Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alteration of the tumor suppressor gene p53 is the most frequent genetic feature of human cancer and leads to over-expression and loss of function of the p53 protein in affected cells. Patients with many types of cancer, including breast, lung, and colon carcinoma, were shown to develop auto-immune response against the overexpressed protein and to produce autoantibodies directed to immunodominant epitopes common for both wild type and mutants. The presence of p53 autoantibodies (p53-aAb) seems to be, at least in patients with breast and bronchial tumors, related to an unfavorable prognosis. The present study aimed to investigate the presence of p53-aAb in patients with malignant glioma. Sera from 70 consecutive patients with gliomas graded WHO G III and IV were collected and assayed together with sera from 30 controls. A new photometric sandwich-ELISA was used for semiquantitative analysis of p53-aAb titers. p53 gene and its protein product were examined in formalin-fixed and fresh-frozen tumor tissues using immunohistochemistry, PCR-single-strand conformational polymorphism, and sequencing. Sixty percent of the glioma cases showed immunohistochemically positive cells, thus indicating intracellular accumulation of p53. Sequencing of the hot-spot exons 5-8 revealed mutations in 39% of the tumor cases. In contrast to results in other types of malignant tumors, where up to 40% of patients have high serum titers of p53-aAb, no such antibodies were found in patients with malignant cerebral glioma despite the presence of mutated or alterated p53 protein in the primary tumors. None of the non-cancer control patients had detectable titers of p53-aAb, although sera from five of six lung cancer patients had medium to high titers. The presented data suggest that glial tumors are unusual in the absence of serum antibodies to p53. It is hypothesized that impaired function of most immunocompetent cells invading brain tumors could be the cause for the absence of an autoimmune response.
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PMID:Absence of p53 autoantibodies in sera from glioma patients. 981 45

Technetium-99m sestamibi (MIBI), an alternative radiopharmaceutical for myocardial perfusion imaging, has also been proposed for use as an imaging agent for various tumours, including breast cancer, lung cancer, lymphomas, melanomas and brain tumours. After routine radiation therapy, deteriorating clinical status or treatment failure may be due to either radiation-induced changes or recurrent tumour. Computed tomography and magnetic resonance imaging offer imperfect discrimination of tumour viability and radionecrosis. Against this background we undertook a retrospective study of 35 malignant glioma patients in whom clinical deterioration had occurred, in order to clarify the value of 99mTc-MIBI SPET in identifying tumour recurrence. SPET was performed 15 min after intravenous injection of 1110 MBq with a dual-headed gamma camera using a fan-beam collimator. Transverse, coronal and sagittal views were reconstructed. Intense MIBI uptake was found in 31 patients. This uptake was correlated with tumour recurrence as proved by histology and/or rapid, fatal evolution of these cases. The statistical analysis performed on this population of patients with MIBI uptake revealed a group of patients with a long mean survival and a group with a short mean survival. Two subgroups were found within each of these groups, according to the functional index ratio (tumour uptake/pituitary gland uptake ratio). No MIBI uptake was found in four patients who are still alive and can be considered to be disease-free. In those cases showing MIBI uptake, death occurred an average of 6.69 months following brain SPET. According to our results, the specificity and sensitivity of 99mTc-MIBI brain SPET seem to be high. Moreover, this technique is more accurate than computed tomography or magnetic resonance imaging for discriminating between tumour recurrence and radionecrosis.
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PMID:Technetium-99m sestamibi brain single-photon emission tomography for detection of recurrent gliomas after radiation therapy. 987 Oct 97

A novel derivative of camptothecin, 9-aminocamptothecin (9-AC), is currently under Phase II evaluation in various cancers. Exceptionally mild toxicities were observed in patients with brain tumors who were treated with anticonvulsants. To investigate a pharmacokinetic interaction between 9-AC and anticonvulsants, and to evaluate the pharmacodynamics of 9-AC, we investigated the clinical pharmacology of 9-AC, administered by a 72-h infusion, in three Phase II studies. Plasma concentrations of total 9-AC (lactone plus carboxylate) at a steady state were measured in 56, 10, and 14 patients with non-small cell lung cancer, malignant glioma, and head and neck cancer, respectively. For lung cancer or glioma patients, 9-AC was infused at 45 (51 patients) or 59 (15 patients) microg/m2/h, and 9-AC was infused at 35.4 microg/m2/h in head and neck cancer patients. All glioma patients had been treated with phenytoin or carbamazepine. 9-AC clearance did not differ among the dosage rates, but differed according to the diseases (P = 0.002). Glioma patients had a higher clearance (1.0-18.0; median, 2.0 liters/h/m2) than lung cancer patients (0.3-5.1; median, 0.9 liters/h/m2). A logistic regression model described the relationship between the 9-AC concentration and the probability of grade 4 neutropenia, which was the main toxicity. Observed incidences of grade 4 neutropenia for patients with model-predicted probability of 0-20%, 20-40%, and 40-100% were 10%, 32%, and 67%, respectively, and corresponded to 9-AC concentration of <54, 54-86, and >86 ng/ml, respectively. Anticonvulsants seem to induce the clearance of 9-AC, and the concentration of 9-AC predicts the probability of grade 4 neutropenia.
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PMID:Pharmacokinetics and pharmacodynamics of 9-aminocamptothecin infused over 72 hours in phase II studies. 1038 15

We studied AG3340, a potent metalloproteinase (MMP) inhibitor with pM affinities for inhibiting gelatinases (MMP-2 and -9), MT-MMP-1 (MMP-14), and collagenase-3 (MMP-13) in many tumor models. AG3340 produced dose-dependent pharmacokinetics and was well tolerated after intraperitoneal (i.p.) and oral dosing in mice. Across human tumor models, AG3340 produced profound tumor growth delays when dosing began early or late after tumor implantation, although all established tumor types did not respond to AG3340. A dose-response relationship was explored in three models: COLO-320DM colon, MV522 lung, and MDA-MB-435 breast. Dose-dependent inhibitions of tumor growth (over 12.5-200 mg/kg given twice daily, b.i.d.) were observed in the colon and lung models; and in a third (breast), maximal inhibitions were produced by the lowest dose of AG3340 (50 mg/kg, b.i.d.) that was tested. In another model, AG3340 (100 mg/kg, once daily, i.p.) markedly inhibited U87 glioma growth and increased animal survival. AG3340 also inhibited tumor growth and increased the survival of nude mice bearing androgen-independent PC-3 prostatic tumors. In a sixth model, KKLS gastric, AG3340 did not inhibit tumor growth but potentiated the efficacy of Taxol. Importantly, AG3340 markedly decreased tumor angiogenesis (as assessed by CD-31 staining) and cell proliferation (as assessed by bromodeoxyuridine incorporation), and increased tumor necrosis and apoptosis (as assessed by hematoxylin and eosin and TUNEL staining). These effects were model dependent, but angiogenesis was commonly inhibited. AG3340 had a superior therapeutic index to the cytotoxic agents, carboplatin and Taxol, in the MV522 lung cancer model. In combination, AG3340 enhanced the efficacy of these cytotoxic agents without altering drug tolerance. Additionally, AG3340 decreased the number of murine melanoma (B16-F10) lesions arising in the lung in an intravenous metastasis model when given in combination with carboplatin or Taxol. These studies directly support the use of AG3340 in front-line combination chemotherapy in ongoing clinical trials in patients with advanced malignancies of the lung and prostate.
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PMID:Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials. 1041 35

Inactivating germline mutations of the novel putative tumor-suppressor gene LKB1/STK11 at 19p13.3 have been shown to cause Peutz-Jeghers syndrome (PJS), an autosomal dominantly inherited disease characterized by a predisposition to mucocutaneous pigmentations, as well as various benign and malignant neoplasms. To elucidate the role of LKB1/STK11 in the carcinogenesis of primary and secondary human brain tumors, a total of 309 tumors were analyzed for loss of heterozygosity (LOH) at microsatellite loci D19S886, DI9S878, and D19S565. Low LOH rates were observed for glioma (17.3%, n = 139), meningioma (5.3%, n = 57), schwannoma (0%, n = 21), pituitary adenoma (18.8%, n = 16), primary CNS lymphoma, neuroblastoma, plasmocytoma, medulloblastoma, germinoma, and papilloma of the choroid plexus (6.6%, n = 15). In contrast, brain metastases exhibited a mean LOH frequency of 42.6% (n = 61), with breast (56.3%) and lung cancer metastases (58.3%) being most frequently affected. Genomic DNA sequencing of the complete coding region of LKB1/STK11 was performed in all brain metastases exhibiting LOH (n = 26); no mutation was revealed, but we did find a germline mutation in a PJS patient. Despite high LOH fiequencies at the 19p13.3 locus in carcinoma metastases to the brain and occasional mutations reported for certain primary carcinomas, there are no mutations in LKB1/STK11. This fact suggests that alterations of LKB1/STK11 occur relatively early in tumorigenesis and are rarely involved in the development of carcinoma metastases. Based on these findings, the genes adjacent to LKB1/STK11 may be relevant for the development of metastases to the brain from certain carcinomas.
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PMID:Frequent loss of heterozygosity at the 19p13.3 locus without LKB1/STK11 mutations in human carcinoma metastases to the brain. 1121 97

H11 is a human IgM monoclonal antibody which recognizes a novel tumour-associated antigen expressed on melanoma, glioma, breast cancer, colon cancer, prostate cancer, lung cancer and B-cell lymphoma. In this study, a recombinant single-chain Fv (scFv) fragment of H11 labelled with 111In was investigated for tumour imaging in athymic mice implanted subcutaneously with A-375 human melanoma xenografts. H11 scFv was derivatized with diethylenetriaminepentaacetic acid (DTPA) for labelling with 111In. The immunoreactivity of DTPA-H11 scFv against A-375 cells in vitro ranged from 23% to 36%. 111In-DTPA-H11 scFv was rapidly eliminated from the blood and most normal tissues (except the kidneys) reaching maximum tumour/blood ratios of 12:1 at 48 h post-injection. Tumours were imaged as early as 40 min after injection. The kidneys accumulated the highest concentration of radioactivity (up to 185% injected dose/g). Tumour uptake was 1-3% injected dose/g. The whole-body radiation absorbed dose predicted for administration of 185 MBq of 111In-DTPA-H11 scFv to humans was 37 mSv. The radiation absorbed dose estimates for the kidneys, spleen and intestines were 405 mSv, 698 mSv and 412 mSv, respectively. The results of this preclinical study and a concurrent phase I trial suggest a promising role for H11 scFv for tumour imaging.
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PMID:Rapid imaging of human melanoma xenografts using an scFv fragment of the human monoclonal antibody H11 labelled with 111In. 1138 83

Vascular endothelial growth factor (VEGF) plays a pivotal role in tumor progression via angiogenesis. Recently, gene transduction of wild-type p16INK4A, tumor suppressor gene, has been shown to result in downregulation of VEGF expression in p16INK4A-deleted glioma cells. Because expression of p16INK4A is regulated by methylation of the p16INK4A gene, we examined whether demethylation of the p16INK4A gene by 5-aza-2'-deoxycytidine (5-azadC) could cause the protein expression of VEGF as well as of p16INK4A in human lung cancer cells. For this, five different lung cancer cell lines with or without loss of p16 activity were used. H841 and Ma-10 cells had the methylated p16INK4A gene without expression of p16INK4A protein, whereas Ma-1 and H209 cells had the unmethylated p16INK4A gene with constitutive expression of p16INK4A protein. Neither the p16INK4A gene nor p16INK4A protein was detected in A549 cells. Treatment with 5-azadC caused demethylation of the p16INK4A gene with reexpression of p16INK4A protein in H841 and Ma-10 (methylated p16INK4A gene dominant) cell, but not in other cell lines such as Ma-1, H209 (unmethylated p16INK4A gene dominant), or A549 (p16INK4A gene deleted). In a parallel experiment, 5-azadC inhibited production of VEGF protein by H841 and Ma-10 cells, especially in the later hypermethylated cells, but not Ma-1, H209, or A549 cells. RT-PCR analysis showed that Ma-10 cells expressed VEGF isoforms 121, 165, and 189, all of which were inhibited by 5-azadC. These findings indicate that the methylation status of the p16INK4A gene plays an important role in the regulation of angiogenesis associated with progression of lung cancer, through regulation of VEGF expression.
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PMID:Demethylation by 5-aza-2'-deoxycytidine (5-azadC) of p16INK4A gene results in downregulation of vascular endothelial growth factor expression in human lung cancer cell lines. 1158 4

Tyrosine kinases are enzymes that regulate mitosis, differentiation, migration, neovascularization, and apoptosis. Their spectrum and association with specific malignancies offer multiple targets for therapeutic intervention. Chronic myelogenous leukemia (CML) represents an ideal target for a therapy using a selective inhibitor of the BCR-ABL tyrosine kinase. The 2-phenylpyrimidine derivative STI571 was rationally designed to inhibit ABL and BCR-ABL tyrosine kinase activities through competitive ATP-binding pocket interactions. Phase II data demonstrate hematologic and cytogenetic responses in interferon refractory chronic-phase, accelerated-phase and blast crisis patients. However, long-term observation is needed to confirm that response data result in prolongation of survival. STI571 is being studied in other malignancies, including leukemias characterized by expression of alternate molecular forms of BCR-ABL and those expressing protein tyrosine kinases with ATP-binding pockets structurally similar to ABL, e.g. c-kit and PDGF-R. Gastrointestinal stromal tumor (GIST) cells overexpress the stem cell factor receptor CD117, the product of the proto-oncogene c-kit. Inhibition of c-kit in vivo results in an immediate metabolic change of the tumor cells, detectable by positron emission tomography. Since c-kit overexpression is inhibited in small-cell lung cancer cell lines, a study with STI571 as second-line therapy of c-kit-positive small-cell lung cancer is in progress. Clinical studies are ongoing in malignancies associated with an enhanced activity of the PDGF-R, such as highgrade glioma, prostate cancer and leukemias with rearrangements of PDGF-R. The development of selective tyrosine kinase inhibitors is considered a promising approach for the design of new drugs. Clinical responses to STI571 in various malignancies may stimulate greater interest in the clinical use of tyrosine kinase inhibitors.
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PMID:[Selective inhibition of tyrosine kinases - a new therapeutic principle in oncology]. 1160 Aug 16

We describe here the definition and characterization of antigen CT-8/HOM-TES-85 encoded by a previously unknown gene and identified by serological expression screening using antibodies from a seminoma patient. Intriguingly, the leucine zipper region of CT-8/HOM-TES-85 shows an atypical amphipathy with clusters of hydrophobic residues that is exclusively shared by the N-myc proto-oncogene. CT-8/HOM-TES-85 gene is tightly silenced in normal tissues except for testis. However, it is frequently activated in human neoplasms of different types including lung cancer, ovarian cancer, melanoma and glioma. Endogenous as well as heterogeneously expressed CT-8/HOM-TES-85 targets predominantly to the nucleus forming a distinctive speckled pattern of nuclear dots arranged in macromolecular structures. By co-localization studies these speckles were identified as loci of transcriptional activity and splicing, suggesting that CT-8/HOM-TES-85 may be involved in these processes. The aberrant expression of CT-8/HOM-TES-85 in human neoplasms might therefore be involved in cancer associated alterations of transcriptional or post-transcriptional processes and thus may disclose new mechanisms involved in the manifestation of the cancer phenotype.
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PMID:A novel tumour associated leucine zipper protein targeting to sites of gene transcription and splicing. 1203 26

Common polymorphisms in DNA repair genes may alter protein function and an individual's capacity to repair damaged DNA; deficits in repair capacity may lead to genetic instability and carcinogenesis. To establish our overall understanding of possible in vivo relationships between DNA repair polymorphisms and the development of cancer, we performed a literature review of epidemiological studies that assessed associations between such polymorphisms and risk of cancer. Thirty studies of polymorphisms in OGG1, XRCC1, ERCC1, XPC, XPD, XPF, BRCA2, and XRCC3 were identified in the April 30, 2002 MEDLINE database (National Center for Biotechnology Information. PubMed Database: http://www.ncbi.nlm.nih.gov/entrez). These studies focused on adult glioma, bladder cancer, breast cancer, esophageal cancer, lung cancer, prostate cancer, skin cancer (melanoma and nonmelanoma), squamous cell carcinoma of the head and neck, and stomach cancer. We found that a small proportion of the published studies were large and population-based. Nonetheless, published data were consistent with associations between: (a) the OGG1 S326C variant and increased risk of various types of cancer; (b) the XRCC1 R194W variant and reduced risk of various types of cancer; and (c) the BRCA2 N372H variant and increased risk of breast cancer. Suggestive results were seen for polymorphisms in other genes; however, small sample sizes may have contributed to false-positive or false-negative findings. We conclude that large, well-designed studies of common polymorphisms in DNA repair genes are needed. Such studies may benefit from analysis of multiple genes or polymorphisms and from the consideration of relevant exposures that may influence the likelihood of cancer in the presence of reduced DNA repair capacity.
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PMID:Polymorphisms in DNA repair genes and associations with cancer risk. 1249 39


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