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)

Rapid sequential delivery of doxorubicin 75 mg/m2 q 2 weeksx3 cycles followed by docetaxel 100 mg/m2 q 2 weeksx3 cycles, with filgrastim support was evaluated in patients with inoperable and large operable breast cancers who were not initially candidates for breast conservation therapy. Postoperative CMF chemotherapy and/or radiation were administered based on surgical findings. Median age of the 39 enrolled patients was 47 (range 27-59), stage IIA (6 patients), IIB (14 patients), IIIA (10 patients), IIIB (9 patients), and 23 patients (59%) had clinical nodal involvement. The average bidimensional tumor size before treatment was 30 cm2. Clinical responses included 13 (33%) complete responses, 23 (59%) partial responses, 1 stable disease, and 2 progressive disease, for an overall response rate of 92%. Clinical response rate was 11/13(85%) in HER2/neu positive patients compared to 25/26 (96%) in tumors that did not express HER2/neu. Twenty patients (51%) underwent breast conservation surgery. Pathologic tumor response at the time of definitive surgery included 4 pathologic CR (pCR, 10%), 4 microscopic invasion (pINV), and 14 (36%) pathologically negative axillary nodes. pCR was not observed in any HER2/neu positive patients. 5/39 patients were unable to complete all cycles of docetaxel and 8 patients required dose reduction of docetaxel due to development of grade 3-4 mucositis and hand-foot syndrome. This observation prompted a protocol change requiring 3 weeks between doxorubicin and docetaxel. Primary chemotherapy with dose-dense doxorubicin and docetaxel given sequentially is well tolerated and allows a high rate of breast sparing in patients with large breast cancers.
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PMID:Phase II study of dose-dense sequential doxorubicin and docetaxel for patients with advanced operable and inoperable breast cancer. 1634 15

Renal cell cancer (RCC) is a relatively uncommon malignancy, with 51,190 cases expected to be diagnosed in 2007. Localized disease is curable by surgery; however, locally advanced or metastatic disease is not curable in most cases and, until recently, had a limited response to drug treatment. Historically, biologic response modifiers or immunomodulating agents were tested in clinical trials based on observations that some cases of RCC can spontaneously regress. High-dose aldesleukin is approved by the United States Food and Drug Administration as a treatment for advanced RCC; however, the drug is associated with a high frequency of severe adverse effects. Responses have been observed with low-dose aldesleukin and interferon alfa, but with little effect on overall survival. Sorafenib and sunitinib are novel therapies that target growth factor receptors known to be activated by the hypoxia-inducible factor and the Ras-Raf/MEK/ERK pathways. These pathways are important in the pathophysiology of RCC. Sorafenib and sunitinib have shown antitumor activity as first- and second-line therapy in patients with cytokine-refractory metastatic RCC who have clear-cell histology. Although complete responses are not common, both drugs promote disease stabilization and increase progression-free survival. This information suggests that disease stabilization may be an important determinant for response in RCC and possibly other cancers. Sorafenib and sunitinib are generally well tolerated and are considered first- and second-line treatment options for patients with advanced clear cell RCC. In addition, sorafenib and sunitinib have shown promising results in initial clinical trials evaluating antitumor activity in patients who are refractory to other antiangiogenic therapy. The most common toxicities with both sorafenib and sunitinib are hand-foot syndrome, rash, fatigue, hypertension, and diarrhea. Research is directed toward defining the optimal use of these new agents.
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PMID:Sorafenib and sunitinib: novel targeted therapies for renal cell cancer. 1765 13

Sorafenib (BAY 43-9006) is a novel oral bis-aryl urea compound originally developed as an inhibitor to RAF kinase for its anti-proliferative property. It also inhibits receptor tyrosine kinases of multiple pro-angiogenic factors such as VEGFR-2/3, Flt-3/ and PDGFR-beta. The combination of both its anti-proliferative and anti-angiogenic properties makes sorafenib an attractive agent in cancer treatment. Phase I studies demonstrated that sorafenib was well tolerated, and the recommended phase II dose was 400 mg twice daily continuously. Common toxicities included skin toxicity (rash and hand-foot syndrome), gastrointestinal toxicities (nausea and diarrhea) and fatigue. Anti-tumor activities were observed in multiple tumors types including renal cell carcinoma and hepatocellular carcinoma. Randomized phase III studies in these tumor types are ongoing, and results are eagerly waited.
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PMID:Sorafenib (BAY 43-9006): review of clinical development. 1866 47

Sorafenib (Nexavar) is a targeted therapy acting as VEGFR and PDGFR tyrosine-kinase inhibitor that has been approved in France in the treatment of metastatic renal cell carcinoma and hepatocarcinoma. Hand-foot syndrome is one of the more frequent toxicity related to sorafenib. This paper up lights the main points concerning this toxicity in the view of specialists working together in the care of these patients: a pharmacologist, a dermatologist and a medical oncologist. The clinic and symptoms of hand-foot syndrome as the biological interpretation, the symptomatic treatment and the impact on the specific treatment of sorafenib are developed.
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PMID:[Hand-foot syndrome and sorafenib]. 1925 26

Among the many chemotherapeutic options for metastatic colorectal cancer, none has shown clear superiority in efficacy. All pharmacologic agents in current use have been associated with adverse events. Frequently reported adverse events associated with the chemotherapeutic agents oxaliplatin, irinotecan, 5-fluorouracil, and capecitabine include acute and chronic neuropathy, hypersensitivity reactions, diarrhea, neutropenia, and hand-foot syndrome. Although biologic agents are seemingly less toxic, toxic effects can also arise with their use; antiangiogenic agents result in hypertension, and EGFR inhibitors can cause severe hypersensitivity, paronychial infections, and more commonly, dermatologic rash. Furthermore, a correlation has been reported for the efficacy of anti-EGFR agents and development of rash. Data indicate that elderly patients with colorectal cancer who have adequate function and performance status, who may previously have been dissuaded from pursuing active therapy solely on the basis of age, should receive the same treatment as younger patients. To enhance the survival of patients with metastatic colorectal cancer, many therapies are administered. Recognition of treatment-emergent toxic effects will, therefore, aid the design and implementation of management strategies that minimize treatment interruption and/or discontinuation, and enhance quality of life for patients.
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PMID:Toxic effects and their management: daily clinical challenges in the treatment of colorectal cancer. 1933 27

Sunitinib is an oral oxindole multitargeted kinase inhibitor that inhibits certain receptor tyrosine kinases (RTKs). These include vascular endothelial growth factor receptors (VEGFR type 1 and 2), platelet-derived growth factor receptors (PDGFR-alpha and PDGFR-beta), stem cell factor receptor (KIT), FMS-like tyrosine kinase-3 (FLT3), glial cell-line derived neurotrophic factor receptor (RET) and the receptor of macrophage-colony stimulating factor (CSF1R). Examination of the antitumor effect of sunitinib in a variety of cell lines in vitro suggested an antiproliferative activity that is dependent on the presence of constitutively active RTK targets. The use of sunitinib as first-line therapy in advanced renal cell carcinoma (RCC) has improved the overall survival compared with that observed after cytokine therapy, while its administration in patients with gastrointestinal stromal tumors (GISTs) after progression or intolerance to imatinib achieved an objective response of 7%. Sunitinib is currently approved for the treatment of GISTs in this setting, and as first-line therapy for the treatment of advanced RCC. The relatively long half-life of sunitinib and its major metabolite allow for a once-daily dosing schedule. An interesting antitumor activity of sunitinib was reported in phase II studies of patients with a variety of malignancies, such as hepatocellular cancer, pancreatic neuroendocrine tumors, and non-small cell lung cancer; results of phase III studies are urgently anticipated. Fatigue is one of the most common adverse effects of sunitinib, as 50-70% of patients with advanced RCC and GIST complained of this adverse effect. Other adverse effects are diarrhea, anorexia, nausea and vomiting, oral changes and bleeding events. Most toxicities are reversible and should not result in discontinuation of sunitinib. If necessary, dose adjustments or interruptions should be made. Hypothyroidism has been described in the first 2 weeks of sunitinib therapy and its incidence increases progressively with the duration of therapy. Sunitinib may exert its hypertensive activity through a direct effect on the vasculature, while its most important cardiac adverse effect is left ventricular dysfunction. A variety of skin adverse effects have been described with the use of sunitinib such as hand-foot syndrome, yellow discoloration of the skin, dry skin, subungual splinter hemorrhages, acral erythema, and generalized skin rashes. Administration of sunitinib in the adjuvant and neoadjuvant setting of patients with RCC and of its combination with chemotherapy and other targeted therapies are currently under intense investigation.
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PMID:Sunitinib: a multitargeted receptor tyrosine kinase inhibitor in the era of molecular cancer therapies. 1989 79

Angiogenesis is essential for normal tissue and even more so for solid malignancies. At present, inhibition of tumor angiogenesis is a major focus of anticancer drug development. Bevacizumab, a humanized antibody against VEGF, was the first antiangiogenic agent to be approved for advanced non-small cell lung cancer, breast cancer and colorectal cancer. The most commonly observed adverse events are hypertension, proteinuria, bleeding and thrombosis. Sunitinib, a small molecule blocking intracellular VEGF, KIT, Flt3 and PDGF receptors, which regulate angiogenesis and cell growth, is approved for the treatment of advanced renal cell cancer (RCC) and malignant gastrointestinal stromal tumor. The most frequent adverse events include hand-foot syndrome, stomatitis, diarrhea, fatigue, hypothyroidism and hypertension. Sorafenib, an oral multikinase inhibitor, is approved for the second-line treatment of advanced RCC and upfront treatment of advanced hepatocellular carcinoma. Most common adverse events with sorafenib are dermatologic (hand-foot skin reaction, rash, desquamation), fatigue, diarrhea, nausea, hypothyroidism and hypertension. More recently, cardiovascular toxicity has increasingly been recognized as a potential adverse event associated with sunitinib and sorafenib treatment. Elderly patients are at increased risk of thromboembolic events when receiving bevacizumab, and potentially for cardiac dysfunction when receiving sunitinib or sorafenib. The safety of antiangiogenic drugs is of special concern when taking these agents for longer-term adjuvant or maintenance treatment. Furthermore, newer investigational antiangiogenic drugs are briefly reviewed.
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PMID:Antiangiogenic drugs in oncology: a focus on drug safety and the elderly - a mini-review. 1994 Apr 66

The purpose of this trial was to determine cardiac toxicity and overall efficacy of the pegylated liposome doxorubicin (PLD)-docetaxel couplet alone if HER2-negative metastatic breast cancer (internal control) or with trastuzumab if HER2-positive disease. Upon central HER2 confirmation, 84 eligible patients received induction with PLD (30 mg/m(2)) and docetaxel (60 mg/m(2)) every 3 weeks (maximum eight cycles), alone if HER2-negative (arm A; N = 38) or plus trastuzumab (4 mg/kg once, then 2 mg/kg weekly) if HER2-positive disease (arm B; N = 46) as first-line therapy. Maintenance therapy (without PLD) allowed. Primary objectives were to determine whether congestive heart failure (CHF) rate >3% and the efficacy/toxicity of each arm. CHF rate was <3% in each arm. Response rate, median progression-free-, and overall survival in arms A and B were 47.4 and 45.7%, 11 and 10.6 months, and 24.6 and 31.8 months, respectively. Trastuzumab arm was associated with higher rates of hand foot syndrome (grade 3: 22 vs. 38%; P = 0.16; overall 51 vs. 75%, P = 0.03) and treatment discontinuation due to toxicity/patient withdrawal (13 vs. 28%; P = 0.11). Febrile neutropenia occurred in approximately 10% of patients. In conclusion, concurrent administration of trastuzumab with PLD-docetaxel was not associated with higher risk of cardiac toxicity compared with PLD-docetaxel alone, but led to excessive hand-foot syndrome.
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PMID:Phase II trial of pegylated liposomal doxorubicin plus docetaxel with and without trastuzumab in metastatic breast cancer: Eastern Cooperative Oncology Group trial E3198. 2033 45

Targeting angiogenesis in glioblastoma (GBM) may improve patient outcome by normalizing tumor vasculature and improving delivery of chemotherapeutics and oxygen. Consequently, concomitant administration of small molecule inhibitors of the VEGF pathway will likely have a positive impact on chemoradiation treatment outcome. We conducted a Phase I study of vatalanib, a small molecule inhibitor of VEGFR, PDGFR, and c-kit in patients with newly diagnosed GBM receiving radiation, temozolomide, and an enzyme-inducing anti-epileptic drug in order to determine the MTD of vatalanib in this patient population. We incorporated circulating biomarker and SNP analyses and pharmacokinetic studies. Nineteen patients were enrolled and the MTD was not reached at the time of study termination. Vatalanib was well tolerated with only 2 DLTs (thrombocytopenia and elevated transaminases). Other grade 3/4 toxicities included leukopenia, lymphopenia, neutropenia, and hand-foot syndrome. There were no wound-healing complications. Of the 13 patients evaluable for a radiographic response, 2 had a partial response and 9 had stable disease. Vatalanib significantly increased PlGF and sVEGFR1 in plasma circulation and decreased sVEGFR2 and sTie2. Plasma collagen IV increased significantly by day 50 of treatment. Vatalanib was well tolerated and this study demonstrates the safety of oral small molecule inhibitors in newly diagnosed GBM patients. Blood biomarkers may be useful as pharmacodynamic markers of response to anti-angiogenic therapies.
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PMID:Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomide. 2082 42

BACKGROUND: The oral formulation of vinorelbine together with capecitabine allows for an all-oral combination chemotherapy which promises to raise quality of life of patients with advanced breast cancer. PATIENTS AND METHODS: Patients with HER2-negative, locally advanced, inoperable or metastatic breast cancer were included in this prospective observational trial (treatment schedule: capecitabine 500 mg/m2 twice daily, days 1-14; vinorelbine 60 mg/m2, days 1+8; repeated in 3-week cycles). RESULTS: All 32 patients (median age 50 years) were evaluable for toxicity, and 30 patients for response. Twentyfour patients received therapy as first-line treatment, and 8 patients as beyond first-line treatment. Median time to progression was 8 months, and median overall survival was 32 months. Complete response was observed in 1 patient (3%), partial response in 10 patients (33%), and disease stabilization for more than 6 months (SD > 6) in 10 patients (33%). This results in an overall response rate (ORR) of 37% and a clinical benefit rate (ORR + SD > 6) of 70%. The only grade 3/4 toxicities were neutropenia (19%) and hand-foot syndrome (9%). CONCLUSIONS: The all-oral combination of capecitabine/vinorelbine at this schedule appears to be an effective, well-tolerated regimen for treatment of advanced breast cancer, and offers a promising alternative to single-agent capecitabine and vinorelbine as well as intravenous polychemotherapy.
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PMID:Capecitabine and Vinorelbine as an All-Oral Chemotherapy in HER2-Negative Locally Advanced and Metastatic Breast Cancer. 2104 30


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