Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidermal growth factor receptor (EGFR) signaling inhibition by monoclonal antibodies and EGFR-specific tyrosine kinase inhibitors has shown clinical efficacy in cancer by restoring susceptibility of tumor cells to therapeutic apoptosis induction. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent with tumor-selective apoptotic activity. Here we present a novel approach that combines EGFR-signaling inhibition with target cell-restricted apoptosis induction using a TRAIL fusion protein with engineered specificity for EGFR. This fusion protein, scFv425:sTRAIL, comprises the EGFR-blocking antibody fragment scFv425 genetically fused to soluble TRAIL (sTRAIL). Treatment with scFv425:sTRAIL resulted in the specific accretion to the cell surface of EGFR-positive cells only. EGFR-specific binding rapidly induced a dephosphorylation of EGFR and down-stream mitogenic signaling, which was accompanied by cFLIP(L) down-regulation and Bad dephosphorylation. EGFR-specific binding converted soluble scFv425:sTRAIL into a membrane-bound form of TRAIL that cross-linked agonistic TRAIL receptors in a paracrine manner, resulting in potent apoptosis induction in a series of EGFR-positive tumor cell lines. Co-treatment of EGFR-positive tumor cells with the EGFR-tyrosine kinase inhibitor Iressa resulted in a potent synergistic pro-apoptotic effect, caused by the specific down-regulation of c-FLIP. Furthermore, in mixed culture experiments binding (L)of scFv425:sTRAIL to EGFR-positive target cells conveyed a potent apoptotic effect toward EGFR-negative bystander tumor cells. The favorable characteristics of scFv425:sTRAIL, alone and in combination with Iressa, as well as its potent anti-tumor bystander activity indicate its potential value for treatment of EGFR-expressing cancers.
 ...
PMID:Simultaneous inhibition of epidermal growth factor receptor (EGFR) signaling and enhanced activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis induction by an scFv:sTRAIL fusion protein with specificity for human EGFR. 1564 26

This is a retrospective analysis of 150 patients with advanced non-small cell lung cancer who had failed prior treatment or were unfit for chemotherapy and were treated with oral gefitinib ('Iressa', ZD1839; AstraZeneca) 250 mg/day. Thirty-two patients who received gefitinib for 3 weeks or less were not included in the analysis. For the remaining 118 evaluable patients, the mean age was 63.1 years; most patients had received prior chemotherapy (97.5%), Eastern Cooperative Oncology Group performance status scores 0-2 (97.4%) and stage IV disease (64.4%). The majority were symptomatic (84.6%). Disease control was observed in 30 patients (25.4%), of whom five had a partial response and 25 had stable disease; 18 (15.3%) were not evaluable. Median duration of treatment was 29.9 weeks in responding patients and 11.5 in patients with progressive disease (p<0.0001). Median overall survival was 7.3 months (15.2 months for disease control) and median progression-free survival was 3.2 months. Gefitinib was well tolerated, with grade 3/4 skin rash and diarrhea seen in 2.5 and 4.2% of patients, respectively. Clinical benefit was evaluated using questionnaires before and following treatment with gefitinib. In 82 patients with completed questionnaires, evaluation revealed symptom improvement in 40.1% and improvement in general feeling in 31.4%. Epidermal growth factor receptor (EGFR) analysis found that efficacy did not correlate with tumor EGFR overexpression. Therefore, in this retrospective analysis, gefitinib treatment provided disease control in 25% of patients who derived significant palliative benefit.
 ...
PMID:Treatment of non-small cell lung cancer with gefitinib ('Iressa', ZD1839): the Greek experience with a compassionate-use program. 1565 17

PURPOSE Evaluation of disease-related symptom improvement rate by the Lung Cancer Subscale (LCS) of the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire was a coprimary end point of the pivotal phase II trial of gefitinib (Iressa; AstraZeneca, Wilmington, DE) conducted in the United States. This report includes the results of analyses exploring the relationship between weekly LCS scores and radiographic response and survival, as well as detailed protocol-specified analysis of symptom and quality-of-life data. PATIENTS AND METHODS In this trial, 216 symptomatic patients with advanced non-small-cell lung cancer (NSCLC) who had at least two prior chemotherapy regimens received gefitinib 250 or 500 mg/d. Disease-related symptoms were assessed weekly and quality of life was assessed monthly by LCS and FACT-L, respectively. Results Symptom improvement was rapid and correlated with tumor response and survival. At the recommended gefitinib dose of 250 mg/d, median overall survival times were 13.6 and 4.6 months for patients with and without symptom improvement, respectively, and 9.7 months for patients with symptom improvement without tumor response. Among patients with stable disease or disease progression, those with symptom improvement had significantly better overall survival than those without improvement. At 250 mg/d, 30% of patients showed a quality-of-life improvement that was correlated with tumor response. CONCLUSION This triadic analysis of response, survival, and symptom data supports the hypothesis that tumor response and symptom response are related and that each predicts survival. Among these NSCLC patients treated with gefitinib, symptom improvement was complementary to and, for most patients, preceded evidence of radiographic regression.
 ...
PMID:Clinically meaningful improvement in symptoms and quality of life for patients with non-small-cell lung cancer receiving gefitinib in a randomized controlled trial. 1569 77

The change of therapeutic concepts in oncology in the last few years is demonstrated in many examples like: influence on cell surface receptors, signal transduction, inactivation of oncogenes, activation of tumor suppressor genes, induction of apoptosis and inhibition of degradation of intracellular peptides. Therapeutic targets have become more specific in the last years using the results of experimental laboratories for clinical application. Unfortunately, however, only very few oncologic ailments can be influenced substantially so far. This may be explained by the hypothesis that the mechanisms of tumor growth can fluctuate--adaptation of tumor cell growth to the Controlling molecular biologic pattern may thus be the concequence. Finally we have to admit that in spite of all our efforts our methodology is still not precise enough (well illustrated by the example of the effectivity of Gefitinib) to reach our therapeutic goal--constant inhibition of tumor growth.
 ...
PMID:[Impact of oncologic therapeutic concepts 2004]. 1573 50

This report highlights the case of a symptomatic 77-year-old non-smoking female patient who was diagnosed with advanced non-small-cell lung cancer (NSCLC), metastatic to the liver and contralateral lung. After tumor progression in the liver and lung following polychemotherapy, multiple diffuse brain and cerebellar metastases were apparent. Oral treatment with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa') 250 mg/day resulted in progressive and durable symptom relief, and improvements in quality of life and performance status. Reductions in the size of the primary pulmonary tumor and brain, cerebellar, and liver metastases were observed. Furthermore, gefitinib was well tolerated with an absence of adverse events. These results provide evidence that oral gefitinib is active in patients with advanced NSCLC and central nervous system metastases.
 ...
PMID:Gefitinib ('Iressa', ZD1839) is active against brain metastases in a 77 year old patient. 1573 17

Iressa (ZD1839, Gefitinib), used in clinics to treat non-small cell lung cancer patients, is a tyrosine kinase receptor inhibitor that leads to specific decoupling of epidermal growth factor receptor (EGFR) signaling. Recent data indicate that Iressa is especially effective in tumors with certain EGFR mutations; however, a subset of these tumors does not respond to Iressa. In addition, certain populations have an elevated risk of side effects during Iressa treatment. The human ABCG2 (BCRP/MXR/ABCP) transporter causes cancer drug resistance by actively extruding a variety of cytotoxic drugs, and it functions physiologically to protect our tissues from xenobiotics. Importantly, ABCG2 modifies absorption, distribution, and toxicity of several pharmacologic agents. Previously, we showed that ABCG2 displays a high-affinity interaction with several tyrosine kinase receptor inhibitors, including Iressa. Here, we show that the expression of ABCG2, but not its nonfunctional mutant, protects the EGFR signaling-dependent A431 tumor cells from death on exposure to Iressa. This protection is reversed by the ABCG2-specific inhibitor, Ko143. These data, reinforced with cell biology and biochemical experiments, strongly suggest that ABCG2 can actively pump Iressa. Therefore, variable expression and polymorphisms of ABCG2 may significantly modify the antitumor effect as well as the absorption and tissue distribution of Iressa.
 ...
PMID:Multidrug transporter ABCG2 prevents tumor cell death induced by the epidermal growth factor receptor inhibitor Iressa (ZD1839, Gefitinib). 1575 73

The epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor gefitinib (Iressa, ZD1839) has shown promising activity preclinically and clinically. Because comparative investigations of drug-resistant sublines with their parental cells are useful approaches to identifying the mechanism of gefitinib resistance and select factors that determine sensitivity to gefitinib, we established a human non-small cell lung carcinoma subline (PC-9/ZD) that is resistant to gefitinib. PC-9/ZD cells are approximately 180-fold more resistant to gefitinib than their parental PC-9 cells and PC-9/ZD cells do not exhibit cross-resistance to conventional anticancer agents or other tyrosine kinase inhibitors, except AG-1478, a specific inhibitor of EGFR. PC-9/ZD cells also display significant resistance to gefitinib in a tumor-bearing animal model. To elucidate the mechanism of resistance, we characterized PC-9/ZD cells. The basal level of EGFR in PC-9 and PC-9/ZD cells was comparable. A deletion mutation was identified within the kinase domain of EGFR in both PC-9 and PC-9/ZD, but no difference in the sequence of EGFR cDNA was detected in either cell line. Increased EGFR/HER2 (and EGFR/HER3) heterodimer formations were demonstrated in PC-9/ZD cells by chemical cross-linking and immunoprecipitation analysis in cells unexposed to gefitinib. Exposure to gefitinib increased heterodimer formation in PC-9 cells, but not in PC-9/ZD cells. Gefitinib inhibits EGFR autophosphorylation in a dose-dependent manner in PC-9 cells but not in PC-9/ZD cells. A marked difference in inhibition of site-specific phosphorylation of EGFR was observed at Tyr1068 compared to other tyrosine residues (Tyr845, 992 and 1045). To elucidate the downstream signaling in the PC9/ZD cellular machinery, complex formation between EGFR and its adaptor proteins GRB2, SOS, and Shc was examined. A marked reduction in the GRB2-EGFR complex and absence of SOS-EGFR were observed in PC-9/ZD cells, even though the protein levels of GRB2 and SOS in PC-9 and PC-9/ZD cells were comparable. Expression of phosphorylated AKT was increased in PC-9 cells and inhibited by 0.02 microM gefitinib. But the inhibition was not significant in PC-9/ZD cells. These results suggest that alterations of adaptor-protein-mediated signal transduction from EGFR to AKT is a possible mechanism of the resistance to gefitinib in PC-9/ZD cells. These phenotypes including EGFR-SOS complex and heterodimer formation of HER family members are potential biomarkers for predicting resistance to gefitinib.
 ...
PMID:Establishment of a human non-small cell lung cancer cell line resistant to gefitinib. 1576 68

This review highlights three examples of novel targeted therapeutics for solid tumors that are currently approved in Japan: 1) Trastuzumab (Herceptin) for patients with metastatic breast cancer that demonstrates overexpression of HER2/neu; 2) Imatinib mesylate (Glivec) for patients with gastrointestinal tumors, of which tumor cells express c-Kit; and 3) Gefitini (Iressa) for patients with advanced non-small cell lung cancers, which response to gefitinib is recently suggested to be associated with EGFR mutation. In these molecular targeted therapies, diagnostic tools to verify the presence of an appropriate molecular target is crucial to the success, and thus the methods and its interpretation are discussed in this review.
 ...
PMID:[Molecular diagnosis of solid tumors]. 1577 42

Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has a response rate of 10% to 20% in refractory non-small cell lung carcinoma. Although female gender, adenocarcinoma, and never having smoked are possible markers of a favorable response, mutations of the EGFR gene have also been reported to be highly significant predictors of response. Seventy patients with relapsed non-small cell lung carcinoma were enrolled in the Expanded Access Program. After the drug became available commercially, 28 more patients were treated with gefitinib. Response evaluations were feasible in 80 patients. Twenty-seven tumor specimens (8 responders and 19 nonresponders) were available for the sequence analysis of the EGFR gene. The response rate was 25% (20/80) and the disease control rate (remission + stable disease) was 47.5% (38/80). The response rate was significantly higher for adenocarcinoma (41.0%) versus non-adenocarcinoma (9.8%, P = 0.001), in those who never smoked (58.8%) versus smokers (15.9%, P < 0.001), and in females (42.1%) versus males (19.7%, P = 0.049). A deletion or mutation of the EGFR gene was found in six of eight responders. Remission was noted in all patients with a mutation, whereas the response rate was 9.5% (2/21) in patients without a mutation (P < 0.001). The predictors of response showed significant correlations with survival and time to progression. In a multivariate logistic analysis, the independent predictors of response were smoking history and adenocarcinoma. Given that 9.5% of smokers and 6.7% of those with non-adenocarcinoma showed a mutation of the EGFR gene, the genetic profile may replace those variables as an independent predictor of a response.
 ...
PMID:Predictors of the response to gefitinib in refractory non-small cell lung cancer. 1578 73

Gefitinib ('Iressa, ZD1839) has promising antitumor activity in non-small cell lung cancer (NSCLC). However, patients with advanced NSCLC have few treatment options available if they are refractory to gefitinib. We describe four cases of patients with advanced NSCLC who previously responded to gefitinib and obtained significant tumor regression through retreatment with other cytotoxic agents. Gefitinib might restore chemosensitivity to previously chemorefractory patients.
 ...
PMID:Gefitinib ('Iressa', ZD1839) may restore chemosensitivity in NSCLC patients? 1581 27


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>