Oncology Reserach 20(2-3) Abstracts

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Oncology Research, Vol. 20, pp. 49–59, 2012
096500407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13473664562466
E-ISSN 1555-3906
Copyright ©2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Antitumor Properties of Taxol in Combination With Cyclooxygenase-1 and Cyclooxygenase-2 Selective Inhibitors on Ovarian Tumor Growth In Vivo

Wei Li, Lingyun Zhai, Yunxian Tang, Jiahui Cai, Meilin Liu, and Jun Zhang

Department of Gynecology, Nanjing Medical University of Hangzhou Hospital, Hangzhou, Zhejiang, China

The present study was designed to investigate whether taxol in combination with cyclooxygenase (COX) inhibitors could be superior on inhibitory effect of ovarian cancer growth than taxol alone as drug therapy of mice implanted with human ovarian carcinoma cell line SKOV-3. The animals were treated with 100 mg/kg celecoxib (a COX-2 selective inhibitor) alone or in combination with 3 mg/kg SC-560 (a COX-1 selective inhibitor) by gavage twice a day, 20mg/kg taxol alone by intraperitoneal (IP) once a week or in combination with celecoxib, or SC-560/celecoxib/taxol for 3 weeks. To test the mechanism of the combination treatment, the index of cell proliferation, expression of cyclin D1, and microvessel density (MVD) in tumor tissues were determined by immunohistochemistry and the index of apoptotic cells by the terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) method. Mean tumor volume in the SC-560/celecoxib/taxol group was first significantly lower than control at day 14 (p < 0.05). In the SC-560/celecoxib/taxol group, the index of cell proliferation and apoptosis and quantification of cyclin D1-postive cells were 6.93%, 69.62%, and 19.14%, respectively, which are statistically significant compared with those of the control group (29.85%, p < 0.001; 32.81% and 36.99%, both p < 0.05). Statistical significance on MVD was observed between the SC-560/celecoxib/taxol (39.57 ± 4.98) and the control (73.2 ± 1.96) group (p < 0.001). Our results suggest that the combined antitumor efficacy of taxol and COX inhibitors may be superior to taxol alone as drug therapy against ovarian cancer in mice, and that synergism of the combination treatment in part may be mediated through accelerated apoptosis and suppression of cell proliferation and angiogenesis.

Key words: Ovarian carcinoma; SC-560; Celecoxib; Taxol; Cyclin D1; Cell proliferation; Apoptosis

Address correspondence to Wei Li, Department of Gynecology, Nanjing Medical University of Hangzhou Hospital, 261 Huansha Road, Hangzhou, Zhejiang, 310006, China. Tel: +86-0571-87065701; Fax: +86-0571-87914773; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 61–69, 2012
096500407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13473664562501
E-ISSN 1555-3906
Copyright ©2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Fentanyl Inhibits Progression of Human Gastric Cancer MGC-803 Cells by NF-κB Downregulation and PTEN Upregulation In Vitro

Yi Qin,*1 Li Li,*1 Jing Chen,* Xiaoman Tang,† Chunjie Liao,* Yubo Xie,* and Qiang Xiao‡

*Department of Anesthesiology, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, P.R. China
†Department of Anesthesiology, First People’s Hospital of Nanning, Nanning, Guangxi, P.R. China
‡Department of Surgery, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, P.R. China

Fentanyl is used as an analgesic to treat pain in a variety of patients with cancer. Moreover, fentanyl may affect tumor growth in many cell lines. To gain better insight into the interaction between fentanyl and tumor, we investigated the effects of fentanyl on the growth of gastric carcinoma cells and the expression of some apoptosis-related genes including NF-κB and PTEN. A human gastric cancer cell line MGC-803 was used. The viability and proliferation of gastric cancer MGC-803 cells were detected by MTT assay and colony formation assay. The cell cycle progression and apoptosis were assessed by flow cytometry and the ultrastructure of cells was examined with transmission electron microscope. The migration of cells was investigated by wound healing assay. The expression of NF-κB and PTEN was evaluated by semiquantitative RT-PCR and Western blot. Our data showed that fentanyl could inhibit cell growth and proliferation and made cell cycle arrest at G2/M phase. Compared with control cells, MGC-803 cells that were incubated with fentanyl also had a higher apoptotic rate. Fentanyl could lead to morphological changes of gastric cancer cells and reduce the motility of MGC-803 cells. Moreover, fentanyl could downregulate NF-κB and upregulate PTEN, which might be the mechanism of fentanyl inhibiting gastric cancer progression in vitro.

Key words: Fentanyl; Gastric cancer; Tumor progression; NF-κB; PTEN

1These authors contributed equally to this work.
Address correspondence to Professor Yubo Xie, Department of Anesthesiology, The First Affiliated Hospital, Guangxi Medical University, No. 6 Shuang-yong Road, Nanning, Guangxi 530021, P.R. China. Tel/Fax: 0086-771-5359801; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Professor Qiang Xiao, Department of Surgery, The First Affiliated Hospital, Guangxi Medical University, No. 6 Shuang-yong Road, Nanning, Guangxi 530021, P.R. China. Tel/Fax: 0086-771-5358325; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 71–79, 2012
096500407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13473664562565
E-ISSN 1555-3906
Copyright ©2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Impacts and Predictors of Cytotoxic Anticancer Agents in Different Breast Cancer Subtypes

Takashi Ishikawa,* Daisuke Shimizu,* Akimitsu Yamada,† Takeshi Sasaki,‡ Satoshi Morita,§ Mikiko Tanabe,‡ Kae Kawachi,‡ Akinori Nozawa,‡ Takashi Chishima,† Mariko Kimura,† Yasushi Ichikawa,† and Itaru Endo†

*Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Yokohama, Japan
†Department of Gastrointestinal Surgery and Clinical Oncology, Yokohama City University, Yokohama, Japan
‡Department of Pathology, Yokohama City University Medical Center, Yokohama, Japan
§Department of Biostatistics and Epidemiology, Yokohama City University Medical Center, Yokohama, Japan

Breast cancer is not a single entity. This study therefore aimed to identify differences in the impacts of anticancer agents and predictive factors between different breast cancer subtypes. A total of 234 patients with luminal (n = 109), luminal-HER2 (L-H, n = 29), HER-2 (n = 35), or triple negative (TN, n = 61) breast cancer subtypes were treated with standard neoadjuvant chemotherapy consisting of an anthracycline and/or taxane. Pathological response and prognosis were examined in each subtype. Expression levels of estrogen and progesterone receptors, HER-2, nuclear grade, MIB-1, p53, topoisomerase IIα (topoIIα), cytokeratin (CK) 5/6, and epidermal growth factor receptor (EGFR) were examined in association with quasipathological complete response (QpCR). QpCR rates were 9.1% (10/109) in luminal, 45% (13/29) in L-H, 37% (13/35) in HER2, and 54.1% (33/61) in TN. Non-QpCR patients showed significantly poorer 3-year disease-free survival than QpCR patients in TN, but not in patients with other subtypes. No factors were associated with QpCR in luminal patients. Patients with higher nuclear grade were more likely to achieve QpCR in L-H. The proliferative markers MIB-1 and topoIIα had opposite impacts on pathological response in HER-2 and TN. The QpCR rate was significantly higher in TN lacking CK5/6 and/or EGFR expression, defined as nonbasal subtype, compared with basal subtype (p = 0.049). Cytotoxic anticancer agents were associated with different responses in different breast cancer subtypes. Identifying basal-type cancer and further subdivision of nonbasal types is important for treating TN patients.

Key words: Breast cancer; Chemotherapy; Neoadjuvant; Predictive factor

Address correspondence to Takashi Ishikawa, Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 232-0024, Japan. Tel: +81-45-261-5656; Fax: +81-45-253-5736; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 81–91, 2012
096500407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13473664562628
E-ISSN 1555-3906
Copyright ©2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Quinacrine-Mediated Autophagy and Apoptosis in Colon Cancer Cells Is Through a p53- and p21-Dependent Mechanism

Purusottam Mohapatra,* Ranjan Preet,* Dipon Das,* Shakti Ranjan Satapathy,* Tathagata Choudhuri,† Michael D. Wyatt,‡ and Chanakya Nath Kundu*

*KIIT School of Biotechnology, KIIT University, Orissa, India
†Institute of Life Sciences, Orissa, India
‡Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, USA

We previously showed that quinacrine (QC), a small molecule antimalarial agent, also presented anticancer activity in breast cancer cells through activation of p53, p21, and inhibition of topoisomerase activity. Here we have systematically studied the detailed cell death mechanism of this drug using three colon cancer cell lines (HCT-116 parental, isogenic HCT-116 p53−/−, and HCT-116 p21−/− sublines). QC caused a dose-dependent reduction in cell viability in all three cell lines. However, the parental cells were more susceptible to QC-mediated cell death, suggesting that p53- and p21-dependent processes were involved. QC-mediated cell death was measured with the following endpoints: the Bax/Bcl-xL ratio, cleaved PARP, apoptotic nuclei visualized by DAPI staining, and COMET formation. In addition, markers of autophagy were measured. Acridine orange staining revealed increased accumulation of autophagic vacuoles (AVs) after QC treatment in a dose-dependent manner in parental cells, and decreased staining in isogenic HCT-116 p53−/− and HCT-116 p21−/− cells. Immunofluorescence of LC3B was significantly lowered in QC-treated cells lacking p53 or p21, compared to the parental cells. Interestingly, the expression of the autophagy marker LC3B-II after exposure to QC was decreased in either p53 or p21 null cells compared to parental cells. After deletion of p21 in HCT-116 p53−/− cells, no change in LC3B-II expression was noted following QC treatment. Collectively, the results suggest that QC-mediated autophagy and apoptosis dependent on p53 and p21.

Key words: Quinacrine (QC); Colon cancer; p21; p53; Autophagy; Apoptosis

Address correspondence to Chanakya Nath Kundu, KIIT School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Orissa 751024, India. Tel: +91-0674-272-5466; Fax: +91-0674-272-5732; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 93–101, 2012
096500407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13473664562664
E-ISSN 1555-3906
Copyright ©2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Nonangiogenic Function of VEGF and Enhanced Radiosensitivity of HeLa Cells by Inhibition of VEGF Expression

Xiaokang Hu, Lina Xing, Xing Wei, Xiao Liu, Ranran Pang, Li Qi, and Shigang Song

Cancer Radiotherapy, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China

Vascular endothelial growth factor (VEGF) plays an important role in the initiation and regulation of angiogenesis in various tumor tissues. Recently, several therapeutic approaches based on the inhibition of VEGF function during angiogenesis. However, VEGF function in cervical cancer may not be limited to angiogenesis, and VEGF signaling may be important for the ability of these tumor cells to evade apoptosis and progress towards invasive and metastatic diseases. In our study, VEGF expression was knocked down using plasmid-based RNA interference (RNAi) and detected in cervical carcinoma cells using real-time RT-PCR to screen the best RNA interference plasmid and reveal the VEGF expression level by radiation. Cell apoptosis and tumor xenografts in nude mice were measured by flow cytometry and immunohistochemistry, respectively, to further verify the possibility of enhancing apoptosis and radiosensitivity of cervical carcinoma cells by inhibition of VEGF expression. VEGF expression was significantly inhibited and the apoptosis was efficiently increased by RNAi. Moreover, the expression of VEGF was increased in HeLa cells in vivo and in vitro only by radiation. Increased apoptotic cell death and knockdown of VEGF expression in HeLa cells indicated increased cellular sensitivity to radiation. The data suggested that inhibited VEGF expression enhances radiosensitivity in cervical cancer therapy.

Key words: Vascular endothelial growth factor (VEGF); RNA interference; Radiosensitivity; Apoptosis; Cervical cancer

Address correspondence to Lina Xing, Cancer Radiotherapy, The 2nd Affiliated Hospital of Harbin Medical University, Baojian Road, Harbin 150006, Heilongjiang Province, China. Tel: +86-15046652643; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 103–111, 2012
096500407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13477145152959
E-ISSN 1555-3906
Copyright ©2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Growth Inhibition of Pancreatic Cancer by Experimental Treatment With 4-Phenylbutyrate Is Associated With Increased Expression of Connexin 43

Dmitriy I. Dovzhanskiy,*1 Werner Hartwig,*1 Nóra G. Lázár,* Alexandra Schmidt,* Klaus Felix,* Beate K. Straub,† Thilo Hackert,* Dmitri V. Krysko,‡ and Jens Werner*

*Department of General Surgery, University of Heidelberg, Heidelberg, Germany
†Department of General Pathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
‡Molecular Signaling and Cell Death Unit, Department for Molecular Biochemical Research, VIB and Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium

Histone deacetylase inhibitors are a new and promising drug family with a strong anticancer activity and potent modulation of connexin expression. The restoration of connexins in cancer cells has been suggested as a possible mechanism to control tumor progression. The aim of this study was to investigate the effects of 4-phenylbutyrate (4-PB) on the growth of human pancreatic cell lines in vitro and in vivo with a focus on connexin modulation. The proliferation of tumor cells was determined using an MTT assay, and the effect of 4-PB in vivo was studied in a chimeric mouse model. The expression and localization of connexin 43 (Cx43) were assessed by Western blot, immunofluorescence microscopy, and immunohistochemistry. Antitumoral activity was assessed by immunohistochemistry for Ki-67 and histone H4. Treatment with 4-PB resulted in the significant in vitro and in vivo growth inhibition of pancreatic tumor cells. The reduction of the xenograft tumor volume was associated with the inhibition of histone deacetylation and decrease in cell proliferation. Treatment with 4-PB caused a significant increase in the Cx43 expression in T3M4 cells (up to 2.8-fold). The newly synthesized Cx43 was localized in the cytoplasm but not on the cell membrane. Treatment with 4-PB inhibited the proliferation of human pancreatic tumor cells in vitro and in vivo and increased the expression of Cx43. Therefore, 4-PB might be useful in the therapy of pancreatic cancer.

Key words: Pancreatic cancer; Histone deacetylase inhibitors; 4-Phenylbutyrate (4-PB); Gap junction intercellular communication; Connexin 43 (Cx43); Mice

1These authors provided equal contribution to this work.
Address correspondence to Jens Werner, M.D., Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Tel: +49-6221-565150; Fax: +49-6221-565969; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 113–121, 2012
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DOI: http://dx.doi.org/10.3727/096504012X13477145152995
E-ISSN 1555-3906
Copyright ©2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

PTEN Enhances the Sensitivity of Human Hepatocellular Carcinoma Cells to Sorafenib

Zhi-Ping Ruan,* Rui Xu,†‡ Yi Lv,§ Tao Tian,* Wen-Juan Wang,* Hui Guo,* and Ke-Jun Nan*

*Department of Oncology, First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’an, P.R. China
†Medical College of Xi’an Jiaotong University, Xi’an, P.R. China
‡First Department of Internal Medicine, Shaanxi Cancer Hospital, Xi’an, P.R. China
§Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’an, P.R. China

Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations and ranks as the third highest cause of cancer-related death globally. The unresectable or metastatic HCC has very poor prognosis. Although multikinase inhibitor sorafenib can increase the survival of patients with advanced HCC, it is becoming apparent that combination therapies are critical to overcome the complex genomic aberrations in HCC. PTEN, as one of the most commonly inactivated genes in HCC, exerts a wide range of antitumor effects. In this study, we found that PTEN was downregulated in HCC tissues, especially in those tissues with extrahepatic metastasis. And negative PTEN expression cases showed increased proliferation activity. Overexpression of PTEN significantly reduced the proliferation of tumor cells HepG2. In addition, HepG2 cells transfected with PTEN were more sensitive to sorafenib in terms of its ability to inhibit proliferation and to induce apoptosis. Moreover, overexpression of PTEN decreased phosphorylation of MEK, a key downstream effector of RAF/MEK/ERK cascade, and levels of cyclin D1, antiapoptotic Bcl-2, and VEGF. These observations indicated that combination therapies with sorafenib and PTEN overexpression have potential to further improve therapeutic options for HCC.

Key words: PTEN; Sorafenib; Hepatocellular carcinoma

Address correspondence to Ke-Jun Nan, Department of Oncology, First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China. Fax: +86-29-85324086; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 123–130, 2012
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DOI: http://dx.doi.org/10.3727/096504012X13477145153039
E-ISSN 1555-3906
Copyright ©2012 Cognizant Comm. Corp.
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Epigenetic Inactivation of Wnt Inhibitory Factor-1 in Human Esophageal Squamous Cell Carcinoma

Song-Hua Yang,*1 Sheng-Lei Li,†1 Zi-Ming Dong,‡ and Quan-Cheng Kan*

*Department of Pharmacy, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, P.R. China
†Department of Pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, P.R. China
‡Department of Pharmacology, College of Basic Medicine, Zhengzhou University, Zhengzhou, P.R. China

Wnt inhibitory factor-1 (WIF1), as one of most important Wnt antagonists, has been detected frequently silenced by promoter hypermethylation in various types of cancer. In this study, we aimed to investigate the promoter methylation profiles of WIF1 in human esophageal squamous cell carcinoma (ESCC) tissues and cell lines, as well as the functional roles of WIF1 in the human ESCC metastatic behavior. WIF1 mRNA levels and promoter methylation status in ESCC tissues and cell lines were detected using RT-PCR and methylation-specific PCR (MS-PCR), respectively. WIF1 protein levels were assessed by Western blot. Stable ESCC cell line with restoration of WIF1 was generated in EC109 cells, which naturally do not express detectable WIF1 mRNA. The effects of reexpressed WIF1 on EC109 cell proliferation and migration were investigated using crystal violet and wound healing assay, respectively. Also the effects of WIF1 reexpression on the β-catenin/T-cell factor-dependent transcription activity were measured by luciferase assay. WIF1 promoter methylation was frequently observed in ESCC tissues (46%, 23/50) and cell lines (50%, 2/4). Treatment with demethylating agent, 5-aza-2′-deoxycytidine (5-aza-dC), increased or restored WIF1 expression in these ESCC cell lines. Restoration of the WIF1 in EC109 cells resulted in a significant inhibition on both cell proliferation and migration. Moreover, reexpression of WIF1 caused significant decrease of β-catenin/T-cell factor-dependent transcription activity. These findings demonstrated that WIF1 silencing due to promoter hypermethylation is a major mechanism during carcinogenesis of ESCC. This would be an opportunity to prevent the development and progression of HCC through modulation of WIF1.

Key words: Wnt inhibitory factor-1 (WIF1); Human esophageal squamous cell carcinoma (ESCC); Promoter hypermethylation; Proliferation; Migration

1These authors provided equal contribution to this work.
Address correspondence to Quan-Cheng Kan, Department of Pharmacy, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China. Tel: +86 0371 66913047; Fax: +86 371 66969642; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Zi-Ming Dong, Department of Pathological Physiology, School of Medicine, Zhengzhou University, 100 Science Road, Zhengzhou 450001, P.R. China. Tel: +86 371 67781956; Fax: +86 371 67781956; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 131–137, 2012
096500407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13473664562583
E-ISSN 1555-3906
Copyright ©2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Relationship of Circulating Tumor Cells to the Effectiveness of Cytotoxic Chemotherapy in Patients With Metastatic Non-Small-Cell Lung Cancer

Takashi Hirose,* Yasunori Murata,* Yasunari Oki,* Tomohide Sugiyama,* Sojiro Kusumoto,* Hiroo Ishida,* Takao Shirai,* Masano Nakashima,* Toshimitsu Yamaoka,† Kentaro Okuda,* Tsukasa Ohnishi,* and Tohru Ohmori†

*Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Showa University School of Medicine, Shinagawa, Tokyo, Japan
†Institute of Molecular Oncology, Showa University School of Medicine, Shinagawa, Tokyo, Japan

The aim of this study was to investigate the relationship of the number of circulating tumor cells (CTCs) with the effectiveness of cytotoxic chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC). We prospectively evaluated CTCs in the peripheral blood of patients with previously untreated metastatic NSCLC. From May 2008 through August 2010, 33 patients (23 men and 10 women; median age, 64 years; range, 46–74 years) were enrolled. All patients received combination chemotherapy with gemcitabine and carboplatin. The CTCs were captured from samples of peripheral blood with a semiautomated system using an antibody against epithelial cell adhesion molecule. Blood samples with one or more CTC per 7.5 ml were defined as positive. Of total 33 patients, 12 (36.4%) had positive CTCs and 5 (15.2%) had five or more CTCs before chemotherapy. There were no differences in response rates to cytotoxic chemotherapy between CTC-positive patients and CTC-negative patients. On the other hand, the rate of progressive disease in cytotoxic chemotherapy was significantly higher in CTC-positive patients (66.7%) than in CTC-negative patients (23.8%, p = 0.02). In conclusion, the number of CTCs could be a useful predictive factor for the effectiveness of cytotoxic chemotherapy in patients with metastatic NSCLC.

Key words: Chemotherapy; Circulating tumor cells (CTCs); Predictive factor; Non-small-cell lung cancer (NSCLC)

Address correspondence to Takashi Hirose, M.D., Ph.D., Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8666, Japan. Tel: +81-3-3784-8532; Fax: +81-3-3784-8742; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it