ognizant Communication Corporation

ONCOLOGY RESEARCH
AN INTERNATIONAL JOURNAL
INCORPORATING ANTI-CANCER DRUG DESIGN

ABSTRACTS
VOLUME 15, NUMBER 2

Oncology Research, Volume 15, pp. 59-68
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Copyright © 2005 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Antineoplastic Agents 540. The Indian Gynandropsis gynandra (Capparidaceae)

George R. Pettit, Yanhui Meng, Delbert L. Herald, Andrew M. Stevens, Robin K. Pettit, and Dennis L. Doubek

Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, P.O. Box 872404, Tempe, AZ 85287-2404, USA

The CH3OH-CH2Cl2 extract of an Indian collection (entire plant) of Gynandropsis gynandra (L.) Briq. was separated based on bioassay results employing cancer cell lines. Six cancer cell growth inhibitors were isolated and found to be known flavone apegenin (4) and flavonols 1-3, 5, and 6. The structure of flavonol 2 was confirmed by X-ray crystal structure determination. All of the five flavonols (1-3, 5, 6) inhibited the murine P388 lymphocytic leukemia cell line with ED50 values of 3.0, 9.2, 4.0, 0.37, and 3.9 mg/ml, respectively. All six of the flavonoids (1-6) also exhibited activity against a panel of six human cancer cell lines. Penduletin (3) inhibited growth of the Gram-negative pathogen Neisseria gonorrhoeae and apegenin (4) inhibited growth of the Gram-positive opportunist Enterococcus faecalis.

Key words: Gynandropsis gynandra; Capparidaceae; Flavones; Anticancer activities; Antimicrobial activities

Address correspondence to George R. Pettit, P.O. Box 872404, Tempe, AZ 85287-2404. Tel: (480) 965-3351; Fax: (480) 965-8558; E-mail: bpettit@asu.edu.




Oncology Research, Volume 15, pp. 69-79
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Copyright © 2005 Cognizant Comm. Corp.
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Expression of Estrogen Receptor a Gene in Breast Cancer Cells Treated With Transcription Factor Decoy Is Modulated by Bangladeshi Natural Plant Extracts

Elizabeth Lambertini,1 Ilaria Lampronti,1 Letizia Penolazzi,1 Mahmud Tareq Hassan Khan,2* Arjumand Ather,3 Gianluca Giorgi,4 Roberto Gambari,1 and Roberta Piva1

1ER-GenTech, Department of Biochemistry and Molecular Biology, Ferrara University, Ferrara, Italy
2Pharmacology Research Laboratory, Faculty of Pharmaceutical Sciences, University of Science and Technology Chittagong, Chittagong, Bangladesh
3HEJ Research Institute of Chemistry, International Center for Chemical Sciences, University of Karachi, Karachi, Pakistan
4Department of Chemistry and Interdepartmental Centre of Analysis and Structural Determinations, Siena University, Siena, Italy

The aim of the present study was to determine whether the expression of the estrogen receptor a (ERa) gene may be a possible target for compounds present in plant extracts from Aegle marmelos and Emblica officinalis, used in traditional Asian medicine in the treatment of tissue inflammation and cancer. To this aim, we evaluated the potential of the selected plant extracts to affect proliferation and differentiation of ERa-negative MDA-MB-231 breast cancer cells, which become ERa positive after treatment with a decoy molecule against a regulatory region of the human ERa gene. All the plant extracts inhibited cell proliferation and showed no effect on ERa gene expression, but when they were added in combination with the decoy molecule, a modulatory effect was observed, depending on the extract employed. The extracts exhibiting the greatest effects were those obtained from Aegle marmelos. Gas-chromatography/mass-spectrometry (GC/MS) analysis enabled us to identify lupeol, a known triterpenoid, as the major bioactive component of A. marmelos plant extracts. Similar to the Aegle marmelos extracts, lupeol was found to stimulate the decoy effect of RA4 DNA sequence, increasing at a high level ERa gene expression in MDA-MB-231 ERa-negative breast cancer cells, and also inhibited cell proliferation.

Key words: Estrogen receptor a; Decoy; Breast cancer; Aegle marmelos; Emblica officinalis; Medicinal plants; Lupeol

Address correspondence to Roberto Gambari, Dipartimento di Biochimica e Biologia Molecolare, Università degli Studi di Ferrara, Via Fossato di Mortara, 74-44100 Ferrara, Italy. Tel: +39 532 424443; Fax: +39 532 424500; E-mail: gam@unife.it

*Present address: Dipartimento di Biochimica e Biologia Molecolare, Università degli Studi di Ferrara, Via Fossato di Mortara, 74-44100 Ferrara, Italy.




Oncology Research, Volume 15, pp. 81-86
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Pentoxifylline Inhibits Agonist-Induced Vasoconstriction in Vascular Smooth Muscle and Spontaneous Peristalsis in Isolated Ileum

Mark W. Ruddock and David G. Hirst

Radiation Science Research Group, School of Biomedical Sciences, University of Ulster, Newtownabbey, Co. Antrim, BT37 0QB, UK

Pentoxifylline (PTX) is currently used therapeutically as a tumor oxygenator where it been shown to increase tumor blood flow and potentiate ionizing radiation damage. The clinical benefits of PTX have been primarily attributed to its effect on the rheologic properties of whole blood, although there is speculation that the mechanism for PTX-induced increases in tumor oxygenation may be the direct result of reduced vascular resistance. Therefore, to address the issue of vascular (geometric) resistance directly, we examined the ability of PTX and its hydroxy metabolite, lisofylline (LF), to modulate phenylephrine (PE)-induced constriction in isolated rat tail arteries. PTX or LF significantly attenuated phenylphrine (PE)-induced vasoconstriction in a dose-dependent manner. The EC50 for LF and PTX were 336 and 466 mM, respectively. Gastrointestinal disturbances have been reported following oral ingestion of PTX. To clarify the mechanistic basis for this side effect we examined the potential of PTX to modulate spontaneous peristalsis in isolated rat ileum rings. PTX significantly attenuated the spontaneous contractions (oscillations) in a dose-dependent manner. In comparison to isolated rat arterial vessels, the ileum ring preparations were significantly more sensitive (eightfold) to the relaxing effects of PTX (EC50 58 mM). Our data suggest that PTX- or LF-induced changes in tumor blood flow may be the direct result of vascular smooth muscle relaxation. Furthermore, the gastrointestinal disturbances that have been reported in the literature may be a consequence of PTX-induced inhibition of gut peristalsis.

Key words: Pentoxifylline; Lisofylline; Phenylephrine; Artery; Ileum; Smooth muscle

Address correspondence to David G. Hirst, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK. Tel: 02890 972027; Fax: 02890 247794; E-mail: d.hirst@qub.ac.uk




Oncology Research, Volume 15, pp. 87-94
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Synthesis and Antimelanoma Activity of Sterically Congested Tertiary Amide Analogues of N-Acetyl-4-S-cysteaminylphenol

Jillian Ferguson,1 Paul M. Rogers,2* Lloyd R. Kelland,1,2 and David J. Robins1

1Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK
2Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK

Interference with the biosynthetic pathway to melanin may be a useful means for developing new chemotherapeutic drugs to combat malignant melanoma. N-Acetyl-4-S-cysteaminylphenol (1) is an analogue of tyrosine that is involved in the pathway to melanin. It is probably oxidized selectively in melanocytes to an o-quinone that can alkylate thiol groups on important cellular enzymes, resulting in interference with cell growth and proliferation. We previously synthesized a range of more lipophilic analogues of 1 by independently varying the acyl portion and introducing substitution α to the nitrogen. Most of the new compounds displayed greater cytotoxicity than the original lead compound 1. We also made a series of tertiary amides that again showed higher cytotoxicity than 1. In this work three new acetamides and two new cyclohexanecarboxamides containing 4-S-cysteaminylphenol were prepared incorporating both substitution a to the nitrogen and different substituents on the nitrogen of the amide in each compound to increase lipophilicity and to reduce further the possibility of hydrolysis of the amides. Most of the new tertiary amides showed greater cytotoxicity towards five representative melanoma cell lines than the parent secondary amide. The highest cytotoxicity against these five cell lines with IC50 values of 1-15 mM, comparable to cisplatin, was observed for N-{2-[(4-hydroxyphenyl)thio]-1,1-dimethylethyl}-N-methylcyclohexanecarboxamide (8c). The IC50 values of 14.5 and 5.4 mM for this compound against SK-Mel-24 (not containing tyrosinase) and an ovarian cell line, respectively, suggest that interference with the melanin pathway may not be the only mode of action of this new compound. The cyclohexanecarboxamides were better substrates for mushroom tyrosinase (EC 1.14.18.1) than the acetamides.

Key words: Antimelanoma; Cysteaminylphenol;  Tyrosinase; Amide

Address correspondence to Professor David J. Robins, Department of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK. Tel: +44-(0)141-330-4378; Fax: +44-(0)141-330-4888; E-mail: D.Robins@chem.gla.ac.uk

*Current address: Antisoma plc, St Georges Hospital Medical School, Cranmer Terrace, London SW17 0QS, UK.




Oncology Research, Volume 15, pp. 95-105
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Copyright © 2005 Cognizant Comm. Corp.
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Antitumor Polycyclic Acridines. Part 16. Triplex DNA as a Target for DNA-Binding Polycyclic Acridine Derivatives

Sotiris Missailidis,2 Chetna Modi,1 Valentina Trapani,1* Charles A. Laughton,1 and Malcolm F. G. Stevens1

1Cancer Research UK Experimental Cancer Chemotherapy Research Group, Centre for Bio-molecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK
2Chemistry Department, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK

Triple-stranded DNA structures have been implicated in a number of major biological processes, including the transcription and translation of a number of genes, as well as in the interaction of DNA with a number of proteins. Furthermore, antigene therapies under development are based on the recognition and binding of a single oligonucleotide strand to a double-stranded sequence, thus forming a triple helix. Triplex DNA formation is a relatively weak and temporary phenomenon; therefore, molecules that selectively bind to and stabilize triple helices may show a variety of novel biological effects. The biophysical and biological characterization of a series of antitumor polycyclic acridines that bind to triplex DNA is reported. These compounds, whose synthesis has been previously reported, have been tested for their interaction with both purine and pyrimidine type triple helices and compared with the relevant double-stranded DNA. As a pyrimidine triplex model we have used the T1AT sequence, which we have compared with the AT duplex, whereas the purine triplex oligonucleotide d[G3A4G3]1d[G3A4G3].d[C3T4C3] has been compared with the duplex d[G3A4G3].d[C3T4C3]. The compounds demonstrate various degrees of preferential binding to triplex DNA over normal duplex DNA, as measured by UV, fluorescence, circular dichroism, and thermal denaturation. Tri-substituted acridine derivatives demonstrated the highest affinity and ability to stabilize triplex DNA structures. Furthermore, structure/affinity analysis gives insights into the structural features that optimize affinity and selectivity for triplex DNA, and may play a role in their profile of antitumor activity.

Key words: Polycyclic acridine derivatives; DNA binding; Triplex DNA; Spectrophotometric analysis; UV; Fluorescence; Circular dichroism; Thermal denaturation

Address correspondence to Dr. S. Missailidis, Chemistry Department, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK. E-mail: s.missailidis@open.ac.uk

*Present address: Consorzio Mario Negri Sud, Department of Cell Biology and Oncology, via Nazionale 8/A, 66030 Santa Maria Imbaro (CH), Italy.




Oncology Research, Volume 15, pp. 107-111
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Copyright © 2005 Cognizant Comm. Corp.
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Retreatment of Lung Adenocarcinoma Patients With Gefitinib Who Had Experienced Favorable Results From Their Initial Treatment With This Selective Epidermal Growth Factor Receptor Inhibitor: A Report of Three Cases

Emiko Nakataki, Shinsaku Ohtsuka, Mami Inayama, Hideki Tomimoto, Nobutaka Edakuni, Soji Kakiuchi, Naoki Nishikubo, Hiroaki Muguruma, and Saburo Sone

Department of Internal Medicine and Molecular Therapeutics, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Japan

Gefitinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinases, and shows favorable antitumor activity against chemorefractory non-small cell lung cancer (NSCLC). The majority of responders (patients who are sensitive to gefitinib), however, relapse within 1.5 years, indicating an acquired resistance to gefitinib. Here we report three chemotherapy refractory NSCLC patients who were retreated with gefitinib. All three cases were nonsmokers and showed an adenocarcinoma histology. While they had experienced successful control from their initial treatment with gefitinib for more than 12 months, gefitinib therapy was terminated because two cases (cases 1 and 3) relapsed during the therapy and case 2 suffered alveolar hemorrhage. After more than 7 months from the time of discontinuation of the initial gefitinib treatment, they were retreated with gefitinib, as further tumor progression was observed. Of the three cases, cases 1 and 2 were well controlled by retreatment with gefitinib monotherapy for more than 7 months, suggesting sensitivity to retreatment. Case 3 also showed a regression in size of several tumors, while some other lesions progressively enlarged and developed a malignant pleural effusion after 4 months. These observations suggest the possibility that retreatment with gefitinib might be useful when 1) initial treatment shows a favorable clinical response, and 2) there has been a period of time following the termination of the initial gefitinib treatment.

Key words: Retreatment; Acquired resistance; Gefitinib; Lung cancer; Alveolar hemorrhage

Address correspondence to Seiji Yano, Department of Internal Medicine and Molecular Therapeutics, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. Tel: (81)-88-633-7127; E-mail: manae@clin.med.tokushima-u.ac.jp