ognizant Communication Corporation

ONCOLOGY RESEARCH
AN INTERNATIONAL JOURNAL
INCORPORATING ANTI-CANCER DRUG DESIGN

ABSTRACTS
VOLUME 15, NUMBER 4

Oncology Research, Volume 15, pp. 183-187
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Copyright © 2005 Cognizant Comm. Corp.
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Activity of Bacteriophages in Murine Tumor Models Depends on the Route of Phage Administration

Krystyna Dabrowska,1 Adam Opolski,1,3 Joanna Wietrzyk,1 Dmitry Nevozhay,1  Katarzyna Szczaurska,1 Kinga Switala-Jelen,1 Janusz Boratynski,1 and Andrzej Górski,1,2

1Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla 12, 53-114 Wroclaw, Poland
2Institute of Transplantology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland
3Jan Dlugosz Academy, Waszyngtona 4/8, 42-200 Czestochowa, Poland

Previously we investigated the anticancer activity of bacteriophage preparations in various murine tumor models. We demonstrated the antimetastatic activity of purified and nonpurified bacteriophage preparations injected intraperitoneally (IP). However, in solid tumors we observed antitumor activity of purified bacteriophages, but the lysates (raw preparations obtained by culturing phages with bacteria) stimulated tumor growth. In this article we present a comparison of the antitumor activity of bacteriophages after oral (per os, PO) and IP administration of lysates and purified preparations. Our observations indicate that PO application of a bacteriophage preparation is safer and at least as effective as IP. Stimulation of solid tumors by lysates administered orally was not observed, and bacteriophages applied PO were more effective in inhibiting metastases formation. These observations are of great importance in any consideration of possible therapeutic applications of bacteriophages. The role of the route of bacteriophage administration should be considered in the context of the effectiveness and safety of such therapies.

Key words: Bacteriophage T4; Bacteriophage HAP1; Anticancer activity; Administration routes

Address correspondence to Prof. Andrzej Górski, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. R. Weigla 12, 53-114 Wroclaw, Poland. Tel: (+48)71/3371172; Fax: (+48)71/3371382; E-mail: agorski@ikp.pl




Oncology Research, Volume 15, pp. 189-197
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Copyright © 2005 Cognizant Comm. Corp.
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Inhibition of Cellular Adhesion in Human Umbilical Vein Endothelial Cells by NF-kB Inhibitor DHMEQ Under Flow

Osamu Ohno,1 Yutaka Shima,1 Yasuo Ikeda,2 Kumi Sakurai,3 Kiyoaki Watanabe,3 Yohko Kawai,3 and Kazuo Umezawa1

1Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-0061, Japan
2Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
3Department of Laboratory Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

We previously designed and synthesized DHMEQ as an inhibitor of NF-kB. In the present study, we looked into the effect of DHMEQ on the cell adhesion in human umbilical vein endothelial cells (HUVEC) under flow. We used freshly prepared HUVEC and human mononuclear cells throughout the experiment. DHMEQ inhibited TNF-a-, IL-1b-, and LPS-induced NF-b activation in HUVEC. It also inhibited TNF-a-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. DHMEQ also inhibited TNF-a-induced mononuclear cell-HUVEC adhesion. The effect of DHMEQ was more prominent when the cells were under shear stress. DHMEQ inhibited the adhesion between HUVEC and HT-29 colon cancer cells more clearly under the flow condition than under the static condition of the culture medium. These results suggest that DHMEQ, being a unique inhibitor of NF-&kB, may be effective in suppressing atherosclerosis and metastasis by inhibiting the expression of adhesion molecules.

Key words: DHMEQ; NF-k; ICAM-1; VCAM-1; E-selectin; HUVEC

Address correspondence to Kazuo Umezawa, Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-0061, Japan. Tel/Fax: 45-566-1558; E-mail: umezawa@applc.keio.ac.jp




Oncology Research, Volume 15, pp. 199-213
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Copyright © 2005 Cognizant Comm. Corp.
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Formaldehyde-Releasing Prodrugs in Combination With Adriamycin Can Overcome Cellular Drug Resistance

Suzanne M. Cutts,1 Abraham Nudelman,2 Vinochani Pillay,1 Damian M. S. Spencer,1 Inesa Levovich,2,3 Ada Rephaeli,3 and Don R. Phillips,1

1Department of Biochemistry, La Trobe University, Victoria, 3086, Australia
2Chemistry Department, Bar Ilan University, Ramat Gan, 52900, Israel
3Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Beilinson Campus, Petach Tikva, 49100, Israel

The anticancer drug Adriamycin is widely used in cancer chemotherapy and is classified as a topoisomerase II inhibitor. However, in the presence of formaldehyde, Adriamycin also forms high levels of DNA adducts. In this study, a new series of butyric acid and formaldehyde-releasing drugs related to AN9 (pivaloyloxymethyl butyrate) was assessed for their ability to facilitate Adriamycin-DNA adduct formation in Adriamycin-sensitive and -resistant cell lines (HL60 and HL60/MX2; MES-SA and MES-SA/Dx5). Drugs that released two molar equivalents of formaldehyde per mole of prodrug were superior in their ability to enhance adduct formation compared to those that released one molar equivalent. Adduct formation (as assessed by binding of radiolabeled Adriamycin to genomic DNA) was always lower in the resistant cell lines compared to the sensitive cell lines. However, in growth inhibition experiments, prodrug combinations were able to overcome Adriamycin resistance to varying degrees, and the combination of Adriamycin with selected prodrugs that release two moles of formaldehyde totally overcame resistance in HL60/MX2 cells. These HL60-derived cells express altered levels of topoisomerase II and also express a mutant form of the enzyme. Combinations of Adriamycin with selected prodrugs that release one or two moles of formaldehyde partially overcame P-glycoprotein-mediated resistance in MES-SA/Dx5 cells. Formaldehyde-releasing prodrugs (as single agents) overcame both forms of resistance in the two resistant cell lines, demonstrating that they were not substrates of these resistance mechanisms. Collectively, these results suggest that changing the mechanism via which Adriamycin exerts its anticancer effect by dramatically increasing adduct levels (requiring coadministration of formaldehyde-releasing prodrugs) may be a useful means of cancer treatment, as well as for overcoming Adriamycin-induced resistance.

Key words: AN9; Formaldehyde; Adriamycin; Resistance; DNA adducts; Topoisomerase II

Address correspondence to Suzanne M. Cutts, Department of Biochemistry, La Trobe University, Victoria, 3086, Australia. Tel: 61-3-94791517; Email: s.cutts@latrobe.edu.au




Oncology Research, Volume 15, pp. 215-217
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Copyright © 2005 Cognizant Comm. Corp.
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Phosphor/Sulphur Ratio: An Indicator of Malignant Uterus Change

Kálmán Patai,1 László Dévényi,2 Márta Hubay,2 Sándor Csömör,1 and Romána Zelkó4

1Second Department of Obstetrics and Gynaecology, Semmelweis University, 78/a Üllöi Street, H-1082 Budapest, Hungary
2Department of Materials Science and Engineering, Budapest University of Technology and Economics, 3.Goldmann Sq., 1111 Budapest, Hungary
3Department of Forensic Medicine, Semmelweis University, Üllöi Street 93, 1091 Budapest, Hungary
4University Pharmacy, Department of Pharmacy Administration, Semmelweis University, 7-9. Högyes E. Street, 1092 Budapest, Hungary

The purpose of the present study was to establish a correlation between gynaecological diseases (myoma, adenocarcinoma) and phosphor/sulphur (P/S) ratios of different regions of the uterus. Routine histological specimens were reexamined with the intention to select representative regions of the uteruses for element analysis. Conventional hematoxylin-eosin-stained sections were used to identify histological alterations by light microscopy. Scanning electron microscopic (SEM) and energy-dispersive spectroscopic (EDS) investigations were carried out to analyze the morphology and the related element composition of the samples. The results of the nonparametric statistical test (Wilcoxon rank-sum test) indicate that the P/S ratios were significantly higher in adenocarcinoma (0.8891 ± 0.0757) than in myoma (0.4713 ± 0.0306). P/S ratios of different pathologic regions of uteruses seem worth examining in a larger study population. Combination of routine histological examinations with element analysis of specimens may have useful applications in patients who have undergone radiation therapy and may identify a pattern for local recurrence at certain sites.

Key words: Myoma; Adenocarcinoma; Phosphor/sulpur ratio; Energy dispersive X-ray spectroscopy

Address correspondence to Romána Zelkó, Ph.D., 7-9. Högyes E. Street, 1092 Budapest, Hungary. Tel: 36-1-476 3600; Fax: 36-1-217 0927; E-mail: zelrom@hogyes.sote.hu




Oncology Research, Volume 15, pp. 219-231
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Copyright © 2005 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Interaction of Strong DNA-Intercalating Bioreductive Compounds With Topoisomerases I and II

H. S. Rosenzweig, M. V. Papadopoulou, and W. D. Bloomer

Department of Radiation Medicine, Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, IL 60201, USA

Nitro(imidazole/triazole)-linked acridines (NLAs) have been previously developed in our laboratory as DNA-intercalating bioreductive drugs. Such compounds demonstrate toxicity through the formation of bulky monoadducts with cellular macromolecules upon activation and reductive metabolism under hypoxic conditions. However, NLAs also demonstrate considerable aerobic toxicity. Based on the ability of NLAs to bind strongly to DNA through intercalation, we investigated whether their relatively high aerobic cytotoxicity and their relatively low hypoxic selectivity in vitro are associated with topoisomerases I and II (Topo I and II) inhibition. DNA Topo I or II-mediated activity studies have been performed using supercoiled or kinetoplast DNA plasmids. Calf thymus or human Topo I and human Topo II purified enzymes were used. All NLA derivatives strongly inhibited relaxation of supercoiled DNA catalyzed by either Topo I or II, in a concentration-dependent manner, without stabilization of a cleavable complex. Aerobic toxicity correlated well with the inhibition of Topo II-mediated decatenation of kinetoplast DNA, whereas the intracellular concentrations of NLAs were 27-152-fold greater than those needed for 50% inhibition of Topo-II mediated decatenation of DNA. These results suggest that topoisomerase inhibition accounts for NLAs aerobic toxicity.

Key words: Strong DNA intercalators; Bioreductive drugs; Topoisomerases; Interaction

Address correspondence to Maria V. Papadopoulou, Department of Radiation Medicine, Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, IL 60201, USA.  Tel: (847) 570-2262; Fax: (847)-570-1878; E-mail: m-papadopoulou@northwestern.edu




Oncology Research, Volume 15, pp. 233-238
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Copyright © 2005 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Analysis of Inter-(Simple Sequence Repeat) PCR Products From Human Colorectal Cancers

Neng Chen,1 Daniel L. Stoler,2 Smitha S. Dutt,1 Gerald P. Jahreis,3 Miguel A. Rodriguez-Bigas,4 Nicholas J. Petrelli,5 and Garth R. Anderson,1,6

1Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA
2Department of Experimental Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA
3Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
4MD Anderson Cancer Center, Houston, TX, USA
5Helen Graham Cancer Center, Wilmington, DE, USA
6Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA

Genomic instability is a fundamental characteristic of solid tumors, and understanding genomic instability should significantly clarify the process of tumorigenesis. We adapted the sampling technique of inter-(simple sequence repeat) PCR [inter-(SSR) PCR] to measure genetic alterations between simple sequence repeats in colorectal tumors. It becomes important to precisely define both normal and altered inter-(SSR) PCR products. BLAT searches of 131 cloned inter-(SSR) PCR sequences reveal that inter-(SSR) PCR products are located on almost all the chromosomes except chromosome Y, indicating that inter-(SSR) PCR samples a representative diverse range of the genome. We confirm that a change in the pattern of the inter-(SSR) PCR products as seen on gel electrophoresis reflects a true alteration within the genome.

Key words: Inter-(simple sequence repeat) PCR; Genomic instability; Instability events

Address correspondence to Garth R. Anderson, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Tel: (716) 845-4529; Fax: (716) 845-8126; E-mail: garth.anderson@roswellpark.org