Differential Expression of DNA Topoisomerase IIα and IIβ Genes between Small Cell and Non‐small Cell Lung Cancer

Syahruddin, Elisna; Oguri, Tetsuya; Takahashi, Toshiaki; Isobe, Takeshi; Fujiwara, Yasuhiro; Yamakido, Michio

doi:10.1111/j.1349-7006.1998.tb00640.x

Cited by 10 publications

(22 citation statements)

References 25 publications

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“…Topo II␤ mRNA levels in the tumor samples and normal lung tissues were comparable. Thus, our findings are consistent with the high expression levels of topo II␣ generally observed in dividing cells (Wang, 1996) and with other studies that report increased topo II␣ and similar topo II␤ levels in lung tumors compared to normal lung (Giaccone et al, 1995;Hasegawa et al, 1993;Kreisholt et al, 1998;Syahruddin et al, 1998;Turley et al, 1997).…”

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 71%

“…5, E and F). In other clinical studies of topo II ␣ and ␤ expression in lung cancer, the different histologic subtypes have not been analyzed (Giaccone et al, 1995;Syahruddin et al, 1998). Thus, our study is the first to report a histologic typerelated difference in topo II mRNA levels.…”

Section: Discussionmentioning

confidence: 74%

“…Several groups have reported that levels of topo II␣ protein and/or mRNA correlate with drug sensitivity in lung cancer cell lines and are often higher in SCLC than in NSCLC cell lines, as is consistent with the relative drug sensitivities of the two tumor types (Campling et al, 1997a;Giaccone et al, 1992;Kasahara et al, 1992). There are few studies with patient samples, but they also indicate that levels of topo II␣ mRNA or protein are higher in SCLC than in NSCLC tumors (Dingemans et al, 1998;Guinee et al, 1996;Kreisholt et al, 1998;Syahruddin et al, 1998).In the present study, using a single pair of genespecific primers, we have developed a convenient reverse transcriptase-polymerase chain reaction (RT-PCR) method for the simultaneous quantitation of the relative levels of topo II␣ and topo II␤ mRNAs in both NSCLC cell lines and patient samples. Analysis of 13 NSCLC cell lines, and tumor and normal lung tissues from 25 patients with NSCLC, revealed a wide range in expression levels of both topo II isoforms.…”

mentioning

confidence: 73%

“…Measurement of topo II␤ protein or mRNA levels, in addition to topo II␣ levels, has recently become more common in lung cancer investigations. In studies to date, antibodies, cDNA probes, or PCR primers specific for each topo II isoform have been used, so that direct comparison of topo II␣ and topo II␤ levels has not been possible (Dingemans et al, 1999;Galimberti et al, 1998;Giaccone et al, 1995;Holden et al, 1992;Houlbrook et al, 1996;Syahruddin et al, 1998;Turley et al, 1997). Because both isoforms likely contribute to drug sensitivity, it would be advantageous to be able to measure the proportion of topo II mRNA represented by each isoform in a given sample.…”

Section: Discussionmentioning

confidence: 99%

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Simultaneous Quantitation of Topoisomerase II α and β Isoform mRNAs in Lung Tumor Cells and Normal and Malignant Lung Tissue

Mirski

Voskoglou-Nomikos

Young

et al. 2000

Laboratory Investigation

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SUMMARY:Certain drugs used in the treatment of lung cancer and other human malignancies are cytotoxic because of their ability to interact with the two isoforms of topoisomerase II (topo II), topo II␣ and topo II␤. As part of an effort to evaluate the contribution of topo II alterations to drug sensitivity and resistance in lung cancer, we have developed a semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay to measure levels of topo II ␣ and ␤ mRNAs simultaneously using a single pair of primers with sequences common to both isoforms. The PCR products derived from the topo II ␣ and ␤ mRNAs are both 446 bp but have different electrophoretic mobilities in a nondenaturing polyacrylamide gel, allowing sensitive, rapid quantitation when the products are radiolabeled with [ 35 S]-dATP. Using this RT-PCR method, poly(Aϩ) RNA from 13 non-small cell lung cancer (NSCLC) cell lines was analyzed. The results obtained indicated that the cell lines express a wide range of topo II␣ mRNA levels (12-fold) and topo II␤ mRNA levels (5.5-fold). Tumor and normal lung tissues from 25 patients with NSCLC were also examined. In the tumor samples, the levels of the topo II ␣ and ␤ mRNAs were similar. However, mean topo II␣ mRNA levels in the tumors were approximately 7-fold higher than those of the paired normal lung tissues. In contrast, topo II␤ mRNA levels were similar in both tumor and normal lung. Topo II ␣ and ␤ mRNA levels were both significantly lower in the squamous cell tumors than in the adenocarcinoma samples. Topo II␤ mRNA levels in the squamous cell tumors were also significantly lower than those in paired normal lung tissue. The RT-PCR method described is reliable and convenient, and for the first time, makes the rapid simultaneous direct comparison of topo II␣ and topo II␤ mRNA levels feasible in large numbers of clinical samples. (Lab Invest 2000, 80:787-795).T opoisomerase II (topo II) is a nuclear enzyme that alters the topology of DNA and is essential for normal chromosome segregation at mitosis. In mammalian cells, there are two isoforms, designated topo II␣ and topo II␤, which share more than 70% amino acid identity, but differ in their relative levels of expression in developing embryonic tissues, normal adult tissues, and tumors (Mirski and Cole, 1997). A number of clinically important anticancer drugs interact with topo II to produce DNA damage and cell death by apoptosis. Topo II poisons, such as and doxorubicin, stabilize an intermediate of the enzyme's catalytic cycle, the "cleaved complex" of topo II, DNA, and drug. Resistance to these topo II targeting drugs arises through a number of different mechanisms in human tumor cell lines, including decreased levels of the enzyme, mutations in the ATPase or DNA breakage and religation domains, or, in the case of the ␣ isoform, decreased nuclear localization (Larsen and Skladanowski, 1998;Mirski and Cole, 1997;Nitiss and Beck, 1996). A second class of topo II interactive drugs, which includes the investigational agents ICRF-187 and ICRF...

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 74%

mentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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Simultaneous Quantitation of Topoisomerase II α and β Isoform mRNAs in Lung Tumor Cells and Normal and Malignant Lung Tissue

Mirski

Voskoglou-Nomikos

Young

et al. 2000

Laboratory Investigation

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Topoisomerase IIα gene expression is regulated by the p53 tumor suppressor gene in nonsmall cell lung carcinoma patients

Liu

Huang

Kameyama

et al. 2002

Cancer

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BACKGROUND Topoisomerase IIα (Topo IIα) is an essential nuclear enzyme for chromosome segregation during mitosis. Previous experimental studies using cell lines reported that Topo IIα expression was negatively regulated by wild‐type p53 through the gene's promoter region. METHODS Surgically resected tumor specimens from 98 nonsmall cell lung carcinoma (NSCLC) patients who were not treated with preoperative chemotherapy were studied. Quantitative reverse‐transcription polymerase chain reaction analysis was done to evaluate Topo IIα gene expression. Polymerase chain reaction single strand conformation polymorphism following sequencing was performed to investigate mutations of p53. RESULTS Topo IIα gene expression in squamous cell carcinomas was significantly higher than in adenocarcinomas (P = 0.0007). Topo IIα gene expression in moderately differentiated tumors and poorly differentiated tumors was significantly higher than in well differentiated tumors (P = 0.0032 and P = 0.0005, respectively). Thirty nine tumors (40%) had mutations of p53. Topo IIα gene expression in tumors with mutant p53 was significantly higher than in those with wild‐type p53 (P = 0.0224). CONCLUSIONS The current study suggests that Topo IIα gene expression is regulated by p53 gene status in NSCLC patients and that the overexpression of Topo IIα induced by mutant p53 might cause more aggressive carcinogenesis. Cancer 2002;94:2239–47. © 2002 American Cancer Society. DOI 10.1002/cncr.10450

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Genetic and Molecular Coordinates of Neuroendocrine Lung Tumors, with Emphasis on Small-cell Lung Carcinomas

Koutsami

Doussis-Anagnostopoulou

Papavassiliou

et al. 2002

Mol Med

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Differential Expression of DNA Topoisomerase IIα and IIβ Genes between Small Cell and Non‐small Cell Lung Cancer

Cited by 10 publications

References 25 publications

Simultaneous Quantitation of Topoisomerase II α and β Isoform mRNAs in Lung Tumor Cells and Normal and Malignant Lung Tissue

Simultaneous Quantitation of Topoisomerase II α and β Isoform mRNAs in Lung Tumor Cells and Normal and Malignant Lung Tissue

Topoisomerase IIα gene expression is regulated by the p53 tumor suppressor gene in nonsmall cell lung carcinoma patients

Genetic and Molecular Coordinates of Neuroendocrine Lung Tumors, with Emphasis on Small-cell Lung Carcinomas

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