ognizant Communication Corporation

ONCOLOGY RESEARCH
Featuring PRECLINICAL AND CLINICAL CANCER THERAPEUTICS

ABSTRACTS
VOLUME 17, NUMBER 6

Oncology Research, Vol. 17, pp. 239-246
0965-0407/08 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2008 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Review
Gene Therapy for Malignant Pleural Mesothelioma: Present and Future

Yuji Tada,1 Yuichi Takiguchi,1 Kenzo Hiroshima,2 Hideaki Shimada,3,5 Taro Ueyama,1,6 Makoto Nakamura,1,6 Koichiro Tatsumi,1 Takayuki Kuriyama,1 and Masatoshi Tagawa4,6

1Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
2Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
3Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
4Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
5Division of Gastroenterological Surgery, Chiba Cancer Center, Chiba260-8717, Japan
6Division of Pathology, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan

Malignant pleural mesothelioma is relatively rare in frequency but one of the intractable diseases linked with asbestos exposure. Clinical outcomes with the present treatment modalities are unsatisfactory and no effective prevention method has been reported. Growing numbers of the patients in the Western countries with a long latent period need development of a novel therapeutic strategy. Gene therapy is a candidate for mesothelioma treatment because of its easy accessibility of a vector-mediated gene medicine into the intrapleural cavity. Several preclinical studies demonstrated that the gene medicine produced antitumor effects, suggesting the feasibility in clinical settings. In this article, we review the current status of gene therapy and clinical trials targeting mesothelioma and address possible directions to improve the efficacy.

Key words: Mesothelioma; Gene therapy; Clinical trial; Adenovirus

Address correspondence to Masatoshi Tagawa, Division of Pathology, Chiba Cancer Center Research Institute. 666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan. Tel: +81-43-264-5431, ext. 5101; Fax: +81-43-265-4459; E-mail: mtagawa@chiba-cc.jp




Oncology Research, Vol. 17, pp. 247-255
0965-0407/08 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2008 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Neutral pH Hydrogen-Enriched Electrolyzed Water Achieves Tumor-Preferential Clonal Growth Inhibition Over Normal Cells and Tumor Invasion Inhibition Concurrently With Intracellular Oxidant Repression

Yasukazu Saitoh,1 Hajime Okayasu,1 Li Xiao,1 Yoshikazu Harata,2 and Nobuhiko Miwa1

1Cell-Death Control BioTechnology Laboratory, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Hiroshima 727-0023, Japan
2Takaoka Chemical Co., Ltd., Aichi 790-11, Japan

The properties and effects of neutral pH hydrogen-enriched electrolyzed water (NHE water) on tumor cells were examined. NHE water diminished hydroxyl radicals as demonstrated by ESR in a cell-free system. Human tongue carcinoma cells HSC-4 were inhibited for either colony formation efficiencies or colony sizes by NHE water without significant inhibition to normal human tongue epithelial-like cells DOK. Furthermore, NHE water caused growth inhibition, cell degeneration, and inhibition of invasion through the reconstituted basement membrane to human fibrosarcoma cells HT-1080. Intracellular oxidants such as hydroperoxides and hydrogen peroxides were scavenged in HSC-4 or HT-1080 cells by NHE water. In the human oral cavity, a dissolved hydrogen concentrations (DH) of NHE water was drastically declined from 1.1 to 0.5 ppm, but settled to 0.3-0.4 ppm until 180 s, upon static holding without gargling. Thus, NHE water was shown to achieve tumor-preferential growth inhibition and tumor invasion together with scavenging of intracellular oxidants, and is expected as a preventive material against tumor progression and invasion.

Key words: Neutral pH hydrogen-enriched electrolyzed water; Tumor repression; Human tongue carcinoma; Reactive oxygen species

Address correspondence to Nobuhiko Miwa, Death Control BioTechnology Laboratory, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Nanatsuka 562, Shobara, Hiroshima 727-0023, Japan. Tel: +81-824-74-1754; Fax: +81-824-74-1754; E-mail: miwanob@pu-hiroshima.ac.jp




Oncology Research, Vol. 17, pp. 257-267
0965-0407/08 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2008 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Therapeutic Efficacy of Curcumin/TRAIL Combination Regimen for Hormone-Refractory Prostate Cancer

Tanja Andrzejewski,1 Dorrah Deeb,1 Xiaohua Gao,1 Andrew Danyluk,1 Ali S. Arbab,2 Scott A. Dulchavsky,1 and Subhash C. Gautam1

1Department of Surgery, Henry Ford Health System, Detroit, MI, USA
2Department of Diagnostic Radiology, Henry Ford Health System, Detroit, MI, USA

Because of lack of effective treatment options for hormone-refractory prostate cancer at the present time, the need for developing novel therapeutic strategies and targets to treat and prevent the progression of hormone-sensitive prostate cancer to the hormone-refractory stage is paramount. Our previous in vitro studies have shown that curcumin sensitizes both hormone-sensitive and hormone-resistant prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and that combined curcumin/TRAIL treatment induces apoptosis in cancer cells by inhibiting antiapoptotic p-Akt and nuclear factor-kB (NF-kB). In the present study, we demonstrate that curcumin and TRAIL combination regimen is also the most effective treatment for inhibiting the growth of PC3 xenografts compared to curcumin or TRAIL monotherpy. The inhibition of PC3 tumors by combined treatment correlated with significant reduction in expression of p-Akt and NF-kB in tumor tissue. Furthermore, tumor growth inhibition by curcumin/TRAIL combination regimen was associated with significant decrease in cell proliferation and an increase in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in the tumors without significant change in microvessel density. Based on the significant efficacy in this preclinical model, combined curcumin/TRAIL regimen may be an effective adjuvant therapy for hormone-refractory prostate cancer.

Key words: Prostate cancer; Curcumin; TRAIL; NF-kB; Akt; Apoptosis

Address correspondence to Subhash C. Gautam, Ph.D., Surgical Research 4D, One Ford Place, Detroit, MI 48202, USA. Tel: (313) 874-6998; Fax: (313) 874-3770; E-mail: sgautam1@hfhs.org




Oncology Research, Vol. 17, pp. 269-272
0965-0407/08 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2008 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Expression of Insulin-Like Growth Factor-II mRNA Binding Protein 3 (IMP3) in Osteosarcoma

Sung-Im Do,1 Youn Wha Kim,1 Hye-Rim Park,2 and Yong-Koo Park1

1Department of Pathology, School of Medicine, Kyung-Hee University, Seoul, 130-702, Korea
2Department of Pathology, College of Medicine, Hallym University, Anyang, 431-070, Korea

Insulin-like growth factor-II mRNA binding protein 3 (IMP3) is one of the RNA binding proteins implicated in mRNA localization and translational control. It is expressed during embryogenesis, as well as in some malignant tumors. Recent studies suggest its potential use as a prognostic factor or as a therapeutic target in malignancy. Using tissue microarray, we examined the immunohistochemical staining of IMP3 in osteosarcoma cases to evaluate whether it could serve as a prognostic biomarker. In a tissue microarray analysis of 47 paraffin-embedded osteosarcoma cases, 8 (17.02%) were positive for IMP3 immunostaining, and IMP3 expression was correlated with tumor metastasis (p = 0.020). IMP3 expression was independent of survival, tumor site, histologic type, age, and gender. These results suggest that IMP3 could be used as an independent prognostic factor for cases of osteosarcoma with a high potential for metastasis.

Key words: IMP3; Osteosarcoma; IGF-II; L523S; KOC

Address correspondence to Yong-Koo Park, M.D., Department of Pathology, KyungHee University College of Medicine, 61, Heoigi-dong, Dongdaemun-gu, Seoul 130-702 Korea. Tel: +82-2-958-8742; Fax: +82-2-957-0489; E-mail: ykpark@khmc.or.kr




Oncology Research, Vol. 17, pp. 273-282
0965-0407/08 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2008 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Deletion at Dickkopf (Dkk)-3 Locus (11p15.2) Is Related With Lower Lymph Node Metastasis and Better Prognosis in Head and Neck Squamous Cell Carcinomas

Naoki Katase,1 Mehmet Gunduz,1,2 Levent Beder,2 Esra Gunduz,1,5 Mathieu Lefeuvre,1 Omer Faruk Hatipoglu,3 Silvia Susana Borkosky,1 Ryo Tamamura,1 Susumu Tominaga,4 Noboru Yamanaka,2 Kenji Shimizu,5 Noriyuki Nagai,1 and Hitoshi Nagatsuka1

1Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8525, Japan
2Department of Otolaryngology-Head and Neck Surgery, Wakayama Medical University, Wakayama, 641-8509, Japan
3Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8525, Japan
4Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8525, Japan
5Department of Molecular Genetics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8525, Japan

Head and neck squamous cell carcinoma (HNSCC) is a frequently occurring cancer, and despite improvement of its treatment methods, including chemotherapy, radiotherapy, and surgery, the improvement of survival remains poor. Recent advances in molecular biology of human cancer indicated various molecular abnormalities in HNSCC, including activation of oncogenes and inactivation of tumor suppressor genes (TSGs). Dickkopf (Dkk)-3 gene is known as a negative regulator of Wnt signaling and is suggested to function as TSG in several kinds of malignancies. We hypothesized that Dkk-3 might play an important role in HNSCC, too. Thus, in the current study, we analyzed allelic alteration of Dkk-3 locus (chromosome 11p15.2) by means of loss of heterozygosity (LOH) analysis. The study population consisted of 50 patients with HNSCC (mean age of 65 years old). Furthermore, we also examined the correlation between LOH findings of Dkk-3 locus with clinicopathological parameters to investigate its use as a biomarker in HNSCC. A remarkable LOH ratio (57%) was detected in the cases studied, implying that Dkk-3 is likely to be involved in HNSCC carcinogenesis. However, interestingly and in contrast to the expectations, we found that the group with LOH of Dkk-3 locus had less lymph node metastasis, and showed a favorable overall survival compared to the patients with retention of Dkk-3 area in survival analysis. These results indicate that Dkk-3 can play a role in HNSCC carcinogenesis with unknown mechanism. Moreover, allelic loss at Dkk-3 locus may also be used as a novel prognostic biomarker in HNSCC.

Key words: Loss of heterozygosity; PCR; Dkk-3; Tumor suppressor gene; Head and neck squamous cell carcinoma; 11p15.2

Address correspondence to Mehmet Gunduz, M.D., Ph.D., Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Okayama 700-8525, Japan. Tel: +81-86-235-6652; Fax: +81-86-235-6654; E-mail: mgunduz@md.okayama-u.ac.jp