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)

Lung cancer results from a stepwise accumulation of genetic and molecular abnormalities with unknown temporal relationships to precursor bronchial lesions. In a search for biomarkers of malignant progression, we analyzed the expression of the tumor suppressor gene Rb and of the proteins regulating its phosphorylation and function in G1 arrest, p16INK4A and cyclin D1, in preinvasive bronchial lesions accompanying cancer in 75 patients, in comparison with similar lesions in 22 patients with no cancer history. Rb was constantly expressed in preinvasive lesions, including carcinoma in situ (CIS). In contrast, p16 expression was lost in moderate dysplasia (12%) and in CIS (30%) in patients with lung cancer. p16 loss occurred exclusively in patients who displayed loss of p16 expression in their related invasive carcinoma. Loss of p16 expression was not seen in nine patients with dysplasia but no cancer progression. Cyclin D1 overexpression was seen in hyperplasia and metaplasia (6%), mild dysplasia (17%), moderate dysplasia (46%), and CIS (38%) in patients with cancer but was lost in 5% of the patients during the process of invasion; it was also observed in patients with no cancer progression (14%). Our results indicate that Rb protein function can be invalidated before invasion through alteration of the Rb phosphorylation pathway, by p16 inhibition, and/or by cyclin D1 overexpression and suggest a role for p16 and cyclin D1 deregulation in progression of preinvasive bronchial lesions to invasive carcinoma.
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PMID:Alterations of Rb pathway (Rb-p16INK4-cyclin D1) in preinvasive bronchial lesions. 1003 71

We studied the effect of smoking on tumor progression in 3312 patients with lung cancer registered at the National Matsudo Hospital and National Cancer Center Hospital East between 1977 and 1996. The odds ratios of the following variables for tumor extent (localized versus advanced disease) and hazard ratios for survival were calculated in both sexes separately using the logistic regression and Cox proportional hazard models, respectively: smoking history, number of cigarettes smoked per day, pack-years smoked, age, histological type, and the year of admission. Of the 943 women, 367 (38.9%) were smokers and 694 (73.6%) had adenocarcinoma, whereas of the 2369 men, 2255 (95.2%) were smokers and 1010 (42.6%) had adenocarcinoma. In female adenocarcinoma patients, the odds ratio (95% confidence interval) for advanced disease and the hazard ratio (95% confidence interval) for survival with an increase of 30 cigarettes smoked per day were 2.86 (1.49-5.49) and 1.52 (1.13-2.04), respectively, but in those with non-adenocarcinoma, the odds ratio and hazard ratio were 0.96 (0.41-2.23) and 1.13 (0.75-1.70), respectively. In male patients, smoking history influenced tumor progression regardless of histological type, but the odds ratios and hazard ratios were lower than those for women with adenocarcinoma. In conclusion, smoking habit was closely correlated with progression of adenocarcinoma in women. This association was not observed in women with non-adenocarcinoma and was weaker in men, suggesting various effects of smoking on lung cancer development depending on gender and the histological type of the tumor.
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PMID:Association between smoking and tumor progression in Japanese women with adenocarcinoma of the lung. 1018 82

The positive impact on survival of traditional chemotherapeutic agents has renewed interest in developing newer cytotoxic agents and orally active compounds with improved therapeutic indices. In addition, new insights into the pathways of human tumorigenesis have led to novel approaches aimed at specific mechanism-based targets. The taxane class, of which paclitaxel was the first member, has the unique ability to promote and stabilize microtubule function directly, thereby inhibiting mitotic progression and inducing apoptotic cell death. Paclitaxel provides treatment benefit in a broad range of solid tumors including breast, ovarian, and lung cancer. The success with paclitaxel stimulated interest in the microtubule as a new therapeutic target. Taxane analogues with improved preclinical efficacy have been identified and are entering clinical trials. The enthusiasm for oral anticancer agents and the therapeutic importance of platinum compounds has led to the development of JM216 (satraplatin), a novel platinum IV coordination complex with oral activity in cisplatin-resistant cell lines, which is now in phase III trials in prostate cancer. Another compound in late development is DPPE, a chemopotentiator that enhances the in vivo antitumor effects of cytotoxic agents such as doxorubicin, cyclophosphamide, and cisplatin. Agents that inhibit topoisomerase I and II have also been of interest. TAS-103 is a dual topoisomerase I and II inhibitor with preclinical efficacy in a broad spectrum of tumors and in multidrug-resistant tumor cell lines. Vaccination strategies represent a rational therapeutic approach in the minimal residual disease or high-risk adjuvant therapy setting. The GMK and MGV vaccines utilizing ganglioside antigens overexpressed on human tumors such as melanoma and small cell lung cancer appear to induce antibody production reliably at tolerable doses and are under further clinical investigation. Inhibition of matrix metalloproteinases (MMPs) is another attractive target for intervention in several aspects of tumor progression. Local production of MMPs with subsequent degradation of the extracellular matrix is implicated in supporting tumor growth, invasion, and angiogenesis. The development of orally active, nontoxic MMP inhibitors is critical since these compounds will likely require chronic administration in conjunction with other therapies. Oncogenes and tumor suppressor genes are appealing targets for therapy since they are thought to be responsible for a significant number of cancers. Mutations in the Ras oncogene occur with great frequency in a number of human cancers including lung, pancreas, and colon cancer. Clinical development of potent and selective inhibitors of farnesyltransferase, the Ras-processing enzyme, is ongoing. These compounds uncouple Ras activity, affect tumor growth, and have demonstrated significant antitumor activity against experimental models of human cancer. The exciting compounds and novel therapeutic approaches currently under investigation by Bristol-Myers Squibb Pharmaceutical Research Institute offer great potential as effective cancer chemotherapy agents for the near future.
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PMID:Promising new developments in cancer chemotherapy. 1035 61

Autotaxin (ATX) is one of the newly discovered autocrine motility-stimulating factors with peptide sequences identical to those of the brain-type phosphodiesterase I (PD-Ialpha). Although ATX/PD-Ialpha is believed to play a role in tumor progression, its expression in various human cancers has not been extensively studied. We have studied the expression of ATX messenger RNA (mRNA) in normal human bronchial epithelial cell (HBEC) and non-small-cell lung cancer (NSCLC) cell lines, and in primary NSCLC with their corresponding normal lung tissues, using reverse transcription-polymerase chain reaction, Northern blot analysis, and in situ hybridization. ATX mRNA was commonly expressed in these cell lines and tissues. The predominantly expressed mRNA species corresponded to the ATX complementary DNA isolated from a human teratocarcinoma cell line. Overexpression of ATX mRNA was detected in seven of 12 (58%) tumor cell lines; however, there was no correlation between the levels of expression of ATX mRNA and the spontaneous motility of these cells. In situ hybridization localized ATX mRNA expression to the basal cells of normal bronchial epithelium, stromal B lymphocytes, and tumor cells. An overexpression of ATX mRNA as compared with its expression in normal bronchial epithelium was mainly found in poorly differentiated carcinomas. Our findings suggest that ATX may have roles additional to its motility-stimulating function in undifferentiated NSCLC.
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PMID:Autotaxin expression in non-small-cell lung cancer. 1042 4

A phase II study of combined-modality treatment consisting of uracil and tegafur (in a molar ratio of 4:1 [UFT]) plus cisplatin (Platinol) and concurrent radiotherapy was conducted to evaluate the activity of this regimen in patients with locally advanced non-small-cell lung cancer. Eligible patients with cytologically or histologically confirmed, unresectable stage III non-small-cell lung cancer received UFT (400 mg/m2 orally on days 1 through 52) and cisplatin (80 mg/m2 intravenously on days 8, 29, and 50). Radiotherapy, with a total dose of 60.8 Gy, was delivered in 38 fractions on days 1 through 52. Among the 17 patients entered, 16 experienced partial responses (94%; 95% confidence interval, 83% to 100%). The median time to tumor progression was 30 weeks (range, 8 to 87 weeks), and the 1-year survival rate was 80%. Hematologic toxicity was moderate. Grade 3 leukopenia occurred in 10 patients (59%), but no grade 4 hematologic toxicity was observed. No grades 3 or 4 nonhematologic toxicities were reported. These observations suggest that oral UFT plus cisplatin with concurrent radiotherapy can be safely administered to patients with locally advanced non-small-cell lung cancer. The demonstrated antitumor activity is high, making this combined-modality treatment worthy of further investigation in a multi-institution trial.
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PMID:UFT plus cisplatin with concurrent radiotherapy for locally advanced non-small-cell lung cancer. 1044 74

The plasminogen activator cascade initiated by urokinase type plasminogen activator (u-PA) is involved in extracellular matrix degradation during the tumor invasion process. The plasminogen activator inhibitors 1 (PAI-1) and 2 (PAI-2) are two specific inhibitors of u-PA. We hypothesized that the balance between u-PA and its two inhibitors could be disrupted to favor plasminogen activation during lung cancer progression. Using immunohistochemistry, we analyzed the pattern of expression of u-PA, PAI-1, and PAI-2 in non-small cell lung carcinomas (NSCLC) and neuroendocrine (NE) lung tumors. u-PA and PAI-1 were both detected in stromal fibroblasts and in tumor cells. In 84 NSCLCs, their epithelial expression was strongly correlated and linked to the presence of node metastasis (P = 0.008), whereas their coexpression in fibroblasts was associated with larger tumor size (P = 0.04) and advanced stages (P = 0.009). In 72 NE tumors, u-PA and PAI-1 were more frequently expressed in fibroblasts in high-grade NE tumors (SCLC and large cell NE tumors) than in low- and intermediate-grade tumors (typical and atypical carcinoids). Comparison of in situ hybridization and immunohistochemistry in 14 cases showed that PAI-1 was consistently expressed by stromal fibroblasts, although the protein was also localized in tumor cells. In contrast, the expression of PAI-2 was restricted to fibroblasts and correlated with the absence of nodal involvement (P = 0.005). Considering NE tumors, the frequency of PAI-2 expression decreased along the NE spectrum from typical carcinoids to SCLCs. These data suggest that PAI-lacts in synergy with u-PA to favor tumor invasion process and connotes aggressivity, in contrast with PAI-2, which may block u-PA-mediated proteolysis and is inversely correlated with tumor progression.
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PMID:Expression of plasminogen activator inhibitors 1 and 2 in lung cancer and their role in tumor progression. 1047 92

KAI1, a metastasis suppressor gene of prostate cancer, is located on human chromosome 11p11.2. Down-regulation of KAI1 mRNA during tumor progression and metastasis has been reported for several kinds of cancer, but the mechanism of this down-regulation is not known. In the present study, our aim was to ascertain the relationship between down-regulation of KAI1 mRNA expression and KAI1 gene alterations in lung cancer. Forty-nine cases of adenocarcinoma of the lung were studied by reverse-transcriptase polymerase chain reaction (RT-PCR) assay of KAI1 mRNA and by immunohistochemical detection of KAI1 protein. In addition, markers of the microsatellite loci D11S1344 and D11S1326 were used to investigate loss of heterozygosity (LOH) and replication errors (RERs) of the KAI1 gene region. The RT-PCR assay showed that there was no correlation between KAI1 mRNA expression and either the age of the patients or tumor size. By contrast, KAI1 mRNA expression was significantly correlated with gender (P=0.047), metastasis to the lymph nodes or other organs (P=0.004), the histological grade of the tumor (P=0.036) and the pathological stage (P=0.049). Immunohistochemical staining showed that in one case without metastasis, loss of KAI1 mRNA was associated with invasion of the stroma by KAI1 protein-negative cancer cells. The numbers of informative cases by microsatellite analysis were 14 (28.6%) of 49 at D11S1344 and 27 (55.1%) of 49 at D11S1326; none of 49 adenocarcinomas showed LOH or RERs at these loci. These results suggest that down-regulation of KAI1 mRNA expression rarely if ever involves LOH or RERs of the KAI1 gene region in primary lung adenocarcinoma.
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PMID:Down-regulation of KAI1 messenger RNA expression is not associated with loss of heterozygosity of the KAI1 gene region in lung adenocarcinoma. 1055 26

The outcome of limited field irradiation for medically inoperable patients with peripheral stage I non-small cell lung cancer (NSCLC) was analyzed to discuss the elective irradiation of regional lymph nodes. From 1976 through 1994, 36 patients with peripheral stage I NSCLC were treated with definitive radiation therapy (RT) alone at Gunma University hospital. The total dose ranged from 60 to 81 Gy with a 2 Gy-daily standard fractionation, although only one patient received 48 Gy. Ten patients received elective irradiation of the regional lymph nodes with a total dose of 40 Gy or more. The overall response rate was 97% with 31% complete responses. The overall survival rates at 3 and 5 years were 42 and 23%, and disease-specific survival rates were 56 and 39% at 3 and 5 years, respectively. In 26 patients without the elective regional irradiation, disease-specific survival rates at 3 and 5 years were 53 and 40%, respectively, whereas they were 64 and 39% in 10 patients with the regional nodal irradiation. The cumulative 5-year local progression rate was 28%, and the overall progression rate was 60% at 5 years. Four patients had a local recurrence as the only site of initial tumor progression. Combined local and regional progression was seen in two patients, and one patient had a local recurrence in combination with distant metastasis. Twelve patients had distant failure without evidence of local or regional progression. Only one patient without regional nodal irradiation developed an isolated regional failure. No patient had serious complications related to RT. High-dose limited field RT is justified for medically inoperable patients with peripheral stage I NSCLC. The regional nodal irradiation can be omitted in these pulmonary compromised patients because of the low regional relapse rate. Dose-escalation by a conformal RT with a small target volume can be expected to provide a better local control rate and better survival.
Lung Cancer 1999 Dec
PMID:Limited field irradiation for medically inoperable patients with peripheral stage I non-small cell lung cancer. 1059 23

The integrin family plays a major role in complex biological events such as differentiation, development, wound healing, and the altered adhesive and invasive properties of tumor cells. Integrin (alpha5beta1 is a classical fibronectin receptor, and it has been known as a tumor suppressor gene because tumor cells overexpressing alpha5beta1 are less tumorigenic than their parent cells. However, this finding conflicts with some recent data that suggests that the emergence of alpha5beta1 expression correlates with the tumor progression. We, therefore, investigated the expression of alpha5beta1 integrin in 20 lung cancer cell lines by flow cytometric analysis and in 88 node-negative non-small cell lung cancers (NSCLCs) by RT-PCR and immunohistochemical assays to determine the significance of this prognostic factor. In the 20 lung cancer cell lines, 8 (40.0%) cell lines strongly expressed integrin alpha5, 3 (15.0%) cell lines had moderate or weak alpha5 expression, and the remaining 9 (45.0%) cell lines expressed no integrin alpha5. In the 88 node-negative NSCLC patients, 44 samples (50.0%) were evaluated as having integrin alpha5 overexpression, and the integrin alpha5 expression was significantly associated with the status of differentiation and the age of the patients (P = 0.0379 and 0.0312, respectively). In the node-negative patients, the overall survival rate for patients with integrin alpha5 overexpressed tumors was significantly worse than for those individuals whose tumors had normal integrin alpha5 expression (P = 0.016).
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PMID:Significance of integrin alpha5 gene expression as a prognostic factor in node-negative non-small cell lung cancer. 1065 37

MUC1 mucin is a target protein for many monoclonal antibodies. Human MUC1 detected by a murine anti-KL-6 monoclonal antibody that recognizes a sialylated carbohydrate chain has been designated KL-6/MUC1. Given the heterogeneous antigenicity of KL-6/MUC1, we established a new murine monoclonal antibody, H9, that reacts with epitope DTRP (Asp-Thr-Arg-Pro) peptides within the immunodominant region of the tandem repeat of MUC1 mucin. The reactivity of the H9 antibody differs from that of other previously reported antibodies that recognize the tandem repeat region of MUC1. Immunohistochemical experiments indicate that the reactivity of the H9 antibody is similar to that of other antibodies directed against MUC1 core proteins. A new cancer-associated protein detected by a sandwich assay using the H9 antibody as a catcher and the KL-6 antibody as a tracer is designated HK9. Serum HK9 levels showed a high expression level in lung cancer: 51% (19/37 cases) for adenocarcinoma, 39% (11/28 cases) for squamous cell carcinoma, and 67% (10/15 cases) for small cell carcinoma. The HK9 expression in lung cancer increased with cancer progression. These findings suggest monoclonal antibody H9 to be a novel antibody that reacts with an epitope within the tandem repeat region of MUC1, and that the cancer-associated antigen HK9 may have useful tumor-associated properties.
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PMID:A novel monoclonal antibody, H9, directed against the core protein of MUC1 mucin. 1067 62


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