CD2 or ICAM-1/CD18, which suggests a different mechanism of action. This study shows that multiple mechanisms are involved in NK cell lysis of breast cancer targets, that none of the targets are inherently resistant to killing, and that two distinct mechanisms of ADCC can target immunotherapy to breast cancer cells.
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PMID:Natural killer cell cytotoxicity of breast cancer targets is enhanced by two distinct mechanisms of antibody-dependent cellular cytotoxicity against LFA-3 and HER2/neu. 1051 95

Monoclonal antibody therapy is beginning to realize its promise. Efficacy has been seen in clinical trials using antibodies that target tumor cell surface antigens such as B-cell idiotypes, CD20 on malignant B cells, CD33 on leukemic blasts, and HER2/neu on breast cancer. Unconjugated immunoglobulins directed against CD20 induce partial and complete responses in up to 50% of patients with advanced, indolent non-Hodgkin's lymphoma. When such antibodies are conjugated to radionuclides, complete and overall response rates increase. Conjugates composed of anti-CD33 antibodies and the chemotherapy agent, calicheamicin, show promising activity in patients with relapsed or refractory acute myelogenous leukemia Treatment of patients with advanced breast cancer using the anti-HER2/neu antibody, trastuzumab (Herceptin; Genentech, San Francisco, CA) leads to objective responses in some patients with overexpression of the HER2/neu oncoprotein. These exciting results provide a basis for further refinement of the existing approaches to develop new antibody-based cancer therapy strategies.
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PMID:Monoclonal antibody therapy of cancer. 1056 Oct 17

Single agent antitumor activity of Herceptin, a humanized monoclonal antibody directed against HER2, has been demonstrated in numerous preclinical and clinical studies. Additionally, combination therapy with Herceptin and chemotherapy (CRx) has demonstrated additive antitumor activity in both preclinical models and early clinical trials. STEALTH (pegylated) liposomal (PL) cisplatin, also known as SPI-077, is currently in clinical trials for a variety of solid tumors. The three studies reported here discuss the antitumor activity of the combination of Herceptin and nonliposomal cisplatin or PL-cisplatin in two xenograft tumor models, initiated from the cell lines, BT474 and MDA453, that overexpress the oncogene, HER2. Herceptin alone had significant antitumor activity in all three experiments (p < 0.0001). Nonliposomal cisplatin and PL-cisplatin were both effective antitumor agents but, at tolerable dose levels, PL-cisplatin was superior to nonliposomal cisplatin (p < 0.0003). The effect of combining Herceptin with the chemotherapeutic cisplatin or PL-cisplatin, was most significant at moderate doses of H (0.5 mg/kg, p < 0.0001), but tended to be greater than either agent alone in all experiments. The combination of PL-cisplatin with Herceptin had statistically similar antitumor activity to that of nonliposomal cisplatin with Herceptin in all experiments. We conclude that combination therapy with PL-cisplatin and Herceptin results in significant antitumor activity with the potential for reducing toxicity in metastatic breast cancer patients.
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PMID:Antitumor activity of Herceptin in combination with STEALTH liposomal cisplatin or nonliposomal cisplatin in a HER2 positive human breast cancer model. 1062 63

Monoclonal antibodies specific for the p185HER2/neu growth factor receptor represent a significant advance in receptor-based therapy for p185HER2/neu-expressing human cancers. We have used a structure-based approach to develop a small (1.5 kDa) exocyclic anti-HER2/neu peptide mimic (AHNP) functionally similar to an anti-p185HER2/neu monoclonal antibody, 4D5 (Herceptin). The AHNP mimetic specifically binds to p185HER2/neu with high affinity (KD=300 nM). This results in inhibition of proliferation of p185HER2/neu-overexpressing tumor cells, and inhibition of colony formation in vitro and growth of p185HER2/neu-expressing tumors in athymic mice. In addition, the mimetic sensitizes the tumor cells to apoptosis when used in conjunction with ionizing radiation or chemotherapeutic agents. A comparison of the molar quantities of the Herceptin antibody and the AHNP mimetic required for inhibiting cell growth and anchorage-independent growth showed generally similar activities. The structure-based derivation of the AHNP represents a novel strategy for the design of receptor-specific tumor therapies.
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PMID:Rationally designed anti-HER2/neu peptide mimetic disables P185HER2/neu tyrosine kinases in vitro and in vivo. 1065 27

Measurements of either HER2 gene overexpression or its gene-coded protein (p185) are clinically useful for predicting prognosis in breast cancer. The measurements are also useful for identifying metastatic breast cancer patients who may benefit from Herceptin treatment. Since fine needle aspiration (FNA) of the breast has become an increasingly popular technique for obtaining tissue specimens, we have developed a sensitive method to quantify p185 in the aspirate. For this procedure, p185 from the cell pellet of FNA is extracted with a buffer containing Triton X-100, and the p185 is measured with an enzyme immunoassay. Most of the malignant breast tumors (N=7) in this study were associated with elevated p185 concentrations (6/7, 319+/-222 U/mg), compared to the p185 concentrations in normal breast tissue (42.8+/-35 U/mg, N=47) or benign lesions (43.1+/-20.2 U/mg, N=22). Quantification of p185 in FNA may improve the assessment of breast cancer patients, revealing whether they are at high risk and may benefit from Herceptin treatment.
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PMID:Quantification of HER2 oncoprotein in fine-needle aspirates of the breast. 1067 83

With the successful clinical trials of the engineered antibody Herceptin (in advanced-stage breast cancer) and adriamycin-based chemotherapy regimens (in the adjuvant setting), the need to detect p185HER2 overexpression or associated amplification of the coding gene HER2 in breast cancer patients is escalating. Twenty to 30% of breast carcinomas have overexpression of p185HER2. This condition correlates with poor patient prognosis and predicts response to chemotherapy in lymph node-positive patients. In this study we compare quantitation of p185HER2 in breast cancer at the gene and protein levels using differential polymerase chain reaction (PCR) and immunohistochemistry, respectively. To assign HER2 gene copy numbers, a calibration curve was constructed using normal breast epithelia and breast carcinoma cell lines having known dosages of amplified HER2. We found corresponding molecular and immunohistochemical results in 85% of the 13 paraffin-embedded breast carcinoma cases examined. Two cases were found to have minimum gene amplification but marked p185HER2 overexpression, suggesting an alternative mechanism to overexpression such as transcriptional activation. Although the differential PCR assay exhibits saturation approaching 20 HER2 gene copies, this may not be clinically significant because the immunohistochemical assay also appears to saturate in this gene copy number range.
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PMID:p185HER2 overexpression in human breast cancer using molecular and immunohistochemical methods. 1080 69

In September 1998 Trastuzumab (Herceptin) became the second monoclonal antibody approved for the treatment of a malignant condition, and the first antibody approved for the treatment of a solid tumor. It is a mouse-human chimeric antibody that produces anti-tumor effects by blocking the HER2-neu receptor, and can also interact with human immune cells to effect antibody dependent cell-mediated cytotoxicity. Pivotal trials in breast cancer showed that it has activity as a single agent in a subset of patients whose tumors greatly over-express HER2, but results were even more impressive when it was used in combination with chemotherapy. It should also prove to be useful in the treatment of subsets of patients with other adenocarcinomas whose tumors over-express HER2.
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PMID:Perceptions of Herceptin: a monoclonal antibody for the treatment of breast cancer. 1085 Feb 81

Trastuzumab, a monoclonal antibody against the HER2 receptor, was recently approved for the treatment of metastatic breast cancer. However, 28% of patients receiving both an anthracycline and trastuzumab developed heart failure. Although HER2 overexpression has been associated with the development of cancer, HER2 receptors seem to be cardioprotective because they mediate the activation of important cardiac survival pathways. Because the morbidity and mortality of heart failure surpasses that of many cancers, prudent medical practice mandates that physicians learn more about the mechanisms of trastuzumab-induced cardiotoxicity and develop algorithms for assessing risk/benefit ratios before extending the use of this agent to patients with less invasive forms of breast cancer.
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PMID:Trastuzumab in the treatment of metastatic breast cancer : anticancer therapy versus cardiotoxicity. 1089 87

Herceptin (trastuzamab, Genentech, San Francisco, CA, USA) prolongs survival in metastatic breast cancer patients whose tumours overexpress the HER2/neu protein. Compared with chemotherapy alone, patients receiving chemotherapy and Herceptin have a significantly longer time to progression, a higher response rate and a longer duration of response. These effects are most marked in first-line treatment of metastatic disease. The addition of Herceptin is associated with few additional side-effects, apart from cardiac toxicity in patients concurrently receiving anthracyclines. As such, it seems reasonable for Herceptin to become considered as one of the routine treatment options in metastatic breast cancer. It would therefore be appropriate for HER2 status testing to be incorporated into the assessment of all patients with metastatic disease. The use of this medication will be limited by its cost. Furthermore, data are lacking on appropriate treatments durations in responders.
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PMID:Herceptin (trastuzamab) in advanced breast cancer. 1091 83


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