Lung cancer incidence rates by histologic type in high- and low-risk areas; a population-based study in Osaka, Okinawa, and Saku Nagano, Japan.
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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)
Standard- and high-dose etoposide, ifosfamide, carboplatin, and epirubicin in 100 patients with small-cell lung cancer: a mature follow-up report.
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BACKGROUND: We conducted a phase I-II trial to assess the feasibility and activity of a combination chemotherapy regimen with etoposide, ifosfamide, cisplatin or carboplatin, and epirubicin in limited-disease (LD, stages I-IIIB) and extensive-stage (ED, stage IV) small-cell lung cancer (SCLC). PATIENTS AND METHODS: Standard-dose chemotherapy (SDC) consisting of etoposide (500 mg/m2), ifosfamide (4000 mg/m2), cisplatin (50 mg/m2) and epirubicin (50 mg/m2) (VIP-E), followed by granulocyte colony-stimulating factor (G-CSF), was given to 100 patients with SCLC. Thirty patients with qualifying responses to VIP-E proceeded to high-dose chemotherapy (HDC) with autologous peripheral blood stem-cell transplantation (PBSCT) after etoposide (1,500 mg/m2), ifosfamide (12,000 mg/m2), carboplatin (750 mg/m2) and epirubicin (150 mg/m2) (VIC-E) conditioning. RESULTS OF STANDARD-DOSE VIP-E: Ninety-seven patients were evaluable for response. The objective response rate was 81% in LD SCLC (33% CR, 48% PR; excluding patients in surgical CR) and 77% in ED SCLC (18% CR, 58% PR). The treatment-related mortality (TRM) of SDC was 2%. Two additional patients in CR from their SCLC developed secondary non-small-cell lung cancers (NSCLC), and both were cured by surgery. The median survival was 19 months in LD SCLC and 6 months in ED SCLC. The five-year survivals were 36% in LD and 0% in ED SCLC. RESULTS OF HIGH-DOSE VIC-E: HDC was feasible in 16% of ED-, and 58% of LD-patients. All HDC patients (n = 30) improved or maintained prior responses. Four patients died of early treatment-related complications (TRM 13%). Two additional patients in CR from their SCLC developed secondary malignancies (esophageal cancer, secondary chronic myelogenous leukemia). The median survivals were 26 months in LD SCLC, and 8 months in ED SCLC. The five-year survival was 50% in LD and 0% in ED SCLC. CONCLUSIONS: Despite high response rates, survival after VIP-E SDC and VIC-E HDC in patients with ED SCLC is not superior to that achieved with less toxic traditional regimens. The high five-year survival rates achieved with these protocols in LD SCLC probably reflect both patient selection (high proportion of patients with prior surgical resection) and the high activity of our chemotherapy regimen in combination with radiotherapy. A study comparing protocols using simultaneous radiation therapy and chemotherapy, and other dose-escalated forms of SDC with HDC is needed to further define the role of this treatment modality in SCLC. Given the high rate of secondary malignancies observed in patients in CR > 2 years in our study, close follow-up and early treatment of these neoplasms may contribute to maintaining overall survival in patients with SCLC. (+info)
Human small cell lung cancer NYH cells selected for resistance to the bisdioxopiperazine topoisomerase II catalytic inhibitor ICRF-187 demonstrate a functional R162Q mutation in the Walker A consensus ATP binding domain of the alpha isoform.
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Bisdioxopiperazine drugs such as ICRF-187 are catalytic inhibitors of DNA topoisomerase II, with at least two effects on the enzyme: namely, locking it in a closed-clamp form and inhibiting its ATPase activity. This is in contrast to topoisomerase II poisons as etoposide and amsacrine (m-AMSA), which act by stabilizing enzyme-DNA-drug complexes at a stage in which the DNA gate strand is cleaved and the protein is covalently attached to DNA. Human small cell lung cancer NYH cells selected for resistance to ICRF-187 (NYH/187) showed a 25% increase in topoisomerase IIalpha level and no change in expression of the beta isoform. Sequencing of the entire topoisomerase IIalpha cDNA from NYH/187 cells demonstrated a homozygous G-->A point mutation at nucleotide 485, leading to a R162Q conversion in the Walker A consensus ATP binding site (residues 161-165 in the alpha isoform), this being the first drug-selected mutation described at this site. Western blotting after incubation with ICRF-187 showed no depletion of the alpha isoform in NYH/187 cells in contrast to wild-type (wt) cells, whereas equal depletion of the beta isoform was observed in the two sublines. Alkaline elution assay demonstrated a lack of inhibition of etoposide-induced DNA single-stranded breaks in NYH/187 cells, whereas this inhibition was readily apparent in NYH cells. Site-directed mutagenesis in human topoisomerase IIalpha introduced into a yeast Saccharomyces cerevisiae strain with a temperature-conditional yeast TOP2 mutant demonstrated that R162Q conferred resistance to the bisdioxopiperazines ICRF-187 and -193 but not to etoposide or m-AMSA. Both etoposide and m-AMSA induced more DNA cleavage with purified R162Q enzyme than with the wt. The R162Q enzyme has a 20-25% decreased catalytic capacity compared to the wt and was almost inactive at <0.25 mM ATP compared to the wt. Kinetoplast DNA decatenation by the R162Q enzyme at 1 mM ATP was not resistant to ICRF-187 compared to wt, whereas it was clearly less sensitive than wt to ICRF-187 at low ATP concentrations. This suggests that it is a shift in the equilibrium to an open-clamp state in the enzyme's catalytic cycle caused by a decreased ATP binding by the mutated enzyme that is responsible for bisdioxopiperazine resistance. (+info)
Modulation of multidrug resistance protein expression in porcine brain capillary endothelial cells in vitro.
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Multidrug resistance-associated protein (MRP) is a transport system that is involved in the elimination of xenobiotics and biologically active endogenous substrates. Recently, the presence of MRP has been demonstrated in cultured brain capillary endothelial cells (BCECs). The time-dependent, functional expression of MRP in porcine BCECs was investigated to assess the value of this cell culture model for drug transport at the blood-brain barrier. Western blot analysis was used to investigate MRP expression in freshly isolated porcine BCECs and compared to MRP expression at days 8 and 10 in culture. Subcellular localization of MRP was investigated by immunocytochemistry with an MRP-specific monoclonal antibody, MRPr1. Functional activity of MRP was assessed by efflux studies with the fluorescent MRP substrate glutathione-methylfluorescein (GS-MF). No significant MRP expression was detected in freshly isolated endothelial cells. However, MRP expression is up-regulated in cell culture in a time-dependent manner. Immunostaining revealed predominantly perinuclear and, to a lesser degree, plasma membrane localization of MRP. At 10 degrees C GS-MF efflux was significantly decreased, indicating the involvement of an energy-dependent transport system. Efflux of GS-MF was apparently inhibited by MK571, a specific inhibitor for MRP. Porcine BCECs demonstrate up-regulation of functional MRP expression during culture, as observed in human tissue, and therefore might serve as a useful in vitro system for studying MRP-mediated blood-brain barrier transport. (+info)
How many tumor suppressor genes are involved in human lung carcinogenesis?
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To date, only a limited number of tumor suppressor genes have been identified as being inactivated in lung cancer. The p53 and RB genes are frequently inactivated by genetic alterations such as chromosomal deletions and loss-of-function mutations, while the p16 gene is inactivated not only by genetic alterations but also by transcriptional silencing due to hypermethylation. Recently, it was shown that the FHIT gene encompassing the chromosomal fragile site, FRA3B, is also inactivated in a large proportion of lung cancers. Several lines of evidence indicate the presence of additional tumor suppressor genes involved in lung carcinogenesis. Lung cancer cells often show deletions at multiple chromosomal regions, and deletion mapping studies have defined more than 30 regions dispersed on 21 different chromosome arms as candidate tumor suppressor loci. Several chromosomal regions hypermethylated in lung cancer cells and a number of chromosomal fragile sites have been mapped to the regions deleted in lung cancer. These chromosomal loci can harbor unknown tumor suppressor genes inactivated in lung cancer. Studies on the inherited susceptibility to lung cancer in mice have also indicated the presence of additional tumor suppressor genes for lung cancer. Further analyses of these loci should elucidate how many tumor suppressor genes are involved in human lung carcinogenesis. Molecular and functional analyses of those genes will make it possible to fully understand the molecular mechanism of lung carcinogenesis. (+info)
Is small cell lung cancer the perfect target for anti-telomerase treatment?
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Small cell lung cancer (SCLC) is common in men and women, has a very poor prognosis, and is therefore a major cause of premature mortality. As such, any prospects for improved therapy are of great significance. The promise of telomerase as a therapeutic target is now close to realization with extremely encouraging preclinical studies aimed at the RNA component (hTR) of telomerase. The rational integration of telomerase therapeutics into clinical trials will therefore require tumours to be well characterized for hTR expression. Despite the large number of cancer types now characterized for telomerase or telomerase component gene expression, only a handful of SCLC samples have been analysed. Given the major clinical problem with treating SCLC, we specifically set out to address the issue of hTR expression in neuroendocrine tumours. Our study covers 91 pulmonary neuroendocrine tumours (62 SCLC and 29 carcinoid tumours). We present data to show that upregulation of the RNA component of telomerase occurs in 98% of human SCLCs. Interestingly, the less aggressive carcinoid tumours of the lung had a significantly lower frequency of hTR expression (P < 0.01). Importantly, we compare hTR expression in this series to the well characterized biological targets p53 and BCL2, and show hTR to be expressed more frequently. Therapies directed at the RNA component of human telomerase are in active development and these data show SCLC to be a prime target for such therapies. (+info)
Meta-analyses of p53 tumor suppressor gene alterations and clinicopathological features in resected lung cancers.
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p53 alterations are the most common genetic lesions observed in lung cancers. Because of the limited size of individual studies, the distributions of p53 alterations by clinicopathological features have not been well characterized. Here, we present meta-analyses describing the occurrence of p53 alterations by patient/tumor characteristics in resected lung cancer. The association between p53 alterations (gene and/or protein) and a variety of variables were evaluated by calculating pooled odds ratios (ORs) and confidence intervals (CIs). p53 alterations were detected in 46.8% of 4684 non-small cell lung cancers. p53 alterations occurred more frequently in the more strongly smoking-associated histotypes: squamous cell (51.2%) and large cell (53.7%) carcinomas versus adenocarcinomas [38.8%; OR (squamous versus adenocarcinoma) = 1.81, 95% CI = 1.55-2.11]. p53 alterations were found to be associated with T1-4, N0-3, stage I-III, differentiation, and sex: OR (T3 versus T1) = 1.62 (95% CI = 0.99-2.65), OR (N1-3 versus N0) = 1.65 (95% CI = 1.27-2.15), OR (stage III versus stage I) = 1.98 (95% CI = 1.35-2.89), OR (poorly and moderately versus well-differentiated) = 3.04 (95% CI = 1.56-5.94), and OR (male versus female) = 1.39 (95% CI = 1.10-1.75). No strong associations between p53 and ras or aneuploidy were observed. Lung cancer studies of p53 and smoking need to consider the effect of histotype, and prognostic studies of p53 should adjust for the effects of T and N or stage and histotype. The apparent association between p53 and sex may be confounded by histotype and must be evaluated by multivariate studies. (+info)
Association between O6-alkylguanine-DNA-alkyltransferase activity in peripheral blood lymphocytes and bronchial epithelial cells.
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The activity of the DNA repair enzyme O6-alkylguanine-DNA-alkyltransferase (ATase) may be a risk factor in the pathogenesis of lung cancer. ATase activity has previously been measured in peripheral blood lymphocytes (PBLs), cell extracts from bronchoalveolar lavage fluid, and cell homogenates from resected lung tissue. However, it is not clear whether ATase activity in these samples correlates well with the activity found in bronchial epithelial cells, the progenitor cells for the main types of lung cancer. In this study, cell extracts were prepared from PBLs, bronchial lavage (BL) fluid, and bronchial brushings from normal lung in 20 patients attending for routine bronchoscopy. Bronchial brushing sampled a significantly greater proportion of bronchial epithelial cells than did BL [88+/-9% (mean+/-SD) versus 39+/-19%; P < 0.0001]. ATase activity was determined in each of the cell extracts and was found to be higher in PBLs than in bronchial brushings (P = 0.005) and higher in bronchial brushings than in BL (P = 0.005). No correlation in ATase levels was observed between any of the three samples. We conclude that bronchial brushing is a more specific and reliable way of sampling bronchial epithelial cells than BL and that it samples enough cells for ATase activity to be determined. In addition, in terms of the activity of this potentially critical DNA repair enzyme, PBLs, and cell extracts obtained from BL may not provide good surrogate tissue for bronchial epithelial cells, the critical targets for carcinogenesis. (+info)