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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Risks of secondary lung cancer in patients with non-small cell lung cancer and small cell lung cancer are estimated to be 1-2% and 2-10% per patient per year, respectively. Cisplatin is widely used in the treatment of lung cancer and is also known as a carcinogen in experimental animals. In this study, the effect of (-)-epigallocatechin gallate (EGCG) on cisplatin-induced lung tumors in A/J mice was investigated. Female A/J mice (4 weeks old) were divided into four groups: group 1, control without treatment; group 2, EGCG treatment (1 mg/ml in tap water); group 3, weekly cisplatin treatment (1.62 mg/kg body wt, i.p.) for 10 weeks; group 4, cisplatin plus EGCG treatment (EGCG was started 2 weeks before cisplatin treatment). Four groups of mice were killed at week 30 after treatment. Tumor incidence was 26.3% (5/19) in group 1, 30% (6/20) in group 2, 100% (19/19) in group 3 and 94.4% (17/18) in group 4. Tumor multiplicity (the number of tumors per mouse, mean +/- SD) was 0.4 +/- 0.8 in group 1, 0.4 +/- 0.8 in group 2, 5.1 +/- 2.1 in group 3 and 2.8 +/- 2.3 in group 4. Tumor multiplicity was significantly reduced by adding EGCG to cisplatin-treated mice (P < 0.01). Furthermore, EGCG significantly reduced cisplatin-induced weight loss from 24.7-26.3% (cisplatin treatment) to 10.8-11.6% (cisplatin plus EGCG treatment) (P < 0.01). These findings suggest that EGCG can inhibit cisplatin-induced weight loss and lung tumorigenesis in A/J mice.
Carcinogenesis 2000 May
PMID:(-)-Epigallocatechin gallate can prevent cisplatin-induced lung tumorigenesis in A/J mice. 1078 12

The transcription factor achaete-scute homologue-1 (ASH1) is essential for neural differentiation during fetal development and is a cardinal feature of neuroendocrine (NE) tumors such as small cell lung cancer. To explore the potential of ASH1 to promote NE differentiation and tumorigenesis in the lung, we constitutively expressed the factor in nonendocrine airway epithelial cells using transgenic mice. Progressive airway hyperplasia and metaplasia developed beginning at 3 weeks of life. ASH1 potently enhanced the tumorigenic effect of SV40 large T antigen in airway epithelium. These doubly transgenic animals developed massive NE lung tumors, implying that ASH1 may cooperate with defects in p53, pRb, or related pathways in promoting NE lung carcinogenesis.
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PMID:Constitutive achaete-scute homologue-1 promotes airway dysplasia and lung neuroendocrine tumors in transgenic mice. 1094 98

Allyl sulfur compounds play a major role in the chemoprevention against carcinogenesis. The present study compared the antiproliferative effects of diallyl sulfide (DAS), diallyl disulfide (DADS) and garlic extract on p53-wild type H460 and p53-null type H1299 non small cell lung cancer cells (NSCLC). The DAS and DADS treatment of both H460 and H1299 cells resulted in the highest numbers of cells in apoptotic state as measured by acridine orange staining, however, garlic extract treatment did not induce any significant apoptotic cells by MTT assay. DADS was found to be more effective in inducing apoptosis on NSCLC. The level of p53 protein in H460 cell was increased following DADS treatment. DAS and garlic extract treatment of H460 cells induced a rise in the level of Bax and a fall of Bcl-2 level. These results demonstrate that DAS, DADS and garlic extract are effective in reduction of anti-proliferative gene in NSCLC and suggest that modulation of apoptosis-associated cellular proteins by DAS, DADS and garlic extract may be the mechanism for apoptosis which merit further investigation as potential chemoprevention agents.
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PMID:Effects of allyl sulfur compounds and garlic extract on the expression of Bcl-2, Bax, and p53 in non small cell lung cancer cell lines. 1104 43

Small cell lung cancer (SCLC) is characterised by neuroendocrine differentiation, early metastatic potential and initial responsiveness to cytotoxic therapy. Unfortunately, despite recent therapeutic advances, most patients relapse and the overall five-year survival rate is only 5%. Standard treatment of SCLC consists of platinum-based combination chemotherapy, with thoracic irradiation added for patients with limited-stage disease. Several newer chemotherapeutic drugs have recently been shown to have significant activity in patients with untreated or relapsed SCLC. These agents include: the topoisomerase I inhibitors, topotecan and irinotecan; the taxanes, paclitaxel and docetaxel; the pyrimidine analogue, gemcitabine; and the vinca alkaloid, vinorelbine. Recent advances in our understanding of the molecular events involved in the pathogenesis and progression of SCLC have led to the identification of a variety of potential targets for novel therapeutic interventions. Strategies aimed at inhibiting the myriad of growth factor pathways that control the proliferation of SCLC cells, include: broad spectrum neuropeptide antagonists (e.g., substance P analogues); growth factor/receptor-specific inhibitors (e.g., anti-GRP monoclonal antibodies, bradykinin antagonist dimers); and a variety of selective protein kinase inhibitors. The importance of cell death pathways in carcinogenesis and treatment-resistance has led to several novel strategies targeting apoptotic mediators, such as bcl-2, that are frequently dysregulated in SCLC (e.g., bcl-2 antisense). Our current challenges are to further refine these promising therapeutic strategies, efficiently evaluate their activity in the clinical setting and integrate them into more effective treatment regimens to improve the overall prognosis of patients with SCLC.
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PMID:Therapeutic advances in small cell lung cancer. 1106 Jun 96

Cyclooxygenase (COX)-2 has been reported to play an important role in carcinogenesis. Meloxicam (preferential COX-2 inhibitor) inhibits the growth of COX-2 positive and COX-1 negative colorectal cancer cells. We evaluated the effects of meloxicam on the growth of lung cancer cells. By reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis, COX-2 but not COX-1 was expressed in human non-small cell lung cancer (NSCLC) cell lines (A549 and PC14). In human small cell lung cancer (SCLC) cell line (H841), both COX-1 and COX-2 were not detected. MTT assay and prostaglandin (PG) E2 enzyme immunoassay showed that meloxicam inhibited the growth and PGE2 production of both A549 and PC14, but not H841 cells. These findings suggest that COX-2 may play an important role in the pathogenesis and progression of NSCLC, and that meloxicam may be a useful therapeutic agents in the treatment of NSCLC.
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PMID:Meloxicam inhibits the growth of non-small cell lung cancer. 1106 95

Differential display polymerase chain reaction (DD-PCR) was used to analyze the differentially expressed genes from nickel-transformed human embryonic lung (HEL) cells (MRC-9 and IMR-90) and their control counterparts (non-treated). Two genes, MS515 and IC82, were confirmed by Northern blot analysis. MS515 was detected in control and nickel oxide (NiO)-transformed MRC-9 cells, as well as in non-small cell lung cancer (NSCLC) EBC-1 cells, while very weak expression was observed in nickel subsulfide (Ni(3)S(2))-transformed MRC-9 cells and small cell lung cancer (SCLC) SBC-2 cells. IC82 could not be detected in control IMR-90 cells, while it was expressed in EBC-1 cells and NiO- and Ni(3)S(2)-transformed IMR-90 cells. These findings indicate that individual nickel compounds have their own target gene(s) in inducing lung cancer. Sequencing analyses showed that the MS515 gene shared a high degree of homology (over 80%) with the gene Mena, which is involved in actin polymerization. IC82 showed 99% homology with human chromosome 4 clone C0440E08 and a coding sequence in the brain. The roles of these two genes in nickel carcinogenesis will be discussed.
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PMID:Cloning of differentially expressed sequence tags from nickel-transformed human embryonic lung cells. 1107 13

We used overlapping and nested homozygous deletions, contig building, genomic sequencing, and physical and transcript mapping to further define a approximately 630-kb lung cancer homozygous deletion region harboring one or more tumor suppressor genes (TSGs) on chromosome 3p21.3. This location was identified through somatic genetic mapping in tumors, cancer cell lines, and premalignant lesions of the lung and breast, including the discovery of several homozygous deletions. The combination of molecular manual methods and computational predictions permitted us to detect, isolate, characterize, and annotate a set of 25 genes that likely constitute the complete set of protein-coding genes residing in this approximately 630-kb sequence. A subset of 19 of these genes was found within the deleted overlap region of approximately 370-kb. This region was further subdivided by a nesting 200-kb breast cancer homozygous deletion into two gene sets: 8 genes lying in the proximal approximately 120-kb segment and 11 genes lying in the distal approximately 250-kb segment. These 19 genes were analyzed extensively by computational methods and were tested by manual methods for loss of expression and mutations in lung cancers to identify candidate TSGs from within this group. Four genes showed loss-of-expression or reduced mRNA levels in non-small cell lung cancer (CACNA2D2/alpha2delta-2, SEMA3B [formerly SEMA(V), BLU, and HYAL1] or small cell lung cancer (SEMA3B, BLU, and HYAL1) cell lines. We found six of the genes to have two or more amino acid sequence-altering mutations including BLU, NPRL2/Gene21, FUS1, HYAL1, FUS2, and SEMA3B. However, none of the 19 genes tested for mutation showed a frequent (>10%) mutation rate in lung cancer samples. This led us to exclude several of the genes in the region as classical tumor suppressors for sporadic lung cancer. On the other hand, the putative lung cancer TSG in this location may either be inactivated by tumor-acquired promoter hypermethylation or belong to the novel class of haploinsufficient genes that predispose to cancer in a hemizygous (+/-) state but do not show a second mutation in the remaining wild-type allele in the tumor. We discuss the data in the context of novel and classic cancer gene models as applied to lung carcinogenesis. Further functional testing of the critical genes by gene transfer and gene disruption strategies should permit the identification of the putative lung cancer TSG(s), LUCA, Analysis of the approximately 630-kb sequence also provides an opportunity to probe and understand the genomic structure, evolution, and functional organization of this relatively gene-rich region.
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PMID:The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. 1108 36

Increased expression of cyclooxygenase-2 (COX-2) significantly enhances carcinogenesis and inflammatory reactions. Regulation of COX-2 overexpression may be a reasonable target for cancer chemoprevention. We have tested the hypothesis that levels of COX-2 expression determine the growth of human lung cancer cells in nude mice. Two cell lines, NCI-H460 (non-small cell lung cancer) and NCI-H69 (small cell lung cancer) were selected because the former expresses high levels of COX-2 protein and the latter has no detectable levels. We also examined the effects of 1,4-phenylenebis(methylene)selenocyanate (p-XSC), a highly effective chemopreventive organoselenium compound and known inhibitor of COX-2 expression, in vivo, on cell growth and COX-2 expression in vitro in the NCI-H460 cancer cell line. Cells were exposed to p-XSC at levels between 10 and 100 microM for six days and showed toxicity at approximately 50 microM. Pre-exposure of NCI-H460 to non-toxic levels of p-XSC suppressed COX-2 protein expression in a dose-dependent manner. At 40 microM, p-XSC suppressed phorbol myristate acetate (PMA)-induced COX-2 expression in NCI-H460 cells by more than 66%. In vivo studies in athymic mice showed a significant difference in tumor volume between cell lines. Pre-treatment of NCI-H460 cells with a non-toxic dose of p-XSC, prior to their injection into nude mice, significantly suppressed tumor growth when compared to untreated cells. Collectively, the outcome of our in vitro and in vivo studies supports the hypothesis that levels of COX-2 expression determine the extent of human lung tumor growth in athymic mice. Therefore, inhibition of COX-2 expression by agents such as p-XSC provides a strong rationale for the development of future clinical prevention trials.
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PMID:Cyclooxygenase-2 expression influences the growth of human large and small cell lung carcinoma lines in athymic mice: impact of an organoselenium compound on growth regulation. 1183 68

Cytogenetic deletions and/or loss of heterozygosity (LOH) of the short arm of chromosome 3, often with a break at 3p14, are well documented in lung tumors. The coincidence of a chromosomal fragile site, FRA3B, at a common chromosomal breakpoint in lung cancer has suggested that fragility at this site may predispose to breakage that could contribute to multistep carcinogenesis. This idea is supported by the more recent finding that FRA3B maps within the FHIT (fragile histadine triad) gene, and that aberrant transcripts and genomic deletions of FHIT/FRA3B occur in a variety of tumors including lung tumors. To determine whether some individuals have increased fragility of FRA3B that might increase the risk for breakage or deletion in 3p14.2, fragile site expression was examined in smokers, nonsmokers, and small cell lung cancer (SCLC) patients. The data clearly show that active smokers exhibit a significantly higher frequency of fragile site expression, including FRA3B, compared to that of nonsmokers and patients diagnosed with SCLC who have stopped smoking. These results suggest that active tobacco exposure increases chromosome fragile site expression, and that this fragility is transient and reversible. The data support the hypothesis that exposure to tobacco carcinogens increases the potential for chromosome breakage at fragile sites.
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PMID:Direct correlation between FRA3B expression and cigarette smoking. 1200 94

Some of the glutathione S-transferases (GSTs) are polymorphic and may play a role in lung cancer susceptibility. Our previous study in a French Caucasian study population suggested GSTM1 null genotype as a moderate risk factor for lung cancer. Here we extended the study to investigate the potential role of GSTT1 and GSTP1 polymorphisms in susceptibility to lung cancer, either separately or in combination. The study population consisted of 268 controls and 251 cases. Nineteen percent of the controls and 15% of the cases had GSTT1 null genotype. The distribution of GSTP1*A/*A, *A/*B and *B/*B genotypes were 46.9, 45.5 and 7.6% in controls, and 47.8, 40.2 and 12.0% in cases, respectively. No statistically significant effects in the lung cancer risk were observed for the GSTT1 genotypes, but the GSTP1*B/*B genotype posed a 2-fold risk [odds ratio (OR) = 2.0, 95% confidence interval (CI) 1.0-4.1] of this malignancy compared with the GSTP1*A allele containing genotypes; this association was mainly attributable to small cell lung cancer (OR = 3.6, 95% CI 1.3-9.8). The most remarkable risk was seen for the small cell carcinoma among subjects with the GSTP1*B/*B genotype and concurrent lack of the GSTM1 gene (OR = 6.9, 95% CI 1.6-30.2). The deficient genotypes for GSTM1 and GSTP1 seem thus to be important risk modifiers for lung cancer, especially in combination.
Carcinogenesis 2002 Sep
PMID:Genetic polymorphisms of glutathione S-transferases as modulators of lung cancer susceptibility. 1218 90


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