|ognizant Communication Corporation|
AN INTERNATIONAL JOURNAL
INCORPORATING ANTI-CANCER DRUG DESIGN
VOLUME 16, NUMBER 10
Oncology Research, Vol. 16, pp. 453-463
0965-0407/07 $90.00 + .00
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Valproic Acid Increases the In Vitro Effects of Nitrosureas on Human Glioma Cell Lines
Emilio Ciusani,1 Marco Balzarotti,1 Chiara Calatozzolo,2 Ugo de Grazia,1 Amerigo Boiardi,2 Andrea Salmaggi,2 and Danilo Croci1
1Department of Clinical Investigation,
Neurological National Institute "Carlo Besta," Milan, Italy
2Department of Neurology, Neurological National Institute "Carlo Besta," Milan, Italy
Valproic acid (VPA) has been recently investigated for its anticancer properties in different tumors, including malignant gliomas. The aim of the present work was to evaluate the effects of VPA, alone or in combination with other chemotherapeutic drugs, on in vitro growth of human glioma cell lines. A172, U373, U138, U87, and SW1783 were treated with VPA alone or in combination with mitoxantrone, etoposide, or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The effects of treatments on cell growth were assessed with crystal violet staining and analyzed using the combination index (CI). The percentage of apoptotic cells and the DNA content for cell cycle phases detection were also investigated by flow cytometry. Despite a certain variability, glioma cell lines were rather resistant to the drugs tested. Addition of VPA decreased the IC50 of the chemotherapeutic agents in all cell lines tested. This effect was more evident with BCNU. The synergic effect of the association of VPA and BCNU was related to an increased block of cell cycle with accumulation in S-G2/M phases of cell cycle rather than an increased programmed cell death. In our experimental model, VPA showed anticancer properties per se on human glioma cell lines and our data support the hypothesis that, if used in association with conventional chemotherapy, it might improve the effects of single chemotherapeutic agents.
Key words: Glioma; Valproic acid; BCNU; Histone deacetylase; Cell cycle; Apoptosis
Address correspondence to Dr. Emilio Ciusani, Neurological National Institute "Carlo Besta," Via Celoria 11, 20133 Milan, Italy. Tel: +39 02 23942247; Fax: +39 02 23942535; E-mail: email@example.com
Expression of the Human MTA1 Gene in Breast Cell Lines and in Breast Cancer Tissues
Dan Tong,1 Georg Heinze,2 Michael Schremmer,2 Eva Schuster,1 Klaus Czerwenka,3 Sepp Leodolter,1,4 and Robert Zeillinger1,4
1Division of Gynaecology, Department
of Obstetrics and Gynaecology, Medical University of Vienna, Vienna, Austria
2Section of Clinical Biometrics, Core Unit of Medical Statistics and Informatics, Medical University of Vienna, Vienna, Austria
3Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
4Ludwig-Boltzmann Institute of Gynaecology and Gynaecological Oncology, Vienna, Austria
MTA1 was reported as a metastasis-associated gene. Tumors with higher MTA1 mRNA level were shown to have higher rates of invasion and lymph node metastasis and tended to have higher rates of vascular involvement. The majority of invasive breast carcinomas were demonstrated to overexpress MTA1 compared to surrounding normal tissues. MTA1 was also found to be more expressed in metastatic breast cancer cell lines than in nonmetastatic ones. Originally we were interested in analyzing factors differently expressed in invasive and noninvasive breast cancer cell lines. Therefore we analyzed expression of MTA1 together with several other genes in correlation with cell invasiveness in 25 breast epithelial cell lines. Furthermore, we analyzed it in 90 primary breast tumor tissues and examined its correlation with expression of estrogen receptor, progesterone receptor, plasminogen activator inhibitor-1, E-cadherin, histopathological data, disease-free survival, and overall survival. Our results demonstrated that MTA1 expression was significantly higher in noninvasive cell lines than in invasive ones. It also correlated positively with expression of noninvasive factors and reverse correlated with invasive factors in both cell lines and tumor tissues.
Key words: MTA1; Gene expression; Breast cancer; Invasion; Metastasis
Address correspondence to Dan Tong, Division of Gynaecology, Department of Obstetrics and Gynaecology, Medical University of Vienna, EBO 05, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel: +43-1-40400-7827; Fax: +43-1-40400-7832; E-mail: firstname.lastname@example.org
Evaluation of Adenoviral Oncolytic Effect on Glioma Spheroids by 18F-DG Positron-Emission Tomography
S. Idema,1 A. A. Geldof,2 C. M. F. Dirven,1* M. van der Jagt,1 W. R. Gerritsen,3 W. P. Vandertop,1 and M. L. M. Lamfers1,3*
1Department of Neurosurgery, VU University
Medical Center, Amsterdam, 1007 MB, The Netherlands
2Department of Nuclear Medicine & PET Research, VU University Medical Center, Amsterdam, 1007 MB, The Netherlands
3Department of Medical Oncology, Division of Gene Therapy, VU University Medical Center, Amsterdam, 1007 MB, The Netherlands
Multicellular tumor spheroids are used as a model to assess the efficacy of replicating oncolytic adenoviruses. As most assays used to assess cellular viability are unsuitable for oncolytic viruses because of ongoing viral replication, we have used positron emission tomography (PET) to sequentially determine the incorporation of 18F-labeled deoxyglucose (18F-DG) as a measure of viability and compared the results to more commonly used assays for measuring the effect of oncolytic therapy. Glioma monolayer cultures and spheroids were infected with wild-type replicating adenovirus and viability was measured by 18F-DG incorporation, WST-1 assay, crystal violet assay, and spheroid volume 2 to 10 days following infection. Results show that volume measurements in adenovirus-infected spheroids are confounded by the cytopathic effect occurring in infected cells. 18F-DG PET provides a useful method to assess small differences in cell number and viability following oncolytic viral therapy in glioma monolayer cultures and spheroids without the need for disintegration of these cultures. Moreover, using 18F-DG PET, repeated sequential measurements of spheroid viability can be made, decreasing the required number of spheroids per experiment. This is a valuable feature when using spheroids derived from limited amounts of patient material.
Key words: Multicellular spheroid; Fluoro-deoxyglucose; Glioma; Oncolytic virus; Positron emission tomography
Address correspondence to S. Idema, M.D., Department of Neurosurgery, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. Tel: 31(0)20 4441778; Fax: 31(0)20 4448168; E-mail: email@example.com
*Current address: Department of Neurosurgery, Erasmus Medical Center, Rotterdam, PO box 2040, 3000 CA, The Netherlands.
Cisplatin-Induced Senescence and Growth Inhibition in Human Non-Small Cell Lung Cancer Cells With Ectopic Transfer of p16INK4a
Kang Fang,1 Chien-Chih Chiu,1,2 Chin-Hsiao Li,1 Yung-ta Chang,1 and Hwei-tein Hwang1
1Department of Life Science, National
Taiwan Normal University, Taipei, Taiwan, Republic of China
2Department of Biotechnology, Kaoshiung Medical University, Kaoshiung, Taiwan, Republic of China
DNA damage is lethal and capable of inducing cellular aging or apoptosis. In this work, the highly tumorigenic and cisplatin-resistant human non-small cell lung cancer (NSCLC) cells were transfected with construct encoding the complete sequence of p16INK4a (p16). The stable clones with elevated p16 exhibited enhanced sensitivities to low concentration cisplatin treatment. Further study indicated that cisplatin arrested cells at G2/M phase and the effectiveness is proportional to the level of p16 expressed. The growth of the xenograft tumors established by p16 transfectants in nude mice was also suppres ed by cisplatin by inducing senescence-like phenotype. The data altogether indicated that, in cisplatin-resistant tumor cells with basal endogenous p16, the growth suppression by drugs can be greatly improved by ectopic gene transfer.
Key words: Human non-small cell lung cancer cells; p16INK4a; Cisplatin
Address correspondence to Kang Fang, Department of Life Science, National Taiwan Normal University, Taipei, Taiwan, Republic of China. E-mail: firstname.lastname@example.org
Short-Term Gefitinib Treatment Brought About a Long-Term Regression of Bronchioloalveolar Carcinoma Without EGFR Gene Alterations: A Case Report
Takashi Kijima,1 Mayumi Suzuki,1 Kayo Ueda,2 Seigo Minami,1 Yoshito Takeda,1 Sho Goya,1 Hiroto Matsuoka,1 Toru Kumagai,1 Mitsuhiro Yoshida,1 Tadashi Osaki,1 Isao Tachibana,1 Soichiro Yokota,3 and Ichiro Kawase1
1Department of Respiratory Medicine,
Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine,
Osaka 565-0871, Japan
2Department of Pathology, National Hospital Organization Toneyama National Hospital, Osaka 560-8552, Japan
3Respiratory Medicine, National Hospital Organization Toneyama National Hospital, Osaka 560-8552, Japan
The tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) gefitinib has beneficial effect in some patients with refractory advanced non-small cell lung cancer (NSCLC). However, the majority of responders eventually develop acquired resistance during the course of prolonged continuous treatment. Here we present a case of 76-year-old Japanese female, who had never smoked, with poor performance status from bronchioloalveolar carcinoma (BAC), in whom a brief initial 5-week administration of gefitinib resulted in dramatic antitumor effects that lasted approximately 8.5 months after cessation of the treatment. Furthermore, the relapsed tumor later regressed again by re-treatment with the TKI. She survived 26 months since she first took gefitinib. Unexpectedly, neither sensitizing mutations for EGFR-TKIs nor increased copy numbers were detected in EGFR gene of her BAC cells. This case suggests that, in some patients with NSCLC, even short-term administration of gefitinib may bring about clinical benefits and disease response comparable to the standard long-term daily dosing schedule. Short-term use of gefitinib will also be able to minimize the expensive medical cost of the TKI. The potential role of short-term or pulse-dose therapy with EGFR-TKIs should be clarified in further prospective studies. Moreover, it is urgent to develop better strategies by which we could distinguish responders to the TKIs from nonresponders among patients who do not have any EGFR gene alterations.
Key words: Bronchioloalveolar carcinoma; Epidermal growth factor receptor; Gefitinib; Re-treatment; Acquired resistance; Short-term treatment
Address correspondence to Takashi Kijima, Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. Tel: +81 6 6879 3833; Fax: +81 6 6879 3839; E-mail: email@example.com