Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Troxacitabine [BCH 4556; SPD 758; Troxatyl] is a DNA synthesis inhibitor. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It is a member of a novel class of nucleoside analogues discovered by BioChem Pharma and is the first example of a synthetic L-nucleoside analogue to have shown anticancer activity in animal models. On 11 May 2001, BioChem Pharma was acquired by, and integrated into, Shire Pharmaceuticals Group. In February 2002 Shire announced that it intended to pursue development of troxacitabine as a treatment for solid tumours. In addition, Shire indicated that it would pursue the drug's development for acute myeloid leukaemia. In March 1999, phase II trials were initiated to investigate the efficacy and tolerability of troxacitabine in a variety of solid tumours including pancreas, prostate, colorectal, renal and non-small cell lung cancers and melanoma. The trials were conducted throughout North America and were closed to patient accrual in 2000. Two phase I combination chemotherapy trials in solid tumours (one with cisplatin and another with paclitaxel) have been initiated. One of these trials is in patients with pancreatic cancer. A phase III trial in patients with pancreatic cancer is expected to begin during the second or third quarter of 2003. In addition, further clinical development was initiated in May 2000, in the form of a combination chemotherapy trial in patients with acute leukaemia. A phase II trial in patients with acute myeloid leukaemia (AML) and chronic myeloid leukaemia-blast phase (CML-BP) has reported that troxacitabine demonstrated significant activity in these cancers. However, Shire indicated that no further development for CML-BP will be conducted. The company indicated that it would focus future development in the haematological malignancy area on AML and has initiated an exploratory phase III trial of troxacitabine in previously untreated patients with poor prognosis AML. The study will compare troxacitabine in combination with either cytarabine or idarubicin, with a control drug regimen. The aim is to identify the most promising treatment regimens in a relatively small number of patients before commencing the larger pivotal trial. A pivotal phase III trial is expected to begin in the first half of 2003. In September 2002, Shire Pharmaceuticals forecast Troxatyl to reach peak sales of $US100-200 million, for the indications of pancreatic cancer and myeloid leukaemia.
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PMID:Troxacitabine: BCH 4556, SPD 758, Troxatyl. 1284 94

The farnesyltransferase inhibitors (FTIs) were designed to inhibit the post-translational processing of Ras proteins, which are mutated in 30% of all human cancers. Recent studies suggest, however, that the target of FTIs may be a protein other than Ras, and that these agents may be more appropriately used to treat tumors with activated wild-type ras signaling. Preliminary results from several phase II and phase III studies have been reported. The FTIs fail to show significant single-agent activity in non-small cell lung cancer, small cell lung cancer, pancreatic cancer, refractory colorectal cancer, and bladder cancer. Activity has been shown in hematologic malignancies (acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome), breast cancer, and glioma. Several combination studies of FTIs and standard cytotoxic agents are ongoing.
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PMID:Farnesyltransferase inhibitors. 1498 78

Heat shock proteins (HSPs) exist ubiquitously across all species and function as chaperones stabilizing and delivering peptides. Tumor-derived HSP-peptide complex has been known to induce immunity against the original tumor in preclinical studies. HSP-based vaccines work across tumor types and bypass the need for identifying the responsible peptide(s) for inducing immunity. These vaccines are tumor- and patient-specific in that they capture the tumor cells' fingerprints. HSP-based vaccines have been studied in early phase clinical trials, mostly using HSP glycoprotein 96, for various types of malignancies including melanoma, renal cell carcinoma, gastric cancer, pancreatic cancer, low-grade lymphoma, colorectal cancer and chronic myelogenous leukemia. All showed minimal toxicity and potential efficacy. Phase III studies for melanoma and renal cell carcinoma are ongoing. HSP-based vaccines are a novel vaccine preparation with a promising role in cancer management. Further studies to determine the administering strategy and specific indication are warranted.
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PMID:Heat shock protein-based cancer vaccines. 1527 Jun 45

Receptor and non-receptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating gastrointestinal cancer. Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl TK, which was primarily designed to treat chronic myeloid leukemia is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. The epidermal growth factor receptor (EGFR), which is involved in cell proliferation, metastasis and angiogenesis, is another important target. The two main classes of EGFR inhibitors are the TK inhibitors and monoclonal antibodies. Gefitinib (ZD1839, Iressa(TM)) has been on trial for esophageal and colorectal cancer (CRC) and erlotinib (OSI-774, Tarceva(TM)) on trial for esophageal, colorectal, hepatocellular, and biliary carcinoma. In addition, erlotinib has been evaluated in a Phase III study for the treatment of pancreatic cancer. Cetuximab (IMC-C225, Erbitux(TM)), a monoclonal EGFR antibody, has been FDA approved for the therapy of irinotecan resistant colorectal cancer and has been tested for pancreatic cancer. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are critical regulators of tumor angiogenesis. Bevacizumab (Avastin(TM)), a monoclonal antibody against VEGF, was efficient in two randomized clinical trials investigating the treatment of metastatic colorectal cancer. It is also currently investigated for the therapy of pancreatic cancer in combination with gemcitabine. Other promising new drugs currently under preclinical and clinical evaluation, are VEGFR2 inhibitor PTK787/ZK 222584, thalidomide, farnesyl transferase inhibitor R115777 (tipifarnib, Zarnestra(TM)), matrix metalloproteinase inhibitors, proteasome inhibitor bortezomib (Velcade(TM)), mammalian target of rapamycin (mTOR) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, platelet derived growth factor receptor (PDGF-R) inhibitors, protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors, Rous sarcoma virus transforming oncogene (SRC) kinase inhibitors, histondeacetylase (HDAC) inhibitors, small hypoxia-inducible factor (HIF) inhibitors, aurora kinase inhibitors, hedgehog inhibitors, and TGF-beta signalling inhibitors.
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PMID:Molecularly targeted therapy for gastrointestinal cancer. 1589 18

Imatinib targets KIT and platelet-derived growth factor receptors (PDGFR) and is highly effective in the treatment of CML and GIST patients. Pancreatic cancers express KIT and PDGFRs. Therefore, 26 patients with unresectable pancreatic cancer were randomized to either gemcitabine (1000 mg/m2 weekly) or imatinib (2x400 mg po) treatment daily. Pancreatic adenocarcinoma was confirmed histologically and expression of KIT and PDGFRbeta was determined immunohistochemically in the biopsy specimens. Quality of life was assessed with two standard questionnaires. No objective responses were seen in either group. Median time to progression was 77 and 29 days (P=0.411) and median survival time was 140 and 60 days (P=0.517) for gemcitabine and imatinib, respectively. Survival and treatment responses were independent of KIT and PDGFRbeta expression in patients treated with imatinib. Grade 3/4 toxicities of imatinib treatment were anemia, elevated liver enzymes, vomiting, and dyspnea. Patients treated with imatinib reported diarrhoea and/or altered bowel function more frequently, which were treatable symptomatically. Quality of life was similar in both groups. In this small series of pancreatic cancer patients, treatment with imatinib was not associated with a significant control of cancer progression.
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PMID:The tyrosine kinase inhibitor imatinib fails to inhibit pancreatic cancer progression. 1589 16

Pancreatic cancer (PanC) is an extremely lifethreatening neoplasm due to its late discovery, rapid progression and resistance to chemo- and radiotherapy. In the past years a significant research attention turned to this cancer. Extensive genomic analysis of PanC revealed numerous alterations, however, none of them emerged yet as a key regulator of tumor progression. Our increasing knowledge on the molecular targets in various cancer types started to change their management. Examples of success of the molecular therapies (in CML, GIST, NSCLC) may initiate more activity in pancreatic cancer as well.
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PMID:Genomics of pancreatic cancer: does it make any improvement in diagnosis, prognosis and therapy? 1599 49

Pleural effusion in chronic myeloid leukemia (CML) is poorly understood and rarely reported in the literature. When the pleural effusion is caused by leukemic pleural infiltration, the differential white blood cell count of the effusion is identical to that of the peripheral blood, and the fluid cytology reveals leukemic blasts. We report here a case of bilateral pleural involvement of atypical CML in an 83-yr old male diagnosed with pancreatic cancer with abdominal wall metastasis and incidental peripheral leukocytosis. Based on bone marrow examination, chromosome analysis and polymerase chain reaction he was diagnosed with Philadelphia chromosome negative, BCR/ABL gene rearrangement negative CML. Following 3 months of treatment with gemcitabine for pancreatic cancer, he developed bilateral pleural effusions. All stages of granulocytes and a few blasts were present in both the pleural fluid and a peripheral blood smear. After treatment with hydroxyurea and pleurodesis, the pleural effusion resolved.
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PMID:A case of leukemic pleural infiltration in atypical chronic myeloid leukemia. 1704 33

Hereditary cancer syndromes provide excellent models for molecular genetic studies that may aid significantly in case detection, surveillance, and management. Ultimately, molecularly based designer pharmaceuticals may emerge from this research, such as the case of trastuzumab (Herceptin) in HER-2/neu positive breast cancer, and imatinib (Gleevec) in chronic myelocytic leukemia and gastrointestinal stromal tumors. Importantly, these molecular findings may fuel significant clues to cancer control. This background is mentioned since surveillance and management of pancreatic cancer, a major concern of this manuscript, has been uniformly unsuccessful as evidenced by the close correspondence between its incidence and its mortality. Yet knowledge about its genetic and molecular pathology will hopefully ameliorate this vexing problem. One molecular genetic clue is the recently identified palladin mutation in two pancreatic cancer prone families. However, caution must be used toward the palladin mutation, as several recent publications have questioned its significance as a pancreatic cancer causing mutation. We provide a concise description of pancreatic cancer in concert with malignant melanoma in the familial atypical multiple mole melanoma (FAMMM) syndrome as a potential preventive model. This knowledge should help clinicians and basic scientists seize on the opportunity to develop more sensitive and specific screening and management programs in this disease; while a relatively small subset of pancreatic cancer may be readily identifiable through its FAMMM phenotype, coupled with its CDKN2A mutation, this hereditary disorder, given a keen knowledge of its natural history and molecular genetics, may prove to be an effective clinical preventive model.
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PMID:Pancreatic cancer and the FAMMM syndrome. 1799 82

Imatinib mesylate (imatinib) inhibits the c-Kit-dependent tyrosine kinase activities and highly effective in the treatment of CML and GIST patients. Although pancreatic cancer is reported to express c-Kit, imatinib does not effectively inhibit pancreatic cancer cell growth at physiological concentrations. Therefore, we investigated the mechanism of resistance of pancreatic cancer to imatinib treatment. Imatinib inhibited growth of pancreatic cancer cell lines in concentration and time-dependent fashion regardless of c-Kit expression. However, 5 microM imatinib, which is almost a mean maximal plasma concentration in clinical setting, failed to suppress pancreatic cancer cell growth. Western blot analysis demonstrated that 5 microM imatinib treatment for 1h activated the MEK-MAPK pathway and the activation was independent of Ras activation. Administration of 5 microM imatinib and 1 microM U0126 (MEK inhibitor) significantly suppressed pancreatic cell growth. Our results indicate that a combination therapy of imatinib and MEK inhibitor can be a new therapeutic strategy to suppress the progression of pancreatic cancer.
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PMID:MEK inhibitor enhances the inhibitory effect of imatinib on pancreatic cancer cell growth. 1834 44

Cellular signal transduction pathways and gene expression are tightly regulated to accommodate changes in response to physiological environments. In the current study, molecules were identified that are activated as a result of intracellular signaling and immediately expressed as mRNA in MCF-7 breast cancer cells shortly after stimulation of ErbB receptor ligands, epidermal growth factor (EGF) or heregulin (HRG). For the identification of tyrosine-phosphorylated proteins and expressed genes, a SILAC (stable isotopic labeling using amino acids in cell culture) method and Affymetrix gene expression array system, respectively, were used. Unexpectedly, the overlapping of genes appeared in two experimental datasets was very low for HRG (43 hits in the proteome data, 1,655 in the transcriptome data, and 5 hits common to both datasets), while no overlapping gene was detected for EGF (15 hits in the proteome data, 211 hits in the transcriptome data, and no hits common to both datasets). The HRG overlapping genes included ERBB2, NEDD9, MAPK3, JUP and EPHA2. Biological pathway analysis indicated that HRG-stimulated molecular activation is significantly related to cancer pathways including bladder cancer, chronic myeloid leukemia and pancreatic cancer (p < 0.05). The proteome datasets of EGF and HRG contain molecules that are related to Axon guidance, ErbB signaling and VEGF signaling at a high rate.
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PMID:Phosphoproteome and transcriptome analyses of ErbB ligand-stimulated MCF-7 cells. 1882 Mar 70


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