Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149925 (small cell lung cancer)
 6,491 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bombesin-like peptides can function as autocrine growth factors in lung cancer and candidate tumor suppressor genes on chromosomes 3 and 9 play important roles in lung cancer. Bombesin-like peptides can function as mitogens for normal bronchial epithelial cells and lung cancer cell lines. The monoclonal antibody directed against gastrin releasing peptide and bombesin, 2A11, can inhibit the growth of small cell lung cancer in vitro and in vivo and intravenous administration has induced a clinical remission in a patient with relapsed small cell lung cancer. The loss of a portion of one of the two short arms of chromosome 3 (3p) is identified in nearly 100% of tumor cell lines and tumors from patients with small cell lung cancer. Introduction of chromosome 3 into tumor cell lines suppresses their tumorigenicity in athymic nude mice, one of the characteristics of the cancer phenotype. Both copies of the candidate tumor suppressor gene on chromosome 9, CDKN2, are deleted in approximately one-fourth of lung cancer cell lines examined and the protein product of CDKN2, p16 is undetectable in one-third of the lung cancer cell lines studied. The CDKN2 gene is inactivated more commonly in non-small cell lung cancer than small cell lung cancer while the retinoblastoma gene is inactivated more commonly in small cell lung cancer than non-small cell lung cancer. It appears that a single defect in this cell cycle pathway is necessary for unregulated growth in lung cancer and current evidence suggests these defects differ between small cell and non-small cell lung cancer.
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PMID:Biology of small cell lung cancer. 755 56

Two small cell lung cancer (SCLC) cell lines were established from metastases of a patient during the course of the disease. SCLC 74A was derived from biopsy material obtained at the time of diagnosis and SCLC 74B was from a biopsy specimen of a relapsed tumor obtained after treatment. A transition occurred from SCLC 74A, an intermediate form with 5% large cells to SCLC 74B, a standard mixed form with 20% of large cells, with a decrease in neuroendocrine markers and a substantial increase in P-glycoprotein, a multidrug resistance marker. For both cell lines, R-banding and FISH indicated a del(1)(p35pter) also found in other neural-crest-derived tumors, the loss of regions with suspected tumor suppressor genes at 3p, 5q, and 17p, and a recurrent translocation of the 6q24-6qter region to 10p14. Further genetic modifications in SCLC 74B affected chromosomes 2, 3, 5, 10, 11, 14, and 15. The main observations were a der(2)t(2;5)(p16;q?); a der(3;11)(q10;p10) in SCLC 74A which became der(3;14)(q10;p10) and der(11;14)(p10;q10) in SCLC 74B; and the insertion of the 5q13-5q31 region in the der(10)t(6;10). The finding of the same structural abnormalities in both cell lines suggests a monoclonal origin for both metastases. Hypotetraploid cells were in the same proportion as large cells whose number was a characteristic feature of each cell line. They possessed twice the same chromosomal alterations observed in the hypodiploid cells. This suggests a permanent process of tetraploidization.
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PMID:Evolution of chromosomal alterations and biologic features in two small cell lung carcinoma cell lines established from one patient during the course of the disease. 769 32

cdk4-mediated phosphorylation of the retinoblastoma susceptibility protein (Rb) is stimulated by cyclin D1, an oncogene, and inhibited by p16, a candidate tumor suppressor. We examined these proteins in non-small cell lung cancer (NSCLC), which is predominantly Rb positive, and small cell lung cancer (SCLC), which is Rb negative. Most NSCLC and SCLC resection specimens and cell lines overexpress cyclin D1 (indicating that cyclin D1 overexpression and Rb inactivation can coexist in SCLC). However, 9 of 9 Rb-positive NSCLC cell lines have absent or low p16, while an Rb-negative NSCLC line and 5 of 5 SCLC cell lines have high levels of p16. In primary resection specimens, p16 was undetectable in 18 of 27 NSCLC samples and abundant in 4 of 5 SCLC samples. Our data confirm the predicted reciprocity between Rb inactivation and p16 expression in a common human malignancy and define differential p16 expression as a fundamental distinction between NSCLC and SCLC.
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PMID:Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell lines. 783 18

Frequent homozygous deletions of the p16 (MTS1) gene encoding a cyclin-dependent kinase inhibitor were recently reported in various tumor cell lines including examples derived from lung cancers, but direct evidence for their occurrence in lung cancer patients has not been reported thus far. In the present study, alterations of p16 and/or p15, a p16-related cyclin-dependent kinase, were observed not only in lung cancer cell lines but also in the corresponding tumor specimens in vivo, excluding the possibility of in vitro artifacts. Interestingly, a clear specificity was also noted in terms of the affected histological subtype; i.e., only non-small cell lung cancers carried alterations (6 of 20 as compared to 0 of 20 small cell lung cancer cell lines).
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PMID:In vivo occurrence of p16 (MTS1) and p15 (MTS2) alterations preferentially in non-small cell lung cancers. 783 19

p16/CDKN2/MTS1, a putative tumor suppressor gene, located in the chromosome 9p21 region was cloned in 1994. This gene encodes a protein that binds to and inhibits cyclin-dependent kinase 4 (CDK4), and plays a role in cell cycle regulation. p16 gene has been reported to be homozygously deleted in a variety of human tumors. Using PCR-based assays for exons 2 and 3 of p16 gene, we found homozygous deletions in 15 (48%) of 31 non-small cell lung cancer (NSCLC) cell lines. In contrast, none of 11 small cell lung cancer (SCLC) cell lines had p16 deletions (p = 0.012). Taken together with results previously reported, our data indicate that p16 gene is more frequently deleted in NSCLC than in SCLC. Although the incidence of p16 abnormalities in NSCLC surgical specimens is inconclusive, recent reports suggest that p16 abnormalities are well correlated with tumor dissemination. The role of p16 gene in pathogenesis of lung cancer remains to be elucidated.
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PMID:[p16/CDKN2/MTS1 gene abnormality in lung cancer]. 883 5

Deletion at 9p21 is frequent in many tumor types. A candidate tumor suppressor gene, p16INK4a, was mapped to this region and is frequently inactivated by several different mechanisms in many tumor types, including non-small cell lung cancer, but not in small cell lung cancer (SCLC). p16 functions as a cyclin/CDK inhibitor to prevent phosphorylation of pRB. It has been demonstrated that most SCLCs have lost pRB but retained p16, and the inactivation of pRB excludes the inactivation of p16 and vice versa. To determine the potential existence of other tumor suppressor genes on the short arm of chromosome 9 in SCLC, we tested 46 primary SCLCs by microsatellite analysis. We found that more than 89% of the tumors exhibited loss of heterozygosity (LOH) at 9p with three distinct minimal deleted areas. Among those areas, LOH at 9p21 was most frequent (86%), with a peak at a marker 150 kb telomeric to p16INK4a. LOH was also observed in more than 50% of the tumors at two other regions, 9p22 and 9p13. Our data strongly suggest the presence of at least three novel tumor suppressor loci on 9p in SCLC, and further investigations to clone candidate tumor suppressor genes are warranted.
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PMID:Identification of three distinct tumor suppressor loci on the short arm of chromosome 9 in small cell lung cancer. 901 64

Many antineoplastic drugs and cytotoxic irradiation induce apoptosis in cancer cells. ICE and ICE-like proteases play important roles in drug-induced apoptosis of cancer cells. We evaluated the cellular factors affecting susceptibility to apoptosis using gene-transfected cells. Introduction of bcl 2 gene into human small cell lung cancer cells conferred resistance to mitomycin C and irinotecan. DNA fragmentation was reduced in these cells. These results indicate apoptosis is one of the mechanisms of cell death caused by some antineoplastic drugs. Investigations are ongoing to elucidate the contribution of the Bcl 2 family proteins to antineoplastic drug induced apoptosis. Wild type p53-transfected cancer cells were sensitive to anticancer drugs. On the other hand, p53-depleted cells were reported to be more sensitive to taxanes than p53-proficient cells. Introduction of Rb gene and p16-gene enhanced cytotoxicity of taxanes and topoisomerase I inhibitors, respectively. In clinical studies, patients of non small cell lung cancer with high expression of Bcl-2 were reported to show longer survival than patients with lower expression. However, this result may be confusing because Bcl-2 reduced the efficacy of antineoplastic drugs. Further evaluation is required to determine the cellular proteins serving as markers for treatment efficacy or prognosis.
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PMID:[Apoptosis and chemosensitivity]. 903 Feb 34

Lung cancer is one of the leading causes of cancer death in the world. The high mortality rate for lung cancer probably results, at least in part, from the absence of standard clinical procedures for diagnosis of the disease at early and more treatable stages compared to breast, prostate, and colon cancers. The delineation of genetic alterations that occur in lung tumorigenesis may aid in both developing molecular markers for early detection and predicting of response to chemoprevention/chemotherapy. Cytogenetic and molecular genetic studies have shown that mutations in protooncogenes and tumor suppressor genes (TSGs) are critical in the multi-step development and progression of lung tumors. Inactivation of TSGs are by far the most common mutational events documented during the development of lung cancer. For example, loss of function of the Rb and/or p53 genes has been detected in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In addition, allelic loss analyses have implicated the existence of other tumor suppressor gene loci on 9p as well as on 3p, 5q, 8p, 9q, 11q, 11q, and 17q. We examined the short arm of chromosomes 3 and 9 for TSG loci by analyzing 23 squamous cell carcinomas of the lung with numerous microsatellite markers. On chromosome 9p, loss of heterozygosity was detected in all of the 23 tumors and homozygous deletions of the p16/CDKN2 locus were detected in 6 of the 23 (26%) tumors. In addition, a novel region of homozygous deletion was detected in 6 of the tumors (26%) at D9S126. The homozygous deletion of D9S126 was confirmed by fluorescent in situ hybridization (FISH) analysis of tumor tissue touch preparations and isolated nuclei using P1 and cosmid probes that contain D9S126. Only one tumor harbored a homozygous deletion at both the p16/CDKN2 locus and the D9S126 locus. The data identify a region of homozygous loss on the short arm of chromosome 9, suggesting the presence of a novel TSG locus approximately 2.5 cM proximal to p16/CDKN2. On chromosome 3p, a similar high percentage of the tumors exhibited loss of heterozygosity. Also, homozygous deletions were detected in several tumors at 3p21.3. Thus, FISH analysis with probes containing the D9S126 or p16 locus could be used as molecular markers to assay sputum samples for premalignant cells exfoliated from the bronchial epithelium. Probes from other chromosome regions such as 3p21 could be used in a similar manner.
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PMID:Genetic markers for early detection of lung cancer and outcome measures for response to chemoprevention. 958 50

The retinoblastoma protein (pRB), p16, and cyclin D1 are major components of the RB pathway, which controls the G1 checkpoint of the cell cycle. Proper regulation of this pathway is crucial for normal cell proliferation. Abnormal forms of these proteins have been found in various types of malignant tumours. In the present report, immunohistochemical techniques were applied to study the expression of pRB, p16, and cyclin D1 in 161 samples of primary small cell lung cancer (SCLC) and 20 samples of non-small cell lung cancer (NSCLC). While pRB and cyclin D1 staining was negative in 161 specimens of SCLC, expression of p16 was observed in 153 samples. In contrast to SCLC, 16 out of 20 NSCLC cases exhibited pRB expression and 15 showed cyclin D1 expression, but only very weak p16 staining was found in five samples. These observations could provide additional criteria for the distinction between SCLC and NSCLC. Furthermore, these findings, based on primary tissues, implicate different mechanisms in the tumourigenesis of SCLC and NSCLC.
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PMID:Expression of p16 and lack of pRB in primary small cell lung cancer. 1054 97

To identify the major tumor suppressor gene (TSG) loci involved in the pathogenesis of lung cancer, we have conducted a high-resolution (10 cM), genome-wide search of loss of heterozygosity (LOH). Thirty-six lung cancer cell lines [14 small cell lung cancers (SCLCs) and 22 non-SCLCs (NSCLCs)] and their matched control DNAs were analyzed using 399 fluorescent microsatellite markers from the ABI Prism linkage mapping set v.2 on an ABI 377 sequencer/genotyper. Overall, 22 different regions with more than 60% LOH were identified: (a) 13 regions with a preference for SCLC; (b) 7 regions with a preference for NSCLC; and (c) 2 regions affecting both SCLC and NSCLC. The chromosomal arms with the most frequent LOH were 1p, 3p, 4p, 4q, 5q, 8p, 9p (p16), 9q, 10p, 10q, 13q (Rb), 15q, 17p (p53), 18q, 19p, Xp, Xq. In addition, new homozygous deletions were found at 2p23, 8q24, 18q11, and Xq22. On average, 34% (SCLC) to 36% (NSCLC) of markers showed allele loss in individual tumors, with an average size of subchromosomal region of loss of five to six markers (50-60 cM). Whereas SCLC and NSCLC had different regions of frequent LOH (hot spots), and NSCLC had more of these regions (n = 22) than SCLC (n = 17), in all other parameters (fractional allelic loss, number of breakpoints, and number of microsatellite alterations), SCLC and NSCLC were not significantly different. Clustering analysis revealed correlations between LOH on different chromosomes that suggest previously unknown genetic interactions for lung cancer development. We conclude that (a) in lung cancer cell lines, at least 17-22 chromosomal regions with frequent allele loss are involved, suggesting that the same number of putative TSGs are inactivated; (b) SCLC and NSCLC frequently undergo different specific genetic alterations; and (c) clusters of TSGs are likely to be inactivated together. Overall, these data provide global estimates of the extent of genetic changes leading to lung cancer and will be useful for the positional cloning of new TSGs and for the identification of multiple new biomarkers for translational research.
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PMID:Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. 1098 4


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