Faculty Profiles - KAGAWA Shunsuke

Papers - KAGAWA Shunsuke

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HDAC阻害剤FR901228によるテロメラーゼ特異的制限増殖型アデノウイルスTelomelysinの選択的抗腫瘍効果の増強

渡邉貴紀, 西崎正彦, 香川俊輔, 滝正樹, 岸本浩行, 藤原俊哉, 遠藤芳克, 京哲, 水口裕之, 田中紀章, 藤原俊義

日本癌学会総会記事 63回 499 - 499 2004.9

テロメラーゼ活性を標的とした治療 (特集分子・細胞標的治療--基礎と臨床) -- (基礎)

藤原俊義, 香川俊輔, 田中紀章

現代医療 36 ( 7 ) 1366 - 1372 2004.7

Antitumor effect of intratumoral administration of bone marrow-derived dendritic cells transduced with wild-type p53 gene

T Murakami, N Tokunaga, T Waku, S Gomi, S Kagawa, N Tanaka, T Fujiwara

CLINICAL CANCER RESEARCH 10 ( 11 ) 3871 - 3880 2004.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Dendritic cells (130) are attractive effectors for cancer immunotherapy because of their potential to function as professional antigen-presenting cells for initiating cellular immune responses. The tumor suppressor gene p53 is pivotal in the regulation of apoptosis, and similar to50% of human malignancies exhibit mutation and aberrant expression of p53. We investigated the antitumor effect of intratumoral administration of bone marrow-derived dendritic cells transduced with wild-type p53 gene.
Experimental Design: We examined whether intratumoral administration of DCs infected with recombinant adenovirus expressing murine wild-type p53 (Ad-mp53) could induce systemic antitumor responses against mutant p53-expressing tumors, highly immunogenic MethA, or weakly immunogenic MCA-207 implanted in syngeneic mice.
Results: Accumulation of wild-type p53 protein in bone marrow-derived murine DCs could be successfully achieved by Ad-mp53 infection. Treatment with intratumoral injection of Ad-mp53-transduced DCs caused a marked reduction in the in vivo growth of established MethA and MCA-207 tumors with massive cellular infiltrates. Administration of p53-expressing DCs suppressed the growth of both injected MCA-207 tumors and untreated distant MCA-207 tumors, but not unrelated Lewis lung carcinoma tumors, suggesting the augmentation of systemic immunogenicity against MCA-207 tumor cells. Moreover, intratumoral injection of p53-expressing DCs had a greater antitumor effect than did s.c. immunization.
Conclusions: Our results indicate that intratumoral administration of DCs expressing murine wild-type p53 leads to significant systemic immune responses and potent antitumor effects in mutant p53-expressing murine cancer models. These findings raise the possibility of using this strategy of intratumoral injection of p53-expressing DCs for human cancer treatment.

DOI： 10.1158/1078-0432.CCR-03-0599

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Thoracic tumors treated with CT-guided radiofrequency ablation: Initial experience

K Yasui, S Kanazawa, Y Sano, T Fujiwara, S Kagawa, H Mimura, S Dendo, T Mukai, H Fujiwara, T Iguchi, T Hyodo, N Shimizu, N Tanaka, Y Hiraki

RADIOLOGY 231 ( 3 ) 850 - 857 2004.6

Language：English Publishing type：Research paper (scientific journal) Publisher：RADIOLOGICAL SOC NORTH AMERICA

PURPOSE: To determine the effectiveness of computed tomography (CT)-guided radiofrequency (RF) ablation of malignant thoracic tumors.
MATERIALS AND METHODS: CT-guided RF ablations of 99 malignant thoracic tumors (3-80 mm in largest diameter; mean, 19.5 mm) were performed in 35 patients in 54 sessions. Ablation was performed with an RF generator by using a single internally cooled electrode. Tumors were both primary (three lesions) and, secondary (pulmonary or pleural metastases, 96 lesions). Follow-up was 1-17 months (mean, 7.1 months). Follow-up CT and histopathologic examinations were evaluated. Univariate analysis was performed with the Fisher exact test and Welch, t test was used to evaluate differences between group means. P < .05 represented a significant difference. The maximal diameter of each residual tumor or local recurrence or the proportion of primary lesions of pulmonary metastatic tumors with recurrence after RF ablation were analyzed. Complications, management, and outcomes of the complications were recorded.
RESULTS: The appearance of each ablation zone, including the target tumor and surrounding normal lung parenchyma, showed involution at follow-up CT. Local recurrence was demonstrated histopathologically or radiologically in nine tumors. The other 90 tumors showed no growth progression at follow-up CT. Probable complete coagulation necrosis obtained with initial RF ablation was achieved in 91% (90 of 99) of the tumors. The mean maximal diameter of the nine tumors (19.6 mm +/- 7.7 [SD]) was not significantly different (P = .994) from that of the other 90 tumors (19.5 mm +/- 13.0). Primary lesions of those nine metastatic tumors varied and did not demonstrate a specific tendency. Complications included pneumothorax, fever higher than 37.5&DEG;C, hemoptysis, cough, pleural effusion, abscess formation, and hemothorax. The overall complication rate was 76% (41 of 54 sessions).
CONCLUSION: RF ablation seems to be a promising treatment for malignant (C) RSNA, 2004.

DOI： 10.1148/radiol.2313030347

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Late resistance to adenoviral p53-mediated apoptosis caused by decreased expression of Coxsackie-adenovirus receptors in human lung cancer cells

Y Tango, M Taki, Y Shirakiya, S Ohtani, N Tokunaga, Y Tsunemitsu, S Kagawa, T Tani, N Tanaka, T Fujiwara

CANCER SCIENCE 95 ( 5 ) 459 - 463 2004.5

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPANESE CANCER ASSOC

Adenovirus-mediated wild-type p53 gene transfer induces apoptosis in a variety of human cancer cells. Although clinical trials have demonstrated that a replication-deficient recombinant adenovirus expressing the wild-type p53 gene (Ad-p53) is effective in suppressing growth of non-small cell lung cancer (NSCLC), we often experienced late resistance to this treatment. To elucidate the mechanism of late resistance to Ad-p53 in human lung cancer cells, we generated 5 different resistant variants from p53-susceptible H1299 NSCLC cells by repeated infections with Ad-p53. We first examined the transduction efficiency of adenoviral vector by Ad-LacZ transduction followed by X-gal staining in parental and 5 resistant H1299 cell lines. Their sensitivity to viral infection decreased in correlation with the magnitude of resistance, and Ad-p53-mediated tumor suppression could be restored by dose escalation of Ad-p53 in the resistant variants. The expression of Coxsackie and adenovirus receptor (CAR) and alphaV integrins, which are cellular receptors for attachment and internalization of the virus, respectively, was next investigated in these cell lines. Flow cytometry revealed that alphaVbeta3 and alphaVbeta5 integrin expression was consistent, while p53-resistant cell lines showed that diminished CAR expression correlated with the magnitude of the resistance. Our results demonstrated that decreased CAR expression could be one of the mechanisms of late resistance to Ad-p53, which may have a significant impact on the outcome of adenovirus-based cancer gene therapy.

DOI： 10.1111/j.1349-7006.2004.tb03232.x

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Molecular therapy for peritoneal dissemination of xenotransplanted human MKN-45 gastric cancer cells with adenovirus mediated Bax gene transfer

Y Tsunemitsu, S Kagawa, N Tokunaga, S Otani, T Umeoka, JA Roth, B Fang, N Tanaka, T Fujiwara

GUT 53 ( 4 ) 554 - 560 2004.4

Language：English Publishing type：Research paper (scientific journal) Publisher：B M J PUBLISHING GROUP

Background: Gene therapy is an innovative therapeutic approach for cancer. An adenoviral vector expressing the tumour suppressor p53 gene (Ad/p53) is currently under clinical evaluation for various cancers. We recently developed a binary adenoviral vector system that can express the strong proapoptotic gene Bax (Ad/ PGK-GV16+ Ad/ GT-Bax: Ad/Bax).
Aims: To evaluate the potential of Bax gene therapy for gastric cancer, we assessed its antitumour effect in comparison with that of p53.
Methods: The human gastric cancer cell lines MKN-1, MKN-7, MKN-28, and MKN-45 were treated with Ad/ Bax or Ad/ p53, and cell viability, transgene expression, and caspase activation were assessed in vitro. To compare the antitumour effects of Ad/ Bax and Ad/ p53 treatment in vivo, subcutaneous tumours and peritoneal dissemination of MKN-45 cells were generated in nude mice. Each mouse underwent intratumoral or intraperitoneal administration of viruses and the growth of implanted tumours was observed after treatment.
Results: Treatment with Ad/ Bax and Ad/ p53 resulted in marked Bax and p53 protein expression and effective apoptosis induction in MKN-1, MKN-7, and MKN-28 cells in vitro. In contrast, MKN-45 cells showed resistance to Ad/ p53 and only treatment with Ad/ Bax resulted in activation of caspase 3 expression and massive apoptosis. Ad/ Bax treatment was more effective in suppressing both subcutaneous and peritoneally disseminated MKN-45 tumours compared with Ad/ p53 treatment.
Conclusion: Ad/ Bax treatment significantly inhibited the growth of even p53 resistant gastric cancer in vitro and in vivo. Therefore, adenovirus mediated Bax gene transfer may be useful in gene therapy for gastric cancers.

DOI： 10.1136/gut.2003.021683

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Telomerase-specific replication-selective virotherapy for human cancer

T Kawashima, S Kagawa, N Kobayashi, Y Shirakiya, T Umeoka, F Teraishi, S Kyo, M Taki, N Tanaka, T Fujiwara

CLINICAL CANCER RESEARCH 10 ( 1 ) 285 - 292 2004.1

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Replication-selective tumor-specific viruses present a novel approach for treating neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis, and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We investigated the antitumor effect of the hTERT-specific replication-competent adenovirus on human cancer cells.
Experimental Design: We constructed an adenovirus 5 vector [tumor- or telomerase-specific replication-competent adenovirus (TRAD)], in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site, and we examined the selective replication and antitumor effect in human cancer cells in vitro and in vivo.
Results: TRAD induced selective E1A and E1B expression in human cancer cells, but not in normal cells such as human fibroblasts. TRAD replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human fibroblasts lacking telomerase activity. In nu/nu mice carrying s.c. human lung tumor xenografts, intratumoral injection of TRAD resulted in a significant inhibition of tumor growth. No evidence of TRAD was identified in tissues outside of the tumors, despite the presence of TRAD in the circulation. Moreover, TRAD replication in the distant, noninjected tumors was demonstrated.
Conclusions: Our results suggest that the hTERT promoter confers competence for selective replication of TRAD in human cancer cells, an outcome that has important implications for the treatment of human cancers.

DOI： 10.1158/1078-0432.CCR-1075-3

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Quantitative analysis of p53-targeted gene expression and visualization of p53 transcriptional activity following intratumoral administration of adenoviral p53 in vivo

S Ohtani, S Kagawa, Y Tango, T Umeoka, N Tokunaga, Y Tsunemitsu, JA Roth, Y Taya, N Tanaka, T Fujiwara

MOLECULAR CANCER THERAPEUTICS 3 ( 1 ) 93 - 100 2004.1

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

To analyze the mechanism of the antitumor effect of an adenoviral vector expressing the p53 tumor suppressor (Ad-p53) in vivo, we quantitatively assessed p53-targeted gene expression and visualized transcriptional activity of p53 in tumors in nude mice treated with Ad-p53. Human lung cancer (H1299) xenografts- established in nude mice were treated by intratumoral administration of Ad-p53. The levels of expression of exogenous p53 and p53-targeted genes p21, MDM2, Noxa, and p53AIP1 were quantified by real-time reverse transcription-PCR (RT-PCR) and induction of apoptosis was observed histochemically on days 1-3, 7, and 14 after treatment. Expression of mRNA of exogenous p53 and p53-targeted genes (except p53AIP1) was at its maximum 1 day after Ad-p53 treatment and then decreased rapidly; apoptosis was evident in situ 2-3 days after treatment. We developed a noninvasive and simple method for monitoring the transcriptional activity of exogenous p53 following intratumoral administration of Ad-p53 in nude mice. We established H1299 cells that express the green fluorescent protein (GFP) reporter gene under the control of p53-responsive p21 promoter (i.e., the p53R-GFP reporter system). Xenografts of these cells in nude mice were treated by intratumoral administration of Ad-p53, and the transcriptional activity of exogenous p53 could be visualized as intratumoral GFP expression in real time by 3-CCD camera. Expression of GFP was maximal 3 days after treatment and decreased remarkably by 7 days after treatment. We demonstrated that Ad-p53 treatment rapidly induced p53-targeted genes and apoptosis in tumors and succeeded in visualizing p53 transcriptional activity in vivo. We also found that Ad-p53 infection induced phosphorylation of p53 at Ser(46) in p53-sensitive H1299 cells in vitro but not in p53-resistant H226Br cells, suggesting that phosphorylation of Ser(46) is involved in p53dependent apoptosis. Our data indicate that quantitative analysis of p53-targeted gene expression by real-time quantitative RT-PCR and visualization of p53 transcriptional activity in fresh xenografts by using the p53R-GFP reporter system may be useful in assessing the mechanisms of the antitumor effects of Ad-p53 and novel therapeutic approaches.

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進行非小細胞肺癌に対してp53遺伝子治療を施行し奏効が得られた1例

香川俊輔, 藤原俊義, 大谷彰一郎, 田中紀章, 岡山大病院, 遺伝子, 細胞治療センタ

癌と化学療法 31,11,1788-1790 2004

A case of advanced non-small lung cancer responding to tumor suppressor p53 gene therapy

Shunsuke Kagawa, Shoichiro Ohtani, Noriaki Tanaka, Toshiyoshi Fujiwara

Gan to kagaku ryoho. Cancer & chemotherapy 31 ( 11 ) 1788 - 1790 2004

Language：Japanese Publishing type：Research paper (scientific journal)

The phase I study of the tumor suppressor p53 gene therapy for advanced lung cancer was performed. A 57-year-old man with locally advanced squamous cell carcinoma at the tracheal bifurcation, clinical stage IIIB, had previously been treated by radiotherapy and chemotherapy. Because of the local recurrence, he was enrolled to the study. He was treated by a local injection of ADVEXIN once every 4 weeks for 14 times without marked adverse events, which resulted in tumor regression and relief of his symptom for a year. In conclusion, gene therapy with ADVEXIN may be an effective treatment for locally advanced non-small lung cancer.

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RGDファイバー変異を挿入した腫瘍特異的増殖可能アデノウイルス(TRAD)の抗腫瘍効果の増強

滝正樹, 藤原俊義, 川嶋健, 岸本浩行, 藤原俊哉, 水口裕之, 京哲, 香川俊輔, 西崎正彦, 田中紀章

日本癌学会総会記事 62回 161 - 161 2003.8

Ectopic p21(sdi1) gene transfer induces retinoic acid receptor beta expression and sensitizes human cancer cells to retinoid treatment

F Teraishi, Y Kadowaki, Y Tango, T Kawashima, T Umeoka, S Kagawa, N Tanaka, T Fujiwara

INTERNATIONAL JOURNAL OF CANCER 103 ( 6 ) 833 - 839 2003.3

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

The biological effects of retinoic acid (RA) are mediated by nuclear retinoic acid receptors (RARs) that function as ligand-activated transcriptional factors. The response of human cancer cells to RA is known to be associated with the expression of RARbeta. Recent studies have demonstrated that the loss of RARbeta expression is involved in the development of a variety of human malignancies. We show that recombinant adenovirus-mediated p21(sdi1) gene transfer enhances RARbeta mRNA expression as well as protein expression and induces the sensitivity to all-trans RA (ATRA) in human cancer cells. Semi-quantitative reverse transcription-polymerase chain reaction analysis demonstrated that infection with adenovirus carrying human p21(sdi1) gene (AdSCMV-p21), which encodes a cyclin-dependent kinase inhibitor, induced RARbeta mRNA and protein expression in H1299 human non-small cell lung cancer cells and DLD-1 human colorectal cancer cells. We also found that exogenous introduction of the p21(sdil) gene transcriptionally activated the upstream promoter function of the RARbeta gene. Treatment with I muM of ATRA showed no significant inhibitory effects on the growth of H 1299 and DLD-1 cells; after Ad5CMV-p21 infection, however, cells underwent apoptosis with ATRA treatment at the same concentration, suggesting that p21(sdil) gene transfer sensitized H1299 and DLD-1 cells, presumably, through RARbeta upregulation. We also demonstrated the efficacy of intratumoral injection of AdSCMV-p21 in combination with systemic administration of ATRA in a nude mice xenograft model. Our results indicate that recombinant adenovirus-mediated p21(sdil) gene transfer could be potentially useful for the local induction of RA sensitivity in human premalignant and malignant lesions lacking appropriate RARbeta expression. (C) 2002 Wiley-Liss, Inc.

DOI： 10.1002/ijc.10892

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Clinical study of adenoviral mediated p53 gene therapy for non-small cell lung cancer in Japan

Shunsuke Kagawa, Toshiyoshi Fujiwara, Noriaki Tanaka

Gan to kagaku ryoho. Cancer & chemotherapy 30 ( 2 ) 193 - 197 2003

Language：Japanese

The prognosis in case of non-small cell lung cancer (NSCLC) remains poor, and novel treatment modalities are urgently needed for advanced NSCLC. Backed by advances in the understanding of cancer biology, gene therapy has been developed in recent years. The p53 gene is altered in over 50% of cancers and has been extensively studied as a tumor suppressor gene. Adenoviral-mediated p53 gene transfer is currently under clinical evaluation worldwide for the treatment of cancer. We are now conducting a phase I study of Ad-p53 for advanced NSCLC patients in Japan. As an interim report, we provide a brief summary of the current status of this study, highlighting the safety and clinical efficacy of Ad-p53. As of September 2002, 13 patients were enrolled to this study, and safety and antitumor effects have been noted.

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肺癌の遺伝子治療

香川俊輔, 藤原俊義, 田中紀章

病理と臨床 21,519-522 2003

遺伝子治療の実際

香川俊輔, 藤原俊義, 田中紀章

癌と化学療法 30,193-197 2003

制限増殖型アデノウイルスによる非増殖型p53遺伝子発現アデノウイルスベクター(Ad5CMV-p53)の腫瘍選択的増殖

谷本光隆, 藤原俊義, 高田佳子, 大谷彰一郎, 川嶋健, 香川俊輔, 西崎正彦, 田中紀章

日本癌学会総会記事 61回 187 - 187 2002.10

A recombinant adenovirus expressing wild-type Bax induces apoptosis in prostate cancer cells independently

T Honda, S Kagawa, KB Spurgers, BT Gjertsen, JA Roth, BL Fang, SL Lowe, JS Norris, RE Meyn, TJ McDonnell

CANCER BIOLOGY & THERAPY 1 ( 2 ) 163 - 167 2002.3

Language：English Publishing type：Research paper (scientific journal) Publisher：LANDES BIOSCIENCE

Using a binary co-transfection strategy of Ad/GT Box and Ad/PGK-GV16, we have succeeded in inducing overexpression of Box protein in three prostate cell lines (androgen-insensitive DU145 and PC3, and androgen-sensitive LNCaP). The expression of Box protein by this system was sufficient to induce all three prostate lines to undergo apoptosis. The fact that DU145 cells which have a p53 mutation and are deficient in Box, responded to this treatment, suggests that this effect is independent of these pathways. Initiation of the cleavage of Caspase-3 (CPP32/Yama/apopain) and PARP (poly (ADP-ribose) polymerase) by the introduction of Box were confirmed by western blot analysis. Bcl-2 expression is relevant in the progression of prostate cancer and contributes to an androgen, apoptotic-resistant phenotype in the advanced stages. We examined stable Bcl-2 overexpressing DU145, PC3 and LNCaP cell lines as models of advanced prostate cancer. The adenoviral co-transfection system induced Box protein expression and apoptosis even in these Bcl-2 transfected cell lines. Taken together, our results suggest that this Box expression system might represent a useful gene therapy strategy when applied to the treatment of prostate cancer and its efficacy would be independent of the Bcl-2 status and androgen sensitivity of these cancers.

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肺癌に対する遺伝子治療：p53発現アデノウイルスベクターによる肺癌遺伝子治療臨床試験の現況.

香川俊輔, 藤原俊義, 田中紀章

医学のあゆみ 203,5,302-306 2002

肺癌非手術療法の新しい試み 7.遺伝子治療.

片岡正文, 藤原俊義, 香川俊輔, 田中紀章

日本外科学会雑誌 103,2,244-249 2002

p53を用いた肺癌遺伝子治療.

香川俊輔, 藤原俊義, 田中紀章

日本臨床 60,Suppl 5, 630-634 2002

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Papers - KAGAWA Shunsuke