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

Clinical development of ZD1839 (Iressa; AstraZeneca Pharmaceuticals LP, Wilmington, DE) was initiated based on strong preclinical studies that showed antitumor responses in a variety of solid tumor types and established its oral bioavailability and tolerability. In phase I trials, ZD1839 was investigated in patients with a wide variety of solid tumors that commonly express epidermal growth factor receptor-tyrosine kinase. More than 250 patients with advanced refractory disease were enrolled in phase I studies; of these, 100 had non-small cell lung cancer (NSCLC). All patients had been recipients of substantial prior therapy. Intermittent and continuous dosing schedules with ZD1839 were well tolerated by these patients for up to 6 months or more. The most frequently reported adverse events were grade 1 or 2 diarrhea and grade 1 or 2 acneiform rash; these effects were reversible on discontinuation of therapy and either required no management or were easily managed. Grade 3 or 4 adverse events were rare and most were attributed to disease progression rather than being drug related. In phase I trials, the maximum tolerated dose of ZD1839 was determined to be 700 to 1000 mg/day; diarrhea was found to be the dose-limiting toxicity. Pharmacokinetic profiles supported once-daily oral dosing and indicated that biologically active plasma concentrations were achieved at the doses studied. Pharmacodynamic results in skin biopsies showed that ZD1839 produced inhibition of epidermal growth factor receptor-tyrosine kinase in these patients. Durable tumor responses and stable disease were observed with ZD1839 treatment in patients with advanced NSCLC. Symptoms related to NSCLC also appeared to improve rapidly in some patients. Prolonged time on therapy was observed for other tumor types in addition to NSCLC, including hormone-refractory prostate, colorectal, head and neck, breast, ovarian, and renal cancers. The promising phase I results observed in heavily pretreated patients with advanced NSCLC and other solid tumors have warranted investigation in phase II/III clinical trials in these populations. Phase II/III trials are being conducted in patients with advanced NSCLC. Phase II trials of ZD1839 are also being conducted in patients who have hormone-refractory prostate, breast, or colorectal cancer, as well as other solid tumors. Based on the phase I study results, once-daily oral doses of 250 mg and 500 mg, which are well below the maximum tolerated dose, were selected for further clinical investigation of ZD1839.
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PMID:Phase I studies of ZD1839 in patients with common solid tumors. 1264 81

Patients with non-small cell lung cancer (NSCLC) frequently present, or relapse, with unresectable disease that is resistant to standard chemotherapy. There is, therefore, an urgent need for new treatments for NSCLC and other solid tumors. ZD1839 (Iressa; AstraZeneca Pharmaceuticals LP, Wilmington, DE), an orally active, selective epidermal growth factor receptor-tyrosine kinase inhibitor, has shown promising antitumor responses in phase I clinical trials in heavily pretreated patients with advanced NSCLC and other solid tumors. Randomized, multicenter global and US-based clinical trials were conducted to investigate two doses of ZD1839 as second- or third-line monotherapy in patients with advanced NSCLC. The global trial, Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1, was a double-blind, randomized, dose-comparative study that enrolled 210 patients with NSCLC at centers in Europe, Japan, South Africa, and Australia. This trial included patients with advanced unresectable stage III or IV NSCLC who had recurrent or progressive disease following one or two chemotherapy regimens, at least one of which was platinum based. IDEAL-1 showed that once-daily oral treatment with ZD1839 at 250 or 500 mg/day resulted in tumor response rates of 18% and 19%, respectively. Disease control rates, which included both tumor responses and stable disease, were 54% and 51%, respectively. Median progression-free survival was 83 days in the 250 mg/day group and 85 days in the 500 mg/day group. Rapid improvements in NSCLC-related symptoms were seen in the subpopulation of patients who were symptomatic and had completed a Lung Cancer Subscale questionnaire at baseline. Both the 250 mg/day and 500 mg/day doses of ZD1839 were well tolerated by patients in this trial. The majority of adverse events were grades 1 or 2 skin rash and diarrhea, which were readily manageable and reversible, and withdrawals were rare. The US monotherapy study in NSCLC, IDEAL-2, comprised 30 trial centers and enrolled 221 patients with NSCLC for third-line or greater therapy; 216 patients received treatment and were evaluable. This trial included patients with advanced stage III or IV NSCLC who had received two or more chemotherapy regimens that contained platinum and docetaxel, either concurrently or in separate regimens, with most patients having received more than two prior regimens. Although the IDEAL-1 and IDEAL-2 trials were similar in study design, patients in IDEAL-2 were sicker, as evidenced by a higher percentage of patients with a performance status of 2, metastatic disease, and disease-related symptoms. Because measuring the symptom improvement rate was a primary objective in IDEAL-2, all patients were symptomatic and were required to have a Lung Cancer Subscale score of 24 or less at trial entry. Objective tumor response rates (all partial responses) were 12% for the 250 mg/day group and 9% for the 500 mg/day group. Symptom improvement rates (increase of at least two points on the Lung Cancer Subscale) were 43% and 35%, respectively. Both doses of ZD1839 were well tolerated in this trial. The results of IDEAL-1 and IDEAL-2 indicate that ZD1839 monotherapy may offer a single-agent alternative for patients with advanced solid tumors who have received and progressed on prior chemotherapy, many of whom have exhausted their therapy options.
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PMID:Dose-comparative monotherapy trials of ZD1839 in previously treated non-small cell lung cancer patients. 1264 82

The majority of patients with non-small cell lung cancer (NSCLC) present with advanced disease, which is associated with a poor prognosis and symptoms such as pain, coughing, and shortness of breath. In patients who present at an earlier stage, the progressive nature of NSCLC and its resistance to treatment often result in recurrence, with the associated symptoms of advanced disease. These symptoms negatively affect patient quality of life and performance status rating, both of which are predictive of treatment response and survival. There is increasing interest in using assessments of improvements in symptoms and quality of life as outcomes in clinical trials for patients with advanced NSCLC. Patients with NSCLC have limited therapeutic options. Even those patients who are able to tolerate chemotherapy can expect median survival increases of only 2 to 4 months. The new targeted therapies for lung cancer, in contrast, are relatively nontoxic and may provide benefits for symptoms and quality of life in addition to tumor responses. The Functional Assessment of Cancer Therapy-Lung (FACT-L) scale is a validated, sensitive, and reliable patient questionnaire that evaluates and quantifies quality of life across several dimensions, including lung cancer-related symptoms (Lung Cancer Subscale). The Lung Cancer Subscale ranges from 0 (severe debilitation) to 28 (asymptomatic). A change of two points reflects a clinically significant change in NSCLC-related symptoms and quality of life. In phase I studies and also in the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2 phase II monotherapy trials, treatment of patients with advanced NSCLC with the epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca Pharmaceuticals LP, Wilmington, DE) has shown tumor responses as well as rapid improvements in NSCLC-related symptoms and quality of life. In IDEAL-1 and IDEAL-2, improvements in NSCLC-related symptoms and quality of life, as measured by FACT-L, correlated with tumor response, and improvements in symptoms also correlated with progression-free and overall survival. Although symptom response is correlated with tumor response, it is also uniquely predictive of progression-free and overall survival. The FACT-L questionnaire has also been included in phase III trials of ZD1839 treatment in combination with chemotherapy regimens.
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PMID:Impact of ZD1839 on non-small cell lung cancer-related symptoms as measured by the functional assessment of cancer therapy-lung scale. 1264 83

In-depth analysis of molecular regulatory networks in cancer holds the promise of improved knowledge of the pathophysiology of tumor cells so that it will become possible to design a detailed molecular tumor taxonomy. This knowledge will also offer new opportunities for the identification and validation of key molecular tumor targets to be exploited for novel therapeutic approaches. Some signaling proteins have already been identified as such, e.g. c-Myc, Cyclin D1, Bcl-XL, kinases and some nuclear receptors. This has led to the successful development of a few function-modulatory drugs (Glivec, SERM, Iressa), providing proof-of-principle of the validity of this approach. Further developments are likely to derive from "-omic" approaches, aimed at the understanding of signaling networks and of the mechanism of action of newfound lead molecules. High-throughput screening of small drug-like molecules from combinatorial chemical libraries or from microbial extracts will identify novel, "intelligent" drug candidates. An additional medicinal chemistry strategy (via 40-50 unit rosary-bead chains) has the potential to be much more effective than small molecules in interfering with protein-protein interactions. This may lead to considerably higher selectivity and effectiveness compared with historical approaches in drug discovery.
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PMID:Signaling protein networks as targets of new antineoplastic drugs. 1269 65

Recent progress in development of molecular cancer therapeutics revealed new types of antitumor drugs, such as Herceptin, Gleevec, and Iressa as potent therapeutics for each specific tumor. We have been working on molecular cancer therapeutics, and in particular, those related to drug resistance, Here, I describe several resistance mechanisms, including apoptosis regulation, cellular stress response and cellular survival signals which have show close relevance to drug resistance. P-glycoprotein (P-gp) is the key molecule in multidrug resistance (MDR) and a good target for chemotherapy. Proteasome is involved in the resistance mechanism to topo II-targeted chemotherapy in solid tumors. Apoptosis program in tumor cells plays a critical role in chemotherapy-induced tumor cell killing, and the blockade of the apoptosis-inducing pathway could be another mechanism for drug resistance. Glyoxalase I is a molecule involved in apoptosis resistance mechanism in tumors. Survival (antiapoptosis) signals are the good targets for various antitumor drugs to overcome innate drug resistance. Our present studies provide novel targets for effective molecular cancer therapeutics in future.
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PMID:Molecular cancer therapeutics: recent progress and targets in drug resistance. 1270 87

Recent progress in the development of molecular cancer therapeutics has revealed new types of antitumor drugs, such as Herceptin, Gleevec, and Iressa, as potent therapeutics for specific tumors. Our work has focused on molecular cancer therapeutics, mainly in the areas of drug resistance, apoptosis and apoptosis resistance, and survival-signaling, which is related to drug resistance. In this review, we describe our research on molecular cancer therapeutics, including molecular mechanisms and therapeutic approaches. Resistance to chemotherapeutic drugs is a principal problem in the treatment of cancer. P-Glycoprotein (P-gp), encoded by the MDR1 gene, is a multidrug transporter and has a major role in multidrug resistance (MDR). Targeting of P-gp by small-molecular compounds and/or antibodies is an effective strategy to overcome MDR in cancer, especially hematologic malignancies. Several P-gp inhibitors have been developed and are currently under clinical phased studies. In addition to the multidrug transporter proteins, cancer cells have several drug resistance mechanisms. Solid tumors are often placed under stress conditions, such as glucose starvation and hypoxia. These conditions result in topo II poison resistance that is due to proteasome-mediated degradation of DNA topoisomerases. Proteasome inhibitors effectively prevent this stress-induced drug resistance. Glyoxalase I, which is often elevated in drug- and apoptosis-resistant cancers, offers another possibility for overcoming drug resistance. It plays a role in detoxification of methylglioxal, a side product of glycolysis, which is highly reactive with DNA and proteins. Inhibitors of glyoxalase I selectively kill drug-resistant tumors that express glyoxalase I. Finally, the susceptibility of tumor cells to apoptosis induced by antitumor drugs appears to depend on the balance between pro-apoptotic and survival (anti-apoptotic) signals. PI3K-Akt is an important survival signal pathway, that has been shown to be the target of various antitumor drugs, including UCN-01 and geldanamycin, new anticancer drugs under clinical evaluation. Our present studies provide novel targets for future effective molecular cancer therapeutics.
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PMID:Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal. 1270 68

We have examined the possible mechanisms of resistance to the epidermal growth factor receptor (EGFR) inhibitors in tumor cells with variable levels of EGFR. ZD1839 (Iressa) is a small-molecular-weight, ATP-mimetic that specifically inhibits the EGFR tyrosine kinase. A431 cell growth was markedly inhibited by ZD1839 (IC(50)< or =0.1 microM) whereas the MDA-468 cells were relatively resistant (IC(50)2 microM). Low doses of ZD1839 delayed cell cycle progression and induced apoptosis in A431 cells but not in MDA-468 cells. In both cell lines, 0.1 microM ZD1839 eliminated EGFR phosphorylation. However, the basal activity of the phosphatidylinositol-3 kinase (PI3 K) target Akt was eliminated in A431 but not in MDA-468 cells, implying that their Akt activity is independent of EGFR signals. A431 cells express PTEN/MMAC1/TEP, a phosphatase that can dephosphorylate position D3 of phosphatidylinositol-3,4,5 trisphosphate, the site that recruits the plecstrin-homology domain of Akt to the cell membrane. On the contrary, MDA-468 cells lack the phosphatase and tensin homolog (PTEN), potentially setting Akt activity at a high threshold that is unresponsive to EGFR inhibition alone. Therefore, we reintroduced (PTEN) by retroviral infection in MDA-468 cells. In MDA-468/PTEN but not in vector controls, treatment with ZD1839 inhibited P-Akt levels, induced relocalization of the Forkhead factor FKHRL1 to the cell nucleus, and increased FKHRL1-dependent transcriptional activity. ZD1839 induced a greater degree of apoptosis and cell cycle delay in PTEN-reconstituted than in control cells. These data suggest that loss of PTEN, by permitting a high level of Akt activity independent of receptor tyrosine kinase inputs, can temporally dissociate the inhibition of the EGFR with that of Akt induced by EGFR inhibitors. Thus, in EGFR-expressing tumor cells with concomitant amplification(s) of PI3K-Akt signaling, combined blockade of the EGFR tyrosine kinase and Akt should be considered as a therapeutic approach.
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PMID:Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. 1274 4

To date, no single or multiple molecular markers have been successful in predicting sensitivity of individual patients to anti-cancer drugs. As the nature of a specific cancer is considered to be defined by the proteins being expressed in the tumor cells, systematic analysis of gene-expression profiles may provide information reflecting sensitivity of a given tumor to certain drugs. Recent progress in genome technology has enabled us to examine expression profiles of thousands of genes in a single experiment. We used this approach to examine 13 xenografts of human tumors implanted into nude mice for sensitivity to an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (Iressa). To identify genes that might be associated with sensitivity to this drug we used a cDNA microarray representing 23,040 genes to analyze expression profiles of the 13 xenografts and identified 114 genes whose expression levels correlated significantly with sensitivity of the tumors to ZD1839. We then investigated alteration of expression profiles in response to the ZD1839 treatment in four non-small cell lung cancer (NSCLC) xenografts, of which two (LC6 and LC11) were sensitive and the other two (Lu116 and L27) were resistant to this EGFR-TKI. Systematic analysis of expression at various time points during oral treatment for 14 days, compared with corresponding untreated samples, identified a set of genes whose expression levels changed in the two sensitive tumors but not in the two resistant tumors. The data obtained here should provide useful information on the molecular mechanism underlying clinical responses to EGFR-TKIs, aid the development of novel therapies for lung cancer, and potentially identify predictive molecular markers for sensitivity to ZD1839.
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PMID:Gene-expression profiles of human tumor xenografts in nude mice treated orally with the EGFR tyrosine kinase inhibitor ZD1839. 1279 73

The epidermal growth factor receptor (EGFR) is highly expressed in many human tumors and provides a new target for anticancer drug development. EGFR-targeted agents have shown promising antitumor activity in preclinical and clinical trials. However, little is yet known about the effect of these new agents on tumor metastasis. Here, we investigate the effects of ZD1839 (Iressa), a selective EGFR tyrosine kinase inhibitor, on the metastatic properties of murine hepatocellular carcinoma CBO140C12. ZD1839 inhibited not only cell growth but also epidermal growth factor-induced chemotactic migration and production of active matrix metalloproteinase-9 in vitro. In mice, orthotopic implantation of a fragment of CBO140C12 tumor into the liver resulted in the formation of a solitary tumor nodule and intrahepatic metastasis. ZD1839, given p.o., inhibited growth of the implanted tumor and intrahepatic metastasis by approximately 50%. These results indicate that EGFR signaling plays an important role in tumor metastasis and that ZD1839 is effective at inhibiting intrahepatic metastasis.
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PMID:ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, shows antimetastatic activity using a hepatocellular carcinoma model. 1281 35

Overexpression of epidermal growth factor receptor (EGFR) in epithelial tumors, including head and neck, lung, breast, colon and other solid tumors, has frequently been correlated with poor prognosis, thus stimulating efforts to develop new cancer therapies that target EGFR. Monoclonal antibodies and tyrosine kinase inhibitors specifically targeting EGFR are the most well-studied and hold substantial promise of success. Several compounds of monoclonal antibodies and tyrosine kinase inhibitors targeting EGFR have been studied and clinical trials are now underway to test the safety and efficacy of these targeting strategies in several human tumors. This review will address each of these agents alone or in combination with radiation or chemotherapy and highlight some of these promising developments. Cetuximab (Erbitux) is being evaluated in combination with radiation or chemotherapy in Phase III trials. Other compounds such as h-R3, ABX-EGF, EMD-55900 and ICR-62 have proved to be effective in targeting malignant cells alone or in combination with traditional therapies. Tyrosine kinase inhibitors targeting the intracellular domain of EGFR, including ZD-1839 (gefitinib, Iressa), OSI-774 (Erlotinib/Tarceva), PD-153053, PD-168393 and CI-1033, have been studied in clinical setting alone or in combination with radiation or chemotherapy. ZD-1839 is being studied in a Phase III trial in patients with advanced non-small cell lung cancer. EGFR targeted treatment by monoclonal antibodies and tyrosine kinase inhibitors have been proven to sensitize tumor cells to the effects of chemotherapy and radiation therapy. The synergistic activities and nonoverlapping toxicities of these compounds allow concomitant administration with cytotoxic therapy. Challenges of evaluating EGFR targeted agents exist in selecting the optimal dosages and determining long-term toxicity.
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PMID:Targeting epidermal growth factor receptor: novel therapeutics in the management of cancer. 1282 Jul 79


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