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Hiroyuki Yamaguchi,
Hiroshi Soda,
Yoichi Nakamura, Mineyo Takasu,
Nanae Tomonaga,
Hirofumi Nakano,
Seiji Doi,
Katsumi Nakatomi,
Seiji Nagashima,
Hiroshi Takatani,
Minoru Fukuda,
Tomayoshi Hayashi,
Kazuhiro Tsukamoto,
Shigeru Kohno
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ABSTRACT: Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has dramatic effects in selective patients with non-small cell lung cancer (NSCLC). A simple non-invasive method for predicting the efficacy of gefitinib is preferable in clinical settings. In this study, we evaluated prospectively whether surfactant protein-A (SP-A) and -D (SP-D) may be new conventional predictors of the efficacy of gefitinib treatment.
We measured serum SP-A and SP-D levels on days 0 and 29 in 40 patients with advanced NSCLC treated with 250 mg gefitinib daily. Eligibility criteria included performance status ≤3, age ≤80 years, and stage IIIB-IV disease. In addition, EGFR mutations were analyzed in 24 patients.
Multivariate analysis showed that favorable progression-free survival (PFS) after gefitinib treatment was associated with adenocarcinoma and high serum SP-D levels before treatment. EGFR mutation analysis of 24 patients showed that 16 patients had exon 19 deletion and/or exon 21 point mutations. EGFR mutations were significantly correlated with response to gefitinib and serum SP-D levels before treatment was significantly high in patients with the EGFR mutations. Serum SP-A levels were not associated with PFS.
The present study showed that measurement of serum SP-D levels before treatment in patients with NSCLC may be a new surrogate marker for predicting the response to gefitinib.
Cancer Chemotherapy and Pharmacology 02/2011; 67(2):331-8. · 2.83 Impact Factor
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Hirofumi Nakano,
Hiroshi Soda, Mineyo Takasu,
Nanae Tomonaga,
Hiroyuki Yamaguchi,
Katsumi Nakatomi,
Satoru Fujino,
Tomayoshi Hayashi,
Yoichi Nakamura,
Kazuhiro Tsukamoto,
Shigeru Kohno
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ABSTRACT: It has been proposed that stepwise progression occurs from atypical adenomatous hyperplasia (AAH) through bronchioloalveolar carcinoma (BAC) to invasive lung adenocarcinoma. However, the underlying molecular mechanisms have not been identified. We report a patient with a mixed adenocarcinoma of the lung that had different EGFR mutations in the papillary subtype, the acinar subtype, and the surrounding AAH and BAC areas. EGFR mutations may accumulate during tumor progression and lead to heterogeneity of EGFR mutations within the tumor.
Lung Cancer 05/2008; 60(1):136-40. · 3.43 Impact Factor
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Hirofumi Nakano,
Yoichi Nakamura,
Hiroshi Soda,
Megumi Kamikatahira,
Kanako Uchida, Mineyo Takasu,
Takeshi Kitazaki,
Hiroyuki Yamaguchi,
Katsumi Nakatomi,
Katsunori Yanagihara,
Shigeru Kohno,
Kazuhiro Tsukamoto
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ABSTRACT: Breast cancer resistance protein (BCRP) functions as a drug efflux transporter that mediates drug resistance. Topoisomerase I inhibitors, including 7-ethyl-10-hydroxycamptothecin (SN-38), are substrates effluxed by BCRP. However, it remains unclear whether the overexpression of BCRP induces drug resistance during chemotherapy. The objectives of the current study were to examine a correlation of altered promoter methylation of BCRP with BCRP expression and to investigate the correlation between methylation status according to methylation-specific polymerase chain reaction (MSP) analysis and BCRP expression levels in several small cell and nonsmall cell lung cancer cells.
Non-BCRP-expressing PC-6 cells, which were sensitive to SN-38, were treated with DNA methyltransferase inhibitor to induce BCRP re-expression by means of reverse transcriptase-polymersae chain reaction, Western blot, and flow cytometric analyses. Subsequently, bisulfite sequencing analysis in both PC-6 cells and SN-38-resistant PC-6/SN2-5H, highly expressing BCRP cells was performed to identify the methylated region in the BCRP promoter. Finally, the authors established an MSP method on the basis of methylated and unmethylated DNA sequences.
DNA methyltransferase inhibitor treatment of PC-6 cells induced BCRP re-expression at the messenger RNA and protein levels. Bisulfite sequencing analysis revealed that both alleles at all CpG sites were methylated completely in PC-6 cells, whereas alleles at portions of CpG sites in PC-6/SN2-5H cells were unmethylated. There was an inverse correlation between promoter methylation of BCRP determined by MSP and BCRP expression in both small cell and nonsmall cell lung cancer cells.
The current results indicated that demethylation of at least 1 allele is necessary for BCRP re-expression and that promoter demethylation of BCRP may be a mechanism of BCRP expression in lung cancer cells.
Cancer 04/2008; 112(5):1122-30. · 4.77 Impact Factor
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Hirofumi Nakano,
Hiroshi Soda,
Yoichi Nakamura,
Kanako Uchida, Mineyo Takasu,
Katsumi Nakatomi,
Kinichi Izumikawa,
Tomayoshi Hayashi,
Takeshi Nagayasu,
Kazuhiro Tsukamoto,
Shigeru Kohno
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ABSTRACT: Recently, the frequency of lung adenocarcinoma has been increasing among nonsmokers, though the etiology remains unclear. Mutations of the epidermal growth factor receptor (EGFR) gene are frequently detected in the lung adenocarcinomas seen in nonsmokers. Thus, EGFR mutations can be implicated in carcinogenesis of lung adenocarcinoma. Herein, we report a case of 2 synchronous lung adenocarcinomas composed of 2 distinct pathological subtypes with different EGFR mutations: homozygous deletion in exon 19 in the papillary subtype of adenocarcinoma and a point mutation of L858R in exon 21 in the tubular adenocarcinoma. These findings suggest that specific mutations can occur randomly in the EGFR hot spot, and that these EGFR mutations can contribute to the distinct carcinogenic process of each adenocarcinoma.
Clinical Lung Cancer 12/2007; 8(9):562-4. · 2.94 Impact Factor
