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(1/382) Mechanisms of apoptosis induced by the synthetic retinoid CD437 in human non-small cell lung carcinoma cells.

The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) has been shown to induce apoptosis in various tumor cell lines including human non-small cell lung carcinoma (NSCLC) cells, which are resistant to the natural all-trans retinoic acid and to many synthetic receptor-selective retinoids. Although the mechanism of this effect was not elucidated, it was found to be independent of nuclear retinoid receptors. In the present study, we analysed the mechanisms by which CD437 induces apoptosis in two human NSCLC cell lines: H460 with wild-type p53 and H1792 with mutant p53. Both cell lines underwent apoptosis after exposure to CD437, although the cell line with wild-type p53 (H460) was more sensitive to the induction of apoptosis. CD437 increased the activity of caspase in both cell lines, however, the effect was much more pronounced in the H460 cells. The caspase inhibitors (Z-DEVD-FMK and Z-VAD-FMK) suppressed CD437-induced CPP32-like caspase activation and apoptosis in both cell lines. CD437 induced the expression of the p53 gene and its target genes, p21, Bax, and Killer/DR5, only in the H460 cells. These results suggest that CD437-induced apoptosis is more extensive in NSCLC cells that express wild-type p53, possibly due to the involvement of the p53 regulated genes Killer/DR5, and Bax although CD437 can also induce apoptosis by means of a p53-independent mechanism. Both pathways of CD437-induced apoptosis appear to involve activation of CPP32-like caspase.  (+info)

(2/382) A case of synchronous double primary lung cancer with neuroendocrine features.

We report a case of unique double primary lung cancers with neuroendocrine features in a 63-year-old male smoker. The mass in the left lower lobe (LLL) was a small cell/large cell carcinoma with spindle cell sarcomatous areas and organoid structure. The mass in the left upper lobe (LUL) was a tubular adenocarcinoma with neuroendocrine features including organoid nests showing occasional rosette formation, nuclear palisading in the periphery of the nests and positive immunoreaction for CD56, chromogranin A and synaptophysin. The difference in histological structures between the two masses led us to diagnose double primary lung cancer. The combination of small cell lung carcinoma and spindle cell carcinoma is very uncommon. The relationship between LLL and LUL tumors remains unclear. Multiple lung cancers with neuroendocrine features have only rarely been reported in the literature. The patient in our case died of widespread cancer 2 years and 4 months after the surgery without adjuvant chemotherapy, a longer postoperative survival time than in cases of ordinary extensive small cell lung cancer. Multiple lung cancers with neuroendocrine features are extremely rare and similar cases have not been reported in the literature. Neuroendocrine differentiation has attracted widespread attention and, therefore, examining neuroendocrine features in lung cancers is important.  (+info)

(3/382) Lung cancer incidence rates by histologic type in high- and low-risk areas; a population-based study in Osaka, Okinawa, and Saku Nagano, Japan.

We investigated lung cancer incidence by histologic type using the data from population-based cancer registries in high-risk (Osaka and Okinawa) and low-risk (Saku Nagano) areas. Since the proportion of cases with histologic types identified was not sufficiently high, sex- and age-specific incidence rates by histologic type were estimated assuming that the distribution of histologic types was the same across the same sex and age groups regardless of reporting status. Compared to Saku in Nagano Prefecture, the cumulative risk of lung cancer incidence rates in Osaka and Okinawa were 1.3 and 1.5 times higher for males and 1.3 and 1.2 times higher for females, respectively. When divided by histologic type, male adenocarcinoma and small cell carcinoma were 1.6-2.1 times higher in Osaka and Okinawa, while squamous cell carcinoma was 1.6 times higher only in Okinawa compared to Saku Nagano. In females, squamous cell carcinoma and small cell carcinoma were 2.5-3.3 times higher in Osaka and Okinawa compared to Saku Nagano, while adenocarcinoma was almost equal in the 3 areas. These results indicate that the pattern of incidence of lung cancer by histologic type may differ between high- and low- risk areas.  (+info)

(4/382) Ethnic differences in poly(ADP-ribose) polymerase pseudogene genotype distribution and association with lung cancer risk.

Poly(ADP-ribose) polymerase (PADPRP) is a nuclear DNA-binding enzyme that can modulate chromatin structure close to DNA replication, recombination and repair regions. Two-allele polymorphism on the PADPRP chromosome 13 pseudogene has been studied in several ethnic subpopulations, and the association of each allele with different types of cancer has been investigated. To study the frequency of the allele in the context of lung cancer, we performed a PCR assay for the PADPRP polymorphism in 288 lung cancer patients and 292 matched controls and examined the frequency of the alleles in different ethnic groups. Our results showed that the allele distribution was significantly different among members of different ethnic groups. Specifically, the A allele was dominant in Mexican-American and Caucasian groups but not in the African-American group. The frequencies of the B allele in Mexican-American, Caucasian and African-American controls were 0.184, 0.218 and 0.606, respectively, with the Caucasian cases and controls showing an almost identical lower B allele frequency (0.199 in cases versus 0.218 in controls), and the African-American cases and controls showing an almost identical but considerably higher frequency (0.578 in cases versus 0. 606 in controls). In contrast, the Mexican-American cases and controls exhibited a considerable difference in the B allele frequency (0.306 in cases versus 0.184 in controls). When we combined subjects with the AB or BB genotype into a susceptible genotype group and compared them with the AA group using univariate analysis, the susceptible genotype was not shown to be associated with a risk of lung cancer in either the Caucasian or African-American subpopulation but was significantly associated with an increased risk (2.29-fold) of lung cancer in the Mexican-American group. When lung cancer was categorized by histologic type, no elevated risk was noted for squamous cell carcinoma in any ethnicity. However, in Mexican-Americans, susceptible genotypes were associated with significantly increased risks of adenocarcinoma (3. 21-fold) and large cell carcinoma (10.79). Our study and others have demonstrated that the PADPRP polymorphism may modify an individual's susceptibility to certain cancers. Assessment of the interaction between genetic constitution and environmental exposure might expand our understanding of carcinogenesis and enhance our ability to evaluate the populational cancer risk.  (+info)

(5/382) p53 protein, EGF receptor, and anti-p53 antibodies in serum from patients with occupationally derived lung cancer.

The oncogene product epidermal growth factor receptor (EGF-R), the tumour suppressor gene product p53 and anti-p53 antibodies are detectable in the serum of certain cancer patients. Increased levels of some of these products were reported in lung cancer patients after occupational asbestos exposure and after exposure to polycyclic aromatic hydrocarbons or vinylchloride. In the first step, this study investigated the possible diagnostic value of serum EGF-R, p53-protein and anti-p53 antibodies, measured by an enzyme-linked immunosorbent assay, in lung tumour patients. In addition to being investigated on a molecular epidemiological basis, these parameters were examined as biomarkers of carcinogenesis, especially with regard to asbestos incorporation effects or of radon-induced lung cancers. Also, a possible effect of cigarette smoking and age dependence were studied. A total of 116 male patients with lung or pleural tumours were examined. The histological classification was four small-cell cancers, six large-cell cancers, 32 adenocarcinomas, 47 squamous carcinomas, 12 mixed lung carcinomas, five diffuse malignant mesotheliomas and ten lung metastasis of extrapulmonary tumours. Twenty-two lung cancers and all mesotheliomas were related to asbestos, 22 lung cancers were related to ionizing radiation and 61 patients had cigarette smoke-related lung cancer. Besides these patients 50 male patients with non-malignant lung or pleural diseases were included; of the latter eight subjects suffered from asbestosis. Controls were 129 male subjects without any lung disease. No significantly elevated or decreased serum values for p53 protein, EGF-R, or anti-p53 antibodies as a function of histological tumour type, age, or degree and type of exposure (asbestos, smoking, ionizing radiation) could be found. The utility of p53-protein, EGF-R and anti-p53 antibodies as routine biomarkers for screening occupationally derived lung cancers is limited.  (+info)

(6/382) Overexpression of bax associated with mutations in the loop-sheet-helix motif of p53.

Recent investigations have revealed that mutations of the loop-sheet-helix motif of p53 is a significant factor for a poor prognosis in patients with non-small-cell lung cancer (NSCLC). To clarify this mechanism, bcl-2 and bax expression were evaluated in relation to mutations of p53. Tumor tissues of 203 patients with NSCLC were analyzed. Immunohistochemistry was performed to evaluate bcl-2 and bax expression, and polymerase chain reaction single-strand conformation polymorphism following direct sequencing was performed to investigate p53 status. A total of 79 carcinomas were bcl-2 positive, 146 carcinomas were bax positive, and 72 carcinomas had missense mutations of p53. There was no difference in bcl-2 expression in relation to p53 status. On the other hand, tumors with structural mutations of p53 had significantly lower expression of bax than those with wild-type p53 (P = 0.0026). In contrast, tumors with mutations of the loop-sheet-helix motif of p53 had significantly higher expression of bax than those with wild-type p53 (P = 0.0236). The frequency of a bcl-2/bax ratio of >/=1 was significantly lower in tumors with mutations of the loop-sheet-helix motif than that in tumors with wild-type p53 (P = 0.0240). The bcl-2/bax ratio status was a significant factor for a prognosis in patients with NSCLC (P = 0.0083). Mutations of the loop-sheet-helix motif of p53 were correlated with overexpression of bax, while other mutations of p53 were correlated with low levels of bax expression. This variation in pattern of bax expression in relation to mutant p53 might reflect the biological behavior of tumors in patients with bcl-2-positive NSCLC.  (+info)

(7/382) k-ras mutation and occupational asbestos exposure in lung adenocarcinoma: asbestos-related cancer without asbestosis.

Environmental carcinogen exposure is requisite for the development of nearly all lung cancer, and it is well known that asbestos exposure interacts synergistically with tobacco smoke to induce lung cancer. However, the precise molecular lesions induced by asbestos are unknown. Furthermore, it is also unknown whether asbestos carcinogenesis proceeds in a fashion independent of or dependent upon the induction of fibrosis in workers with high asbestos exposures. Previous studies have suggested that asbestos is associated with the presence of a k-ras mutation in adenocarcinoma of the lung. We aimed to test whether occupational asbestos exposure was associated with k-ras codon 12 mutations in lung adenocarcinoma tumors and to determine whether this was conditional on the presence of asbestosis. All newly diagnosed, resectable lung cancer patients receiving treatment at the Massachusetts General Hospital between November 1992 and December 1996 were eligible to participate. Because k-ras mutation is very strongly associated with adenocarcinoma, and men were more likely to be occupationally exposed to asbestos, the study was restricted to males with this histological diagnosis. There were 84 male patients with available questionnaire-derived work history data and paraffin-embedded tumor tissue for determination of k-ras mutation status. Chest radiographic evaluation was done for all of the patients who reported occupational exposure to asbestos. The prevalence of k-ras mutation was higher among those with a history of occupational asbestos exposure (crude odds ratio, 4.8; 95% confidence interval, 1.5-15.4) compared to those without asbestos exposure, and this association remained after adjustment for age and pack-years smoked (adjusted odds ratio, 6.9; 95% confidence interval, 1.7-28.6). An index score that weights both the dates of exposure and the estimated intensity of exposure indicated that those with k-ras mutations had significantly greater asbestos exposures than those without mutations (P < 0.01). Analysis of the descriptive components of exposure indicated that the duration of exposure was not associated with k-ras mutation, but that the time since initial exposure was significantly associated with mutation status. The association of k-ras mutation and reported asbestos exposure was not dependent on the presence of radiographic evidence of asbestos-related disease. These data suggest that asbestos exposure increases the likelihood of mutation at k-ras codon 12 and that this process occurs independently of the induction of interstitial fibrosis.  (+info)

(8/382) Multiple clonal abnormalities in the bronchial epithelium of patients with lung cancer.

BACKGROUND: Several molecular changes, including loss of heterozygosity (i.e., deletion of one copy of allelic DNA sequences) and alterations in microsatellite DNA, have been detected early in the pathogenesis of lung cancer, even in histologically normal epithelium. In the bronchial epithelium of patients with lung cancer, we have determined the frequency, size, and patterns of molecularly abnormal clonal patches. METHODS: We studied formalin-fixed, paraffin-embedded samples from 16 surgically resected lung carcinomas (five squamous cell carcinomas, four small-cell carcinomas, six adenocarcinomas, and one large-cell carcinoma). From each carcinoma, we microdissected foci (each containing about 200 cells) of tumor tissue and equivalent samples of histologically normal and abnormal epithelium. Furthermore, multiple discontinuous foci of bronchial epithelium were analyzed from methanol-fixed samples from three additional patients with lung cancer (two with squamous cell carcinoma and one with adenocarcinoma). We used two-step polymerase chain reaction-based assays involving 12 microsatellite markers at seven chromosomal regions frequently deleted in lung cancer. RESULTS: Two hundred eighteen foci of nonmalignant bronchial epithelium (195 of histologically normal or slightly abnormal epithelium and 23 of dysplastic epithelium) were studied from the 19 surgically resected lobectomy specimens. Thirteen (68%) of the 19 specimens had at least one focus of bronchial epithelium with molecular changes. At least one molecular abnormality was detected in 32% of the 195 histologically normal or slightly abnormal foci and in 52% of the 23 dysplastic foci. Extrapolating from our two-dimensional analyses, we estimate that most clonal patches contain approximately 90 000 cells. Although, in a given individual, tumors appeared homogeneous with respect to molecular changes, the clonally altered patches of mildly abnormal epithelium were heterogeneous. CONCLUSIONS: Our findings indicate that multiple small clonal or subclonal patches containing molecular abnormalities are present in normal or slightly abnormal bronchial epithelium of patients with lung cancer.  (+info)