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Expression of heme oxygenase in arsenic-resistant human lung adenocarcinoma cells
Abstracts/Lung
Cancer 11 (1994) 423-444
commonly deleted regions were at most 1.2 Mb in HCC and CRC and 0.6 Mb in NSCLC. As four of the 12 physically ordered markers are located within the 0.6 Mb region commonly deleted in all three tumor types, nearly one fourth to ooe fiti of the target region has already bee0 covered with cosmid inserts.
Carcinogenqecific
mutation in the ~53 tumor suppressor gene in
lung= Kandioler D, Foedmger M, Mueller MR, Eckersberger F, Mannhalter C, Wolner E. Second Department of Surgery, Uniwr&y of Vienna, Spitolgasse23, A-1090 Wenno.J’hwacCarciovascSurg 1994; 107: 10958. Mutations of the p53 hunor suppressor gene, whose. encoded protein is one of the chief regulators of the cell cycle, are proving to be the most common genetic alter&i00 in human cancer. Point mutations have been detected in numerous human solid tumors. The types of point mutations in the p53 gene vary umsiderably in different kinds of human cancers, suggesting that specific diologic agentsare reeponsible fortypical kinds and sites of mutations in the p53 gene. This study reports the detection of two unusual p53 mutations in P series of patients with lung cancer. The first caseshowed aooe-basepairdeletiooat theend ofexon 8, which is rarely affected by mutatioos, leading to a frameshift involving the following iotron 8, exoo 9. and intro0 9. The second case exhibited two point mutations in codon 273, both either localized in the same codoo on one allele or each mutation localized oo a different allele in codoo 273. Interestingly, the two mutations can be attributed to different mechanisms of base substitution. This is the first report of this kind. Because of evidence that the nature and site of p.53 mutations reflect not only the mutagens involved in tumorigenesis but also the capacity for malignant transformation, the characterization of mutations of the p53 gene may provide a basis for assessing further risk factors, as well as for estimating prognosis in patients with lung cancer.
MappingofmultipIeDNAgainsandlossesinprimarysmallcelllung carcinomas by comparative genomic hybridization Ried T, Petersea I, Holtgreve-Grez H, Speicher MR, S&rock E, Du Manoir S et al. Narl. Ctr. for Human Chuvne Research. NIH, Building 49, Bethesda, MD 20892. Cancer Rea 1994;54:1801-6. Comparativegenomic hybridization wasapplied foracomprehensive screening of under- and overrepreseotatioo of genetic material in 13 autoptic small cell lung cancer specimens. The most abundant genetic cbangesincludeDNAlossesofcbromosomearms3p, Sq. lOq, 13q, and 17p and DNA gains of 3q, 5p, 8q, and 17q. Amplification sites in these tumors were mapped to 22 chromosome bands. The most f&quently iovolvedbandwas 19q13.1(4cases). Bends lp32,2~23,7q11.2,8q24, and 13q33-34 were involved in two cases each.
A frequent deletion of chromosome 5121 in advanced small cell and non-small cell aucimnn of the lung Hosoe S, Ueno K, Shigedo Y, Tachibana I, Osaki T, Kumagai T et al. Deportment of Medicine HI, Osaka University Medical S&ool. 2-2, Yamaokoka. Suita, Osaka 565. Cancer Res 1994$4: 1787-90. Wehaveexamioedthedeletiooofthelongannofchromosome5(5q) in 59 casea of advanced lung cancer [39 casea of small cell lung cancer (SCLC), 20 cases of non-SCLC] using 12 restriction t?agmeat length polymorphism msrkers on 54. Of 59 lung cancer cases, 48 (81%) exhibited deletion at any portion of the 5q locus (loci). Such a high
429
frequency of 5q deletion has not been reported in surgically resectable non-SCLC. One SCLC case showed a 5q deletion only in metastatic sites but not in the primary can=. These data suggest that the inactivation of putative tumor-suppressor gene(s) 00 5q may be ;I late event in the progression of lung cancer. There was no significant difference in frequency of 5q deletion between SCLC and non-SCLC. Compared to non-SCLC, however, SCLC usually showed widespread deletion on 5q. While the most frequent target region was estimated to be about 3-5 megabases at 5q21 around the adenomatous polyposis coli (APC) gene locus, somecasesshowed more telomeric deletion (5q33-35), suggesting that there are at least two different tumor-suppressor genes on 5q associated with the progression of lung cancer.
Frequent allelic deletion at a novel locus on chromnsome 5 in human lung cancer Wieland I, Bohm M. Institut fur Zellbiologie, Uniwrsitatsklinikum Essen, Virchowstrtwse 173,45122 Essen. Cancer Rea 199454: 17724. Frequent allelic deletions in tumor cells are indicative of the inactivation of tumor suppressor genes. Recently, we isolated the single copy sequexe del-27 (I. Wielaod, M. Bohro, and S. Bog&z, Proc. Natl. Acsd. Sci. USA, 89: 9705-9709,1992). Here we show that del-27 detects a restrictioo fragment length polymorphism that allows examination for loss of heteroxygosity (LOH) in tumor specimens. LOH at the del-27 locus occurred in 57 46 (4 of 7) of the informative lung carcinoou~~ iodependeot of the bistoPs&bologicaldifferentiation grade. LOH for exoo 11 of the APC gene occurred in 7 1% (5 of 7) of the informative cases but was oot asskated with LOH at the del-27 locus. Thedel-27sequencewaslocalixedtochromosome5p13-5q14,proximal to the MCC/APC region, using P somatic cell hybrid panel. Together with our previous fiodiig that del-27 is deleted homoxygously in a lung carcinoma cell line, these results suggest that del-27 is linked closely to a novel putative tumor suppressor gene.
Expression of beme oxygenase in arsenic-resistant human lung adenocarcinoma cells Lee T-C, Ho I-C. Institute of Biomedical Sciences, Academia Sinica, Taipei 115. Cancer Rea 1994;54:1660-4. Wehaveestablishedatic-resistantcells(CL3R)andtheirsubclones from a humsn lung adeoocarcinoms cell line (CL3). CL3R cells and their subclooas were maintained in the presence of 4 M sodium arsenite. They were 6-fold more resistant than CL3 cells to arsenite. Heme oxygenase ~88 expressed in CL3R cells and their subclooes, as demonstrated by electrophoretic analysis, Northern blotting, andenzyme activity assay. WhezrCL3R15cellsweregrowninarsenite_freemedium, their arsaite resistance declined in parallel with their decreasing heme oxygenase activity. Tin- protoporphyrio, a heme-oxygenase inhibitor, was found to increase the toxicity of arsenic to CLJR cells. Expression of heme oxygenase might therefore be involved in the mechanism of arsenic resistance. CL3R cells were also shown to be cross-resistant to oxygen-radical generating ageots, such as menadiooe sod Adriamycin. Furthermore, sodium nrsenite treatment dose- depeadeatly increased the dichlomtluorescein fluorescence in CL3 cells but not in CL3R15 cells. These results suggest that heme oxygenase plays an important role in reducing cellular oxidants that are enhanced by sodium arseaite treatment. Detection of oncogene mutations in sputum precedes diagnosis of lungMao L, Hruban RH, Boyle JO, To&man M, Sidrsnsky D. Head/Neck
Cancer 11 (1994) 423-444
commonly deleted regions were at most 1.2 Mb in HCC and CRC and 0.6 Mb in NSCLC. As four of the 12 physically ordered markers are located within the 0.6 Mb region commonly deleted in all three tumor types, nearly one fourth to ooe fiti of the target region has already bee0 covered with cosmid inserts.
Carcinogenqecific
mutation in the ~53 tumor suppressor gene in
lung= Kandioler D, Foedmger M, Mueller MR, Eckersberger F, Mannhalter C, Wolner E. Second Department of Surgery, Uniwr&y of Vienna, Spitolgasse23, A-1090 Wenno.J’hwacCarciovascSurg 1994; 107: 10958. Mutations of the p53 hunor suppressor gene, whose. encoded protein is one of the chief regulators of the cell cycle, are proving to be the most common genetic alter&i00 in human cancer. Point mutations have been detected in numerous human solid tumors. The types of point mutations in the p53 gene vary umsiderably in different kinds of human cancers, suggesting that specific diologic agentsare reeponsible fortypical kinds and sites of mutations in the p53 gene. This study reports the detection of two unusual p53 mutations in P series of patients with lung cancer. The first caseshowed aooe-basepairdeletiooat theend ofexon 8, which is rarely affected by mutatioos, leading to a frameshift involving the following iotron 8, exoo 9. and intro0 9. The second case exhibited two point mutations in codon 273, both either localized in the same codoo on one allele or each mutation localized oo a different allele in codoo 273. Interestingly, the two mutations can be attributed to different mechanisms of base substitution. This is the first report of this kind. Because of evidence that the nature and site of p.53 mutations reflect not only the mutagens involved in tumorigenesis but also the capacity for malignant transformation, the characterization of mutations of the p53 gene may provide a basis for assessing further risk factors, as well as for estimating prognosis in patients with lung cancer.
MappingofmultipIeDNAgainsandlossesinprimarysmallcelllung carcinomas by comparative genomic hybridization Ried T, Petersea I, Holtgreve-Grez H, Speicher MR, S&rock E, Du Manoir S et al. Narl. Ctr. for Human Chuvne Research. NIH, Building 49, Bethesda, MD 20892. Cancer Rea 1994;54:1801-6. Comparativegenomic hybridization wasapplied foracomprehensive screening of under- and overrepreseotatioo of genetic material in 13 autoptic small cell lung cancer specimens. The most abundant genetic cbangesincludeDNAlossesofcbromosomearms3p, Sq. lOq, 13q, and 17p and DNA gains of 3q, 5p, 8q, and 17q. Amplification sites in these tumors were mapped to 22 chromosome bands. The most f&quently iovolvedbandwas 19q13.1(4cases). Bends lp32,2~23,7q11.2,8q24, and 13q33-34 were involved in two cases each.
A frequent deletion of chromosome 5121 in advanced small cell and non-small cell aucimnn of the lung Hosoe S, Ueno K, Shigedo Y, Tachibana I, Osaki T, Kumagai T et al. Deportment of Medicine HI, Osaka University Medical S&ool. 2-2, Yamaokoka. Suita, Osaka 565. Cancer Res 1994$4: 1787-90. Wehaveexamioedthedeletiooofthelongannofchromosome5(5q) in 59 casea of advanced lung cancer [39 casea of small cell lung cancer (SCLC), 20 cases of non-SCLC] using 12 restriction t?agmeat length polymorphism msrkers on 54. Of 59 lung cancer cases, 48 (81%) exhibited deletion at any portion of the 5q locus (loci). Such a high
429
frequency of 5q deletion has not been reported in surgically resectable non-SCLC. One SCLC case showed a 5q deletion only in metastatic sites but not in the primary can=. These data suggest that the inactivation of putative tumor-suppressor gene(s) 00 5q may be ;I late event in the progression of lung cancer. There was no significant difference in frequency of 5q deletion between SCLC and non-SCLC. Compared to non-SCLC, however, SCLC usually showed widespread deletion on 5q. While the most frequent target region was estimated to be about 3-5 megabases at 5q21 around the adenomatous polyposis coli (APC) gene locus, somecasesshowed more telomeric deletion (5q33-35), suggesting that there are at least two different tumor-suppressor genes on 5q associated with the progression of lung cancer.
Frequent allelic deletion at a novel locus on chromnsome 5 in human lung cancer Wieland I, Bohm M. Institut fur Zellbiologie, Uniwrsitatsklinikum Essen, Virchowstrtwse 173,45122 Essen. Cancer Rea 199454: 17724. Frequent allelic deletions in tumor cells are indicative of the inactivation of tumor suppressor genes. Recently, we isolated the single copy sequexe del-27 (I. Wielaod, M. Bohro, and S. Bog&z, Proc. Natl. Acsd. Sci. USA, 89: 9705-9709,1992). Here we show that del-27 detects a restrictioo fragment length polymorphism that allows examination for loss of heteroxygosity (LOH) in tumor specimens. LOH at the del-27 locus occurred in 57 46 (4 of 7) of the informative lung carcinoou~~ iodependeot of the bistoPs&bologicaldifferentiation grade. LOH for exoo 11 of the APC gene occurred in 7 1% (5 of 7) of the informative cases but was oot asskated with LOH at the del-27 locus. Thedel-27sequencewaslocalixedtochromosome5p13-5q14,proximal to the MCC/APC region, using P somatic cell hybrid panel. Together with our previous fiodiig that del-27 is deleted homoxygously in a lung carcinoma cell line, these results suggest that del-27 is linked closely to a novel putative tumor suppressor gene.
Expression of beme oxygenase in arsenic-resistant human lung adenocarcinoma cells Lee T-C, Ho I-C. Institute of Biomedical Sciences, Academia Sinica, Taipei 115. Cancer Rea 1994;54:1660-4. Wehaveestablishedatic-resistantcells(CL3R)andtheirsubclones from a humsn lung adeoocarcinoms cell line (CL3). CL3R cells and their subclooas were maintained in the presence of 4 M sodium arsenite. They were 6-fold more resistant than CL3 cells to arsenite. Heme oxygenase ~88 expressed in CL3R cells and their subclooes, as demonstrated by electrophoretic analysis, Northern blotting, andenzyme activity assay. WhezrCL3R15cellsweregrowninarsenite_freemedium, their arsaite resistance declined in parallel with their decreasing heme oxygenase activity. Tin- protoporphyrio, a heme-oxygenase inhibitor, was found to increase the toxicity of arsenic to CLJR cells. Expression of heme oxygenase might therefore be involved in the mechanism of arsenic resistance. CL3R cells were also shown to be cross-resistant to oxygen-radical generating ageots, such as menadiooe sod Adriamycin. Furthermore, sodium nrsenite treatment dose- depeadeatly increased the dichlomtluorescein fluorescence in CL3 cells but not in CL3R15 cells. These results suggest that heme oxygenase plays an important role in reducing cellular oxidants that are enhanced by sodium arseaite treatment. Detection of oncogene mutations in sputum precedes diagnosis of lungMao L, Hruban RH, Boyle JO, To&man M, Sidrsnsky D. Head/Neck