Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amplification of the human epidermal growth factor receptor 2 protein (HER2) in primary breast carcinomas has been shown to correlate with poor clinical prognosis for certain patients. Trastuzumab (Herceptin, Genentech, Inc., South San Francisco, California) is a highly purified recombinant DNA-derived humanized monoclonal immunoglobulin G1 kappa antibody that binds with high affinity and specificity to the extracellular domain of the HER2 receptor. In vitro and in vivo preclinical studies have shown that administration of trastuzumab alone or in combination with paclitaxel or carboplatin significantly inhibits the growth of breast tumor-derived cell lines that overexpress the HER2 gene product. At therapeutic doses in breast cancer patients, the mean half-life of trastuzumab is 5.8 days. Trastuzumab serum concentrations reach steady state with mean trough and peak concentrations of 79 microg/mL and 123 microg/mL, respectively. In a 222-patient, single-arm clinical study, treatment with a loading dose of trastuzumab 4 mg/kg administered IV followed by weekly IV doses of 2 mg/kg produced an overall response rate of 14% (2% complete remission and 12% partial remission). The beneficial effects were greatest in patients with the greatest degree (3+) of HER2 protein overexpression. In another clinical study, 469 women with metastatic breast carcinoma were randomized to a paclitaxel or anthracycline-plus-cyclophosphamide regimen with or without trastuzumab. The overall response rate was significantly greater in the trastuzumab-plus-chemotherapy group than in the chemotherapy-alone cohort. The magnitude of observed effects was greatest with pacli taxel plus trastuzumab. The most common adverse effects attributed to trastuzumab in clinical studies were fever and chills, pain, asthenia, nausea, vomiting, increased cough, diarrhea, headache, dyspnea, infection, rhinitis, and insomnia. Trastuzumab in combination with chemotherapy can lead to cardiotoxicity, leukopenia, anemia, diarrhea, abdominal pain, and infection. Trastuzumab has been approved by the US Food and Drug Administration as a single agent for the treatment of patients who have metastatic breast cancer involving overexpression of the HER2 protein and who have received 1 or more chemotherapy regimens; in combination with paclitaxel, it has been approved for the treatment of such patients who have not received chemotherapy.
 ...
PMID:Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer. 1021 34

Gefitinib is a low-molecular-weight epidermal growth factor receptor tyrosine kinase inhibitor. To date, gefitinib has been administered to over 65,000 people worldwide. The most commonly reported adverse events were diarrhea, acne-like skin rash, nausea, vomiting and asthenia. Most of them were transient and mild in severity. Interstitial lung disease in patients who have been treated with gefitinib is uncommon and has recently been described with an estimated incidence rate of around 1%. We present here a case of fatal drug-induced pulmonary toxicity after therapy with gefitinib for metastatic non-small cell lung cancer. The patient had been treated with gemcitabine and cisplatin, and developed drug-induced hemolytic-uremic syndrome 6 months before gefitinib use.
 ...
PMID:Fatal pulmonary toxicity in a patient treated with gefitinib for non-small cell lung cancer after previous hemolytic-uremic syndrome due to gemcitabine. 1450 91

Cetuximab is a chimeric monoclonal antibody highly selective for the epidermal growth factor receptor (EGFR), which is over-expressed by 25-80% of colorectal cancer tumours and associated with advanced disease. Cetuximab induces a broad range of cellular responses in tumours expressing EGFR, enhancing sensitivity to radiotherapy and chemotherapeutic agents. In a large, randomised, open-label, multicentre study in adult patients with irinotecan-refractory, metastatic colorectal cancer expressing EGFR, cetuximab 400 mg/m2 initial dose followed by 250 mg/m2 weekly plus irinotecan (various doses) produced a greater rate of partial response and disease control (partial response plus stable disease), and increased time to disease progression, compared with cetuximab monotherapy; survival was similar in both groups. The same dosage of cetuximab combined with irinotecan, fluorouracil and folinic acid (various regimens) produced partial responses in 43-58% of patients, a complete response in 5% of patients (one study only) and stable disease in 32-52% of patients with treatment-naive metastatic colorectal cancer expressing EGFR in three small, open-label trials. The most common grade 3/4 adverse events associated with cetuximab monotherapy were acne-like rash, asthenia, abdominal pain and nausea/vomiting. In patients receiving cetuximab plus irinotecan, these were diarrhoea, asthenia, leucopenia and neutropenia.
 ...
PMID:Cetuximab: in the treatment of metastatic colorectal cancer. 1472 61

Colorectal cancers (CRC) express the epidermal growth factor receptor (EGF-R), a type I transmembrane receptor with tyrosine kinase activity. EGF-R signaling inhibition is a promising target for cancer therapy. ZD1839 (Iressa, AstraZeneca) and OSI-774 (Tarceva, Roche) are small molecular weight molecules with selective and reversible tyrosine kinase inhibition properties directed to EGF-R. Orally administered, these molecules induce sustained tumor stabilizations in previously treated metastatic CRC patients. The most frequent treatment-related toxicities are fatigue, diarrhea and acne-like follicular rash. The addition in the clinic of 5-FU, lOHP or CPT-11 to ZD1839 or OSI-774 does not seem to increase the own toxicity of each cytotoxic agents. Cetuximab (Erbitux, Merck) is an intravenously administered humanized monoclonal antibody which bind with high affinity with the extracellular domain of the EGF-R. The most frequent treatment-related toxicities are diarrhea, fatigue, nausea and cutaneous toxicity (allergic or acne-like follicular rashes, folliculitis). Most, if not all of these adverse events are mild. Partial responses were observed with cetuximab either alone (RR: 10%) or in combination with CPT-11 (RR: 22%) in patients with CPT-11 refractory advanced CRC which expressed EGF-R. The combination of cetuximab to folinic acid, 5-FU and CPT-11 seems tolerable at the cost of a slight increase of severe diarrhea and neutropenia. Finally, the promising activity of these EGF-R inhibitors has to be confirmed throughout randomized studies.
 ...
PMID:[Inhibitors of epidermal growth factor receptor and colorectal cancer]. 1476 44

On May 5, 2003, gefitinib (Iressa; ZD1839) 250-mg tablets (AstraZeneca Inc.) received accelerated approval by the United States Food and Drug Administration as monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes chemistry manufacturing and controls, clinical pharmacology, and clinical trial efficacy and safety results. Gefitinib is an anilinoquinazoline compound with the chemical name 4-quinazolinamine,N-(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. It has the molecular formula C(22)H(24)ClFN(4)O(3). Gefitinib is often referred to as a "specific" or "selective" inhibitor of epidermal growth factor receptor. Studies demonstrate, however, that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal. Maximum plasma concentrations resulting from clinically relevant doses are 0.5-1 microM or more, well within the IC(50) values of several tyrosine kinases. No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed throughout the body. Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces, with <4% of the dose in the urine. After daily oral administration, steady-state plasma levels are reached in 10 days and are 2-fold higher than those achieved after single doses. Gefitinib effectiveness was demonstrated in a randomized, double-blind, Phase II, multicenter trial comparing two oral doses of gefitinib (250 versus 500 mg/day). A total of 216 patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving 250 mg/day gefitinib and in 8% (6 of 76) of patients receiving 500 mg/day gefitinib. The overall objective response rate (RR) for both doses combined was 10.6% (15 of 142 patients; 95% confidence interval, 6.0-16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6-18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV non-small cell lung cancer patients. Patients were randomized to receive gefitinib (250 or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n = 1093) or carboplatin plus paclitaxel (n = 1037). Results from this study showed no benefit (RR, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Interstitial lung disease has been observed in patients receiving gefitinib. Worldwide, the incidence of interstitial lung disease was about 1% (2% in the Japanese post-marketing experience and about 0.3% in a United States expanded access program). Approximately one-third of the cases have been fatal. Gefitinib was approved under accelerated approval regulations on the basis of a surrogate end point, RR. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or increased survival. Accelerated approval regulations require the sponsor to conduct additional studies to verify that gefitinib therapy produces such benefit.
 ...
PMID:United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets. 1497 17

Cannabinoids, the active components of marijuana and their endogenous counterparts were reported as useful analgetic agents to accompany primary cancer treatment by preventing nausea, vomiting, and pain and by stimulating appetite. Moreover, they have been shown to inhibit cell growth and to induce apoptosis in tumor cells. Here, we demonstrate that anandamide, Delta(9)-tetrahydrocannabinol (THC), HU-210, and Win55,212-2 promote mitogenic kinase signaling in cancer cells. Treatment of the glioblastoma cell line U373-MG and the lung carcinoma cell line NCI-H292 with nanomolar concentrations of THC led to accelerated cell proliferation that was completely dependent on metalloprotease and epidermal growth factor receptor (EGFR) activity. EGFR signal transactivation was identified as the mechanistic link between cannabinoid receptors and the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 as well as prosurvival protein kinase B (Akt/PKB) signaling. Depending on the cellular context, signal cross-communication was mediated by shedding of proAmphiregulin (proAR) and/or proHeparin-binding epidermal growth factor-like growth factor (proHB-EGF) by tumor necrosis factor alpha converting enzyme (TACE/ADAM17). Taken together, our data show that concentrations of THC comparable with those detected in the serum of patients after THC administration accelerate proliferation of cancer cells instead of apoptosis and thereby contribute to cancer progression in patients.
 ...
PMID:Cannabinoids induce cancer cell proliferation via tumor necrosis factor alpha-converting enzyme (TACE/ADAM17)-mediated transactivation of the epidermal growth factor receptor. 1502 28

There is an urgent need for new therapies to treat non-small cell lung cancer (NSCLC) because current chemotherapy regimens are of limited effectiveness. The role of vascular endothelial growth factor in promoting tumor angiogenesis, in maintaining existing vasculature, and in resistance to traditional therapies, together with its negative prognostic significance in NSCLC, make it an appropriate target for therapy. Bevacizumab (Avastin), a monoclonal antibody directed against vascular endothelial growth factor, has shown promise in treating a number of different cancers. In a recent Phase II trial in patients with advanced metastatic NSCLC, the addition of bevacizumab to standard carboplatin/paclitaxel chemotherapy significantly increased the time to progression and increased the response rate when compared with chemotherapy alone. This was particularly impressive in the subset of patients with non-squamous histology. Bevacizumab is generally well tolerated and did not appear to increase the incidence or severity of nausea/vomiting, neuropathy and renal toxicity, which are typically associated with carboplatin/paclitaxel chemotherapy. Adverse events in Phase I and II studies included hypertension, thrombosis, proteinuria (with occasional nephrotic syndrome), and epistaxis. Serious tumor-related bleeding episodes (hemoptysis/hematemesis) seem to be the main safety concern in patients with NSCLC, with squamous cell histology as a possible risk factor. Present ongoing studies are under way in NSCLC including (a) a Phase II neo-adjuvant study in combination with paclitaxel and carboplatin in patients with stage IB-IIA NSCLC; (b) a Phase I/II study of bevacizumab in combination with the epidermal growth factor receptor tyrosine kinase inhibitor agent, Tarceva, in patients with previously treated NSCLC; and (c) an Eastern Cooperative Group randomized Phase III study of paclitaxel and carboplatin with/without bevacizumab in patients with previously untreated IIIB (malignant pleural effusion) or metastatic NSCLC. These studies will help to establish the role of bevacizumab in NSCLC.
 ...
PMID:Anti-vascular endothelial growth factor monoclonals in non-small cell lung cancer. 1521 70

Cytotoxic chemotherapy treatment options for patients with non-small-cell lung cancer (NSCLC) have limited efficacy and are often associated with significant toxicity. Therefore, there is an unmet need for novel drugs that are not only effective in treating this disease but are also well tolerated. Gefitinib is an orally active epidermal growth factor receptor tyrosine kinase inhibitor that blocks the signal transduction pathways implicated in cancer cell growth and survival. It has recently been approved for the treatment of advanced/refractory NSCLC. This review presents the tolerability data from phase I and II gefitinib monotherapy trials, along with data from the worldwide 'Expanded Access Programme' and post-marketing use of gefitinib. Gefitinib was found to be generally well tolerated at the approved dosage of 250 mg/day; the most commonly reported adverse drug reactions (ADRs) were mild to moderate skin rash and diarrhoea, which were manageable and non-cumulative. Other ADRs observed with the use of gefitinib included: dry skin, pruritus, acne, nausea, vomiting, anorexia, asthenia and asymptomatic elevations in liver transaminase levels. Well recognised adverse effects seen with cytotoxic chemotherapy (such as bone marrow depression, neurotoxicity and nephrotoxicity) were not observed. Although the frequency and severity of ADRs increased with the dosage across the range studied (50-1000 mg/day), few patients required dosage reductions or the withdrawal of treatment, and those who did usually received gefitinib >or=600 mg/day.Thus, the available data indicate that gefitinib is well tolerated in patients with a range of solid tumours, including locally advanced or metastatic NSCLC.
 ...
PMID:Overview of the tolerability of gefitinib (IRESSA) monotherapy : clinical experience in non-small-cell lung cancer. 1555 44

Despite improvements in conventional treatment, patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis, leaving a significant unmet need for novel treatments. One such novel, biologically targeted agent is the orally active epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. This open-label pilot trial investigated the safety, pharmacokinetics, and efficacy of 2 doses of gefitinib (250 and 500 mg per day) combined with docetaxel (75 mg/m2) in patients with locally advanced or metastatic NSCLC as first- and second-line chemotherapy. Eighteen patients were recruited: 6 received gefitinib 250 mg per day plus docetaxel; 12 received gefitinib 500 mg per day plus docetaxel. Combination therapy was feasible with no overlapping toxicities. No patients experienced dose-limiting toxicities (DLTs) at 250 mg per day; 1 patient had 2 DLT events at 500 mg per day (grade 3 rash and diarrhea for >4 days). Adverse events were mild to moderate, including fatigue, mucositis, nausea, anorexia, rash, diarrhea, and fever. Docetaxel did not appear to alter steady-state exposure to gefitinib. The effect of gefitinib on exposure to docetaxel was equivocal; with the exception of 2 patients in the gefitinib 250 mg per day dose group, there appeared to be no trend toward a higher or lower exposure to docetaxel when given in the presence of gefitinib compared with that when given alone. Combination therapy was associated with antitumor activity and responses were seen with gefitinib in 2 of 6 patients at 250 mg per day and 4 of 12 patients at 500 mg per day. This combination is feasible and has an acceptable and predictable safety profile, as well as associated antitumor activity.
 ...
PMID:A pilot trial of gefitinib in combination with docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer. 1594 94

This phase I trial investigates the safety of combining radiation, 5-fluorouracil (5-FU) and cisplatin with the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, in patients with esophageal carcinoma. From April 2000 to January 2005, 11 patients with squamous or adenocarcinoma of the esophagus were enrolled. Patients received either 50, 100 or 150 mg oral erlotinib/day beginning on the first day of radiation (three patients in each dose cohort). Concurrent cisplatin (75 mg/m2 i.v., days 8 and 36) and 5-FU (1000 mg/m2 i.v., days 8-11 and 36-39) were also given with 50.4 Gy thoracic radiation, delivered at 180 cGy/day, 5 days/week. Toxicity was evaluated using the National Cancer Institute Common Toxicity Criteria (version 3.0). Erlotinib with concurrent 5-FU, cisplatin and thoracic radiation was well-tolerated at 50, 100 and 150 mg/day. The major toxicities were diarrhea (grade 1=18%, grade 2=18%), skin rash (grade 4=54.5%), nausea (grade 1=18%, grade 2=54%, grade 3=9%) and dehydration (grade 3=27%). All patients experienced esophagitis during treatment (grade 1=55%, grade 2=32%, grade 3=9%, grade 4=9%). Two patients were discontinued from the study secondary to non-erlotinib-related toxicities. We conclude that the phase I study demonstrates the safety and tolerability of erlotinib delivered at 150 mg/day with concurrent 5-FU, cisplatin and thoracic radiation. The major toxicities encountered were grade 1-2 diarrhea, grade 1 skin rash, grade 1-3 nausea and grade 3 dehydration. A phase II study is planned.
 ...
PMID:Epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, and concurrent 5-fluorouracil, cisplatin and radiotherapy for patients with esophageal cancer: a phase I study. 1631 96


1 2 3 4 5 6 7 Next >>