|ognizant Communication Corporation|
AN INTERNATIONAL JOURNAL
INCORPORATING ANTI-CANCER DRUG DESIGN
VOLUME 16, NUMBER 5
Oncology Research, Vol. 16, pp. 211-216
0965-0407/06 $90.00 + .00
Copyright © 2006 Cognizant Comm. Corp.
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In Vivo Treatment of Melanoma (B16F10) With a Homeopathic Agent and With a Cytokine (IFN-a)
Fernando Pascual-Carpe,1 Vicente Vicente-Ortega,1 Matilde Campos-Aranda,2 and Josefa Yañez-Gascón1
1Department of Pathology, Faculty of
Medicine, Murcia University, Espinardo Campus, 30100, Murcia, Spain
2Department of Biostatistics, Faculty of Medicine, Murcia University, Espinardo Campus, 30100, Murcia, Spain
Among the numerous agents tested on melanoma, cytokines have attracted much attention over recent decades, in particular interferon-a (IFN-a). However, in a small number of experimental assays, homeopathic products have also been used. This study aimed to analyze the effects of INF-a and Lymphomyosot, administered individually or in combination, on the growth of B16F10 melanoma transplanted in C57BL/6J mice. Two experiments were performed using 72 young male mice, treated with 1 x 106 B16F10 cells and treated with phosphate-buffered saline (I), INF-a (II), Lymphomyosot (III), and both INF-a and Lymphomyosot (IV). Subsequent morphological and immunohistochemical studies were performed. All treatments produced a reduction in tumor weight with significant differences in those treated with INF-a and Lymphomyosot. INF-a reduced the cell proliferation index and the spread of inflammatory infiltrates and produced an increase in the extent of intratumoral necrosis. An antitumour effect was displayed by both agents, as was the cytotoxicity of INF-a and the immune response-stimulating effect of Lymphomyosot.
Key words: IFN-a; Lymphomyosot; B16F10 melanoma; C57BL/6J; Treatment
Address correspondence to Vicente Vicente-Ortega, M.D., Cátedra de Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Campus de Espinardo, 30100, Murcia, España. Tel: (+34) 968 367150; Fax: (+34) 968 364150; E-mail: email@example.com
Aberrant Expression of HOX Genes in Oral Dysplasia and Squamous Cell Carcinoma Tissues
Nur Mohammad Monsur Hassan,1,2 Jun-ichi Hamada,1 Taichi Murai,1 Akihusa Seino,1 Yoko Takahashi,1* Mitsuhiro Tada,1 Xiuru Zhang,1 Haruhiko Kashiwazaki,2 Yutaka Yamazaki,3 Nobuo Inoue,2 and Tetsuya Moriuchi1
1Division of Cancer-Related Genes,
Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
2Geriatric Stomatology, Department of Oral Health Science, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
3Oral Diagnosis and Oral Medicine, Department of Oral Pathobiological Science, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
Human HOX genes consist of 39 genes and encode transcription factors that function as master developmental regulators. We hypothesized that the misexpression of HOX genes was associated with carcinogenesis and malignant progression. The expression levels of 39 HOX genes in 31 human oral squamous cell carcinoma (SCC), 11 dysplasia, and 10 normal mucosa tissues were quantified by the real-time RT-PCR method. The expression levels of 18 HOX genes in the SCC tissues were significantly higher than those in the normal mucosa tissues. The dysplasia tissues showed higher expression of HOXA2, A3, B3, and D10 than normal mucosa tissues whereas they showed lower expression of HOXA1, B7, B9, and C8 than SCC. The SCC with lymph node metastasis showed high expression of HOXC6 compared to the SCC without it. These results suggest that misexpressions of particular HOX genes are implicated in the development of oral dysplasia and SCC.
Key words: HOX; Oral squamous carcinoma; Dysplasia; Oral mucosa; Metastasis
Address correspondence to Jun-ichi Hamada, Ph.D., Division of Cancer-Related Genes, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan. Tel: +81-11-706-6083; Fax: +81-11-706-7870; E-mail: firstname.lastname@example.org
*Present address: Department of Neuro-Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Role of Intercellular Communications in Breast Cancer Multicellular Tumor Spheroids After Chemotherapy
G. Oktem,1* A. Bilir,2* S. Ayla,2 A. Yavasoglu,1 G. Goksel,3 G. Saydam,4 and A. Uysal1
1Department of Histology and Embryology,
Ege University School of Medicine, TR-35100 Izmir, Turkey
2Department of Histology and Embryology, Istanbul University School of Medicine, TR-34390 Istanbul, Turkey
3Department of Oncology, Celal Bayar University School of Medicine, TR-45030 Manisa, Turkey
4Department of Hematology, Ege University School of Medicine, TR-35100 Izmir, Turkey
Tumor heterogeneity is an important feature that is especially involved in tumor aggressiveness. Multicellular tumor spheroids (MTS) may provide some benefits in different steps for investigation of the aggregation, organization, differentiation, and network formation of tumor cells in 3D space. This model offers a unique opportunity for improvements in the capability of a current strategy to detect the effect of an appropriate anticancer agent. The aim of this study was to investigate the cellular interactions and morphological changes following chemotherapy in a 3D breast cancer spheroid model. Distribution of the gap junction protein "connexin-43" and the tight junction protein "occludin" was investigated by immunohistochemistry. Cellular interactions were examined by using transmission and scanning electron microscopies as well as light microscopy with Giemsa staining after treating cells with doxorubicin, docetaxel, and doxorubicin/docetaxel combination. Statistical analyses showed significant changes and various alterations that were observed in all groups; however, the most prominent effect was detected in the doxorubicin/docetaxel combination group. Distinct composition as a vessel-like structure and a pseudoglandular pattern of control spheroids were detected in drug-administered groups. Immunohistochemical results were consistent with the ultrastructural changes. In conclusion, doxorubicin/docetaxel combination may be more effective than the single drug usage as shown in a 3D model. The MTS model has been found to be an appropriate and reliable method for the detection of the changes in the expression of cellular junction proteins as well as other cellular proteins occurring after chemotherapy. The MTS model can be used to validate the effects of various combinations or new chemotherapeutic agents as well as documentation of possible mechanisms of new drugs.
Key words: Occludin; Connexin-43; Breast cancer spheroid; Doxorubicin; Docetaxel
Address correspondence to Dr. Gulperi Oktem, Department of Histology and Embryology, Ege University School of Medicine, TR-35100 Izmir, Turkey. Tel: +90-232-3904091-36; E-mail: email@example.com or firstname.lastname@example.org
*These authors contributed equally to this work.
Restored Expression of the MYO18B Gene Suppresses Orthotopic Growth and the Production of Bloody Pleural Effusion by Human Malignant Pleural Mesothelioma Cells in SCID Mice
Nobutaka Edakuni,1,4 Kenji Ikuta,1 Seiji Yano,1 Emiko Nakataki,1 Hiroaki Muguruma,1 Hisanori Uehara,2 Masachika Tani,3 Jun Yokota,3 Hisamichi Aizawa,4 and Saburo Sone1
1Department of Internal Medicine and
Molecular Therapeutics, University of Tokushima Graduate School, Tokushima
2Department of Molecular and Environmental Pathology, University of Tokushima Graduate School, Tokushima 770-8503, Japan
3Biology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
4First Department of Internal Medicine, Kurume University, Kurume 830-0011, Japan
Malignant pleural mesothelioma (MPM) is closely related to exposure to asbestos, and a rapid increase in the number of MPM patients is therefore estimated to occur from 2010 to 2040 in Japan. Because MPM is refractory to conventional chemotherapy and radiotherapy, the prognosis of MPM patients is extremely poor. MYO18B, a novel member of the myosin family, is a tumor suppressor gene isolated from a homozygously deleted region at 22q12.1 in a lung cancer cell line. The inactivation of the MYO18B gene plays an important role in several malignant diseases. However, the role of MYO18B in the progression of MPM is still unknown. Six different human MPM cell lines were used in this study. Western blot revealed that none of the cell lines expressed a detectable level of MYO18B protein. One of the MPM cell lines, EHMES-10, was transfected with the MYO18B gene. We found that a restored expression of the MYO18B protein in EHMES-10 cells resulted in the inhibition of their anchorage-independent growth and motility in vitro. In addition, it also inhibited their ectopic (subcutaneous space) and orthotopic (thoracic cavity) growth in SCID mice, in association with an increased degree of cell apoptosis. Furthermore, it also suppressed the production of bloody pleural effusion after orthotopic injection. These findings suggest that the restored expression of MYO18B may be a useful therapeutic strategy for the treatment of locally advanced MPM in humans.
Key words: MYO18B; Orthotopic implantation; Malignant mesothelioma; Pleural effusion; Vascular endothelial growth factor (VEGF)
Address correspondence to Dr. Seiji Yano, Department of Internal Medicine and Molecular Therapeutics, University of Tokushima Graduate School, Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. Tel: 81-88-633-7127; Fax: 81-88-633-2134; E-mail: email@example.com
In Vitro Study of Low Molecular Weight Heparin Effect on Cell Growth and Cell Invasion in Primary Cell Cultures of High-Grade Gliomas
Marco Balzarotti, Federica Fontana, Carlo Marras, Amerigo Boiardi, Danilo Croci, Emilio Ciusani, and Andrea Salmaggi
Laboratory of Clinical Investigation, Department of Neurology, Department of Neurosurgery, National Neurological Institute "C. Besta," Via Celoria 11, 20133 Milan, Italy
Heparins represent the first choice for prevention and treatment of venous thromboembolism. In particular, low molecular weight heparins (LMWHs) provide pharmacokinetic advantages compared to unfractionated heparin (UFH): longer half-life, better bioavailability, and lower binding to plasma proteins. In the last years results of preclinical and clinical studies have suggested that LMWH may be able to inhibit cell growth, cell invasion, and angiogenesis, which are key mechanisms involved in tumor progression, possibly influencing favorable clinical outcome in at least a proportion of cancer patients. In this work we investigated the effect of LMWH (enoxaparin) on cell growth and cell invasion in primary cell cultures obtained from high-grade glioma specimens: 5 anaplastic astrocytoma (AA) and 13 glioblastoma multiforme (GBM). Apoptosis and expression of the thrombin receptor PAR1 were also assessed. A significant decrease in tumor cell growth was observed after treatment with 10 U/ml (-21%; p = 0.001) and 100 U/ml (-26%; p < 0.001); tumor cells from AA (grade III; WHO) were more affected by LMWH treatment compared to cell lines from GBM (grade IV; WHO). The antiproliferative effect was more pronounced in cell cultures displaying higher expression of PAR1. Glioma cell cultures were able to invade a model of basement membrane (MatrigelTM matrix) in standard culture conditions, but migration was not modulated significantly by LMWH treatment at any of the concentrations tested (1, 10, 100 U/ml). In conclusion, our results confirm the antineoplastic effect of LMWH, suggesting a potential direct role on tumor cell growth in high grade gliomas.
Key words: Primary cell cultures; Glioma; Low molecular weight heparin (LMWH); Invasion
Address correspondence to Salmaggi Andrea,
M.D., Department of Neurology, National Neurological Institute "C. Besta,"
Via Celoria, 11, 20133 Milan, Italy. Tel: +39 02 23942247; Fax: +39 02
23942535; E-mail: firstname.lastname@example.org