|ognizant Communication Corporation|
AN INTERNATIONAL JOURNAL
INCORPORATING ANTI-CANCER DRUG DESIGN
VOLUME 16, NUMBER 1
Oncology Research, Vol. 16, pp. 1-14
0965-0407/06 $20.00 + .00
Copyright © 2006 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.
Inhibition of DMXAA-Induced Tumor Necrosis Factor Production in Murine Splenocyte Cultures by NF-kB Inhibitors
Liang-Chuan S. Wang, See-Tarn Woon, Bruce C. Baguley, and Lai-Ming Ching
Auckland Cancer Society Research Center, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
The induction of cytokine synthesis within tumor tissue is a key component of the antivascular action of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in murine tumors. We previously showed that DMXAA alone induced only low amounts of tumor necrosis factor (TNF) in cultured spleen cells, but the addition of suboptimal concentrations of lipopolysaccharide (LPS) provided a costimulatory signal that resulted in 6-10-fold increase in secreted TNF. In this study we investigated the molecular pathway involved, and showed that the addition of NF-kB inhibitors salicylate and parthenolide reduced the levels of TNF secreted into the culture supernatants induced with DMXAA (10 mg/ml) alone or in combination with LPS (10 mg/ml). Results from gene arrays, confirmed with RT-PCR, showed that the TNF gene was not upregulated with DMXAA alone, and was only slightly increased above the level of significance when LPS was added simultaneously. This contrasted with secreted TNF protein levels, which increased 5- and 48-fold, respectively, above that in untreated cultures with DMXAA alone or in combination with LPS. In addition to TNF, protein arrays showed IL-6, IL-10, MIP-1a, MIP-2, and RANTES were also secreted following treatment with 10 mg/ml DMXAA alone, and IL-4, IFN-g, MCP-5, and TIMP-1 were additionally induced using a higher dose of 300 mg/ml DMXAA. The drug is currently showing promise in phase II combination trials, and these studies suggest that DMXAA-induced TNF production in the splenocyte cultures was not due to increased expression of the TNF gene, but through effects on NF-kB-dependent posttranscriptional regulation.
Key words: Antivascular; DMXAA; NF-kB; Parthenolide; Tumor necrosis factor (TNF); IFN-g Splenocytes
Address correspondence to Lai-Ming Ching, Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand. Tel: +64-9-3737-599; Fax: +64-9 3737 502; E-mail: firstname.lastname@example.org
ZD6474, an Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase, Inhibits Growth of Experimental Lung Metastasis and Production of Malignant Pleural Effusions in a Non-Small Cell Lung Cancer Model
Yuka Matsumori,1 Seiji Yano,1 Hisatsugu Goto,1 Emiko Nakataki,1 Stephen R. Wedge,2 Anderson J. Ryan,2 and Saburo Sone1
1Department of Internal Medicine and Molecular Therapeutics,
University of Tokushima School of Medicine, Tokushima, 3-18-15 Kuramoto-cho,
2AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK
ZD6474 is a novel, orally active inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase, with some additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. The purpose of this study was to determine the potential of ZD6474 in the control of established experimental lung metastasis and pleural effusions produced by human non-small cell lung cancer (NSCLC) cells. PC14PE6 (adenocarcinoma) and H226 (squamous cell carcinoma) cells express high levels of EGFR and only PC14PE6 cells overexpress VEGF. Neither ZD6474 nor the EGFR tyrosine kinase inhibitor gefitinib inhibit proliferation of PC14PE6 or H226 cells in vitro. Both PC14PE6 and H226 cells inoculated intravenously into nude mice induced multiple lung nodules after 5-7 weeks. In addition, PC14PE6 cells produced bloody pleural effusions. Daily oral treatment with ZD6474 did not reduce the number of lung nodules produced by PC14PE6 or H226 cells, but did reduce the lung weight and the size of lung nodules. ZD6474 also inhibited the production of pleural effusions by PC14PE6 cells. Histological analyses of lung lesions revealed that ZD6474 treatment inhibited activation of VEGFR-2 and reduced tumor vascularization and tumor cell proliferation. Therapeutic effects of ZD6474 were considered likely to be due to inhibition of VEGFR-2 tyrosine kinase because gefitinib was inactive in this model. These results indicate that ZD6474, an inhibitor of VEGFR-2, may be useful in controlling the growth of established lung metastasis and pleural effusions by NSCLC.
Key words: Angiogenesis; Lung metastasis; VEGFR; EGFR; Gefitinib
Address correspondence to Saburo Sone, Department of Internal Medicine and Molecular Therapeutics, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. Tel: 81-88-633-7127; Fax: 81-88-633-2134; E-mail: email@example.com
FGF-1 as a Possible Carrier for Targeted Drug Delivery
Ewa Marcinkowska,1 Katarzyna Superat,1 and Antoni Wiedlocha2
1Institute of Biochemistry and Molecular Biology, University
of Wroclaw, Tamka 2, Wroclaw, Poland
2Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway
Delivery of anticancer chemotherapeuticals to tumor cells raises many problems due to pronounced systemic side effects. Targeted delivery using specific monoclonal antibodies has been postulated; however, monoclonal antibodies very often produce immune response in the human body. Chimeric and humanized antibodies have some advantages over monoclonals, but still some side effects can be observed. Because some tumor cells (e.g., breast cancer cells) overexpress fibroblast growth factor receptors, it is possible to use these receptors for drug targeting. We think that growth factors of human origin can be used for drug delivery to tumor cells. Fibroblast growth factor-1 (FGF-1) is especially suitable as drug carrier because it can cross the barrier of the cell membrane and reach the cytosol and, further, it is translocated to the cell nucleus. One possible approach for anticancer therapy is to use biotinylated growth factors linked to avidin/streptavidin-coated liposomes. Another possibility is to link drug molecules or radioisotopes directly to growth factors. Thus, we wanted to determine if FGF-1 retains its biological activity after chemical modification, and if it is able to bind its receptors and if it can be internalized by the cells. For this purpose we have biotinylated recombinant human FGF-1 and we have verified that it retains its biological activities in NIH/3T3 and MDA-MB-453 cells and it is able to enter the target cells.
Key words: FGF-1; FGFR; Drug delivery; Carrier; Anticancer therapy
Address correspondence to Ewa Marcinkowska, Institute of Biochemistry and Molecular Biology, University of Wroclaw, Tamka 2, Wroclaw, Poland. Tel: +48 71 375 29 29; Fax: +48 71 375 26 08; E-mail: firstname.lastname@example.org
The Role of Cell-Free DNA Size Distribution in the Management of Prostate Cancer
Jane L. Boddy,1 Shira Gal,2 Peter R. Malone,1 Nadeem Shaida,1 James S. Wainscoat,2* and Adrian L. Harris3*
1The Harold Hopkins Department of Urology, Royal Berkshire
Hospital, Reading, RG30 1AG, UK
2Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK
3Cancer Research UK, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK
Cell-free DNA has been shown to have diagnostic potential in a number of malignant diseases. Recently, the integrity or size distribution of these fragments has also been identified as having possible diagnostic value. The current study explores the role of this novel parameter in the clinical diagnosis of prostate cancer. Plasma samples, collected prospectively from men undergoing investigation for prostate cancer, were used to obtain a cell-free DNA sample. Real-time PCR was used to quantify the level of cell-free DNA (ng/ml) and its size distribution (delta Ct) in each case. Sixty-one samples were collected from patients with prostate cancer and 62 from those with benign histology. Analysis failed to reveal a statistically significant relationship between either the level of cell-free DNA (p = 0.82) or its size distribution (p = 0.91) and the presence of cancer. These results demonstrate that cell-free DNA is unlikely to be of diagnostic value in the clinical management of this disease.
Key words: Cell-free DNA; Size distribution; Prostate cancer
Address correspondence to Professor Adrian L. Harris, Cancer Research UK, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK. Tel: 01865 222457; Fax: 01865 222431; E-mail: email@example.com
*Contributed equally to the project.
Are CYP17 Genotypes a Biomarker for Ovarian Cancer in Patients With Cancer History in Their Family?
Hulya Yazici,1 Hulya Tigli,1 Zuleyha Kadehci,2 Seden Kucucuk,2 Pinar Saip,3 Halim Issever,4 Hilmi Ozcelik,5 and Nejat Dalay1
1Department of Basic Oncology, Oncology Institute, Istanbul
University, Istanbul, Turkey
2Department of Radiation Oncology, Oncology Institute, Istanbul University, Istanbul, Turkey
3Department of Medical Oncology, Oncology Institute, Istanbul University, Istanbul, Turkey
4Department of Biostatistics and Demography, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
5Centre for Cancer Genetics, Samuel Lunenfeld Research Institute and Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada
BRCA1 and BRCA2 genes are responsible for 5-10% of breast and ovarian cancer cases. However, the vast majority of ovarian and breast cancer cases do not display the hereditary form of the disease. Estrogen-metabolizing genes may also contribute to the predisposition of breast or ovarian cancer. Polymorphic variants of the estrogen-metabolizing gene, CYP17, have been associated with the risk of hormone-related cancers. In this study we investigated the CYP17 polymorphisms in ovarian cancer patients harboring mutations in the BRCA1 and BRCA2 genes, patients displaying familial characteristics but not carrying mutations and patients with sporadic ovarian cancer. Association between the allele frequencies, the CYP17 genotype and tumor characteristics or clinical parameters was evaluated. Our data suggest evidence for an association between ovarian cancer risk and the CYP17 genotype in the subgroup of patients with familial disease in whom no mutations in the BRCA genes are found. Although there were no statistically significant differences in the genotype distribution between the control group and the subgroup of patients with BRCA mutations, the frequency of the CYP17 A2 allele was significantly higher in the subgroup of patients without BRCA mutations. We found a four- to eightfold higher risk in ovarian cancer patients with family history but without BRCA mutations. Our data indicate that the CYP17 A2 allele polymorphism may confer an increased risk and can provide a biomarker for ovarian cancer patients in whom no mutations in the BRCA genes are observed.
Key words: Ovarian cancer; CYP17 polymorphism; BRCA gene mutations
Address correspondence to Nejat Dalay, Prof. Dr., Oncology Institute, Istanbul University, 34390 Capa, Istanbul, Turkey. Tel: 90 212 414 2434 (4 lines) Ext. 34184; Fax: 90 212 534 8078; E-mail: firstname.lastname@example.org
Serum Levels of IGF-I and IGFBP-3 in Patients With Lung Cancer During Chemotherapy
Tomasz Izycki, Elzbieta Chyczewska, Wojciech Naumnik, and Maria Ossolinska
Department of Lung Diseases and Tuberculosis, Medical University of Bialystok, Poland
The aim of this study was to assess serum levels of insulin-like growth factors (IGF-I and IGFBP-3) in patients with lung cancer during chemotherapy. The study included 38 patients (33 males and 5 females; mean age 59.8) diagnosed histologically with lung cancer. Twenty-five patients (65%) had non-small cell lung cancer (NSCLC) and 13 patients (35%) had small cell lung cancer (SCLC). Squamous cell carcinoma was established in 30% (11 patients) of all patients with NSCLC, adenocarcinoma in 13% (5 patients), and non-small cell cancer in 36% (9 patients). The control group consisted of 10 healthy volunteers. Peripheral blood samples were taken before and after four cycles of chemotherapy. IGF-I and IGFBP-3 levels were assessed by ELISA method. Serum levels of IGF-I measured before chemotherapy were significantly higher in both NSCLC and SCLC groups in comparison with controls. No significant differences were observed in serum IGF-I levels before and after four cycles of chemotherapy. The levels were still high after chemotherapy in patients with NSCLC and SCLC. Serum levels of IGFBP-3 were markedly lower in patients with NSCLC both before and after treatment compared to controls. No significant differences were found in patients with NSCLC before and after cytoreduction treatment. Prior to treatment, serum IGFBP-3 levels were significantly lower in patients with SCLC in comparison with controls. After cytoreduction treatment, the levels were decreased when compared to controls but without statistical significance. In conclusion, both before and after chemotherapy serum levels of IGF-I were significantly higher, whereas IGFBP-3 levels were lower in patients with NSCLC and SCLC compared to controls. Chemotherapy had no influence on the serum levels of IGF-I and IGFBP-3. Neither a histological type of NSCLC nor clinical staging had any effect on the serum levels of IGF-I and IGFBP-3.
Key words: Lung cancer; IGF-I; IGFBP-3; Chemotherapy
Address correspondence to Tomasz Izycki, M.D., Ph.D., ul.Sybirakow 7/84 15-204 Bialystok, Poland. Tel (mobile): +48 606 354 777; E-mail: email@example.com