ognizant Communication Corporation

ONCOLOGY RESEARCH
Featuring PRECLINICAL AND CLINICAL CANCER THERAPEUTICS

ABSTRACTS
VOLUME 18, NUMBER 7

Oncology Research, Vol. 18, pp. 293-304
0965-0407/09 $90.00 + .00
DOI: 10.3727/096504010X12629634366142
E-ISSN 1555-3906
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Treadmill Exercise-Dependent Tumor Growth Retardation in T-Cell Lymphoma-Bearing Host Displays Gender Dimorphism

Vinod Kumar Verma, Vivek Singh, Mahendra Pal Singh, and Sukh Mahendra Singh

School of Biotechnology, Banaras Hindu University, Varanasi-221 005, India

A number of previous investigations have reported that physical exercise renders immunopotentiating and antitumor therapeutic benefits to the tumor-bearing host. As these effects of physical exercise are mainly mediated through the modulation of hormonal and cytokine repertoire, it remains unclear if male and female tumor-bearing hosts show a gender-dependent differential response to the therapeutic action of physical exercise in tumor growth retardation. In the present investigation tumor growth retardation, following physical exercise was investigated in a gender-specific manner in a murine tumor model of a T-cell lymphoma designated as Dalton's lymphoma (DL). The results of the present investigation show that physical exercise of a tumor-bearing host on a treadmill results in a better retardation of tumor progression along with prolongation of survival time in male compared to female tumor-bearing host. Such gender dimorphism of the therapeutic benefits of physical exercise in tumor-bearing host was found to be associated with a gender-dependent variation in cell survival and induction of apoptosis in tumor cells. Moreover, expression of cell growth regulatory proteins-selectin, Hsp70, p53, CAD, SOCS, and IL-2 receptor-was found to vary in a gender-specific manner following physical exercise. The investigation also indicates the role of cytokines and macrophages in manifestation of gender dimorphism in the response of tumor-bearing mice to physical exercise. Thus, the observations of the present investigation suggest for the first time that the beneficial effects of physical exercise in a tumor-bearing host may be variable depending on the gender of the host.

Key words: T-cell lymphoma; Tumor progression; Physical exercise; Gender dimorphism

Address correspondence to Prof. Sukh Mahendra Singh, School of Biotechnology, Banaras Hindu University, Varanasi-221 005, U.P. India. Tel: +91-542-2368331; Fax: +91-542-2368693; E-mail: sukhmahendrasingh@yahoo.com or sukhmahendrasingh@gmail.com




Oncology Research, Vol. 18, pp. 305-314
0965-0407/09 $90.00 + .00
DOI: 10.3727/096504010X12626118079868
E-ISSN 1555-3906
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Arsenic Trioxide and Promyelocytic Leukemia Protein-Adenovirus Synergistically Inhibit In Vitro and In Vivo Growth of a Hepatoma Cell Line

Liming Cui,1* Shide Zhang,1* Weizhe Zhang,2 Zhanliang Hu,3 Zhigang Cao,1 and Tao Li4

1Department of Interventional Radiology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
2Department of Parasitology, Harbin Medical University, Harbin, 150086, China
3Department of Liver and Gall Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
4Center of Animal Experiments, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China

The present study investigated the in vitro and in vivo growth-inhibitory effects of combination therapy with arsenic trioxide (As2O3) and an adenovirus expressing promyelocytic leukemia protein (Ad-PML). Growth of HepG2 cells in culture was not inhibited by As2O3 at concentrations below 5 mmol/L (p > 0.05). However, growth was inhibited by Ad-PML alone and synergistic growth inhibition was observed following combined treatments (p < 0.05). Flow cytometry analyses demonstrated an increase in apoptosis following combined treatment with As2O3 and Ad-PML for 24 h, which was correlated with increased p53 and decreased Bcl-2 expression. To examine treatment effects on in vivo cell growth, control HepG2 cells and cells treated with As2O3, Ad-PML, or both therapies were subcutaneously injected in nude mice. After 6 weeks, tumor volumes were 0.097 ± 0.031 and 0.083 ± 0.005 cm3 in the control and As2O3 alone groups, respectively (p > 0.05), but were undetectable in the Ad-PML alone or Ad-PML plus As2O3 groups. Finally, established HepG2 tumors in nude mice were injected with PBS, Ad-PML, As2O3, or Ad-PML plus As2O3, the tumor volumes were measured by ultrasound, and the therapeutic effects were compared. As2O3 alone had no effect at concentrations below 5 mmol/L (p > 0.05), while Ad-PML alone at a multiplicity of infection of 20 or As2O3 plus Ad-PML significantly decreased tumor volumes (p < 0.05). Thus, the combination of As2O3 and Ad-PML has synergistic inhibitory effects on hepatocellular carcinoma (HCC), possibly resulting from regulation of apoptotic gene expression enhanced HCC apoptosis.

Key words: Arsenic trioxide (As2O3); Adenovirus expressing promyelocytic leukemia protein (Ad-PML); Synergistic inhibition; Hepatic cell carcinoma

Address correspondence to Shide Zhang, Department of Interventional Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, P.R. China. Tel: 86-13766809858; E-mail: zsd6588@sina.com

*These authors contributed equally to the work.




Oncology Research, Vol. 18, pp. 315-322
0965-0407/09 $90.00 + .00
DOI: 10.3727/096504010X12626118079949
E-ISSN 1555-3906
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

The Attenuation of MG132, a Proteasome Inhibitor, Induced A549 Lung Cancer Cell Death by p38 Inhibitor in ROS-Independent Manner

Yong Hwan Han, Hwa Jin Moon, Bo Ra You, and Woo Hyun Park

Department of Physiology, Medical School, Institute for Medical Sciences, Chonbuk National University, JeonJu, Republic of Korea

MG132, as a proteasome inhibitor, can induce apoptotic cell death through formation of reactive oxygen species (ROS). In this study, we investigated the effects of MAPK (MEK, JNK, and p38) inhibitors on MG132-treated A549 lung cancer cells in relation to cell growth, cell death, ROS, and glutathione (GSH) levels. Treatment with 10 mM MG132 inhibited the growth of A549 cells at 24 h. MG132 also induced apoptosis, which was accompanied by the loss of mitochondrial membrane potential (MMP; DYm). ROS were not increased in MG132-treated A549 cells. MG132 increased GSH-depleted cell numbers and decreased GSH levels. MEK and JNK inhibitors did not strongly affect cell growth, cell death, ROS, and GSH levels in MG132-treated A549 cells. In contrast, p38 inhibitor reduced cell growth inhibition, apoptosis, and MMP (DYm) loss by MG132. However, p38 inhibitor did not change ROS level and GSH content. In conclusion, MG132 inhibited the growth of A549 cells via apoptosis without formation of ROS. Treatment with p38 inhibitor rescued some cells from MG132-induced apotposis, which was not affected by ROS and GSH level changes.

Key words: MG132; Apoptosis; A549; Mitogen-activated protein kinase (MAPK); Reactive oxygen species (ROS); Glutathione (GSH)

Address correspondence to Woo Hyun Park, Ph.D., Assistant Professor, Department of Physiology, Medical School, Chonbuk National University, JeonJu, 561-180, Republic of Korea. Tel: +82-63-270-3079; Fax: +82-63-274-9892; E-mail: parkwh71@chonbuk.ac.kr




Oncology Research, Vol. 18, pp. 323-328
0965-0407/09 $90.00 + .00
DOI: 10.3727/096504010X12626118079985
E-ISSN 1555-3906
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

The Relationship Between Helicobacter pylori Infection and Gastric Adenocarcinoma in Northern Iran

Zivar Salehi, Hamidreza Mollasalehi, Mohammad Halimi Jelodar, Masoud Kazemi, and Rasoul Zahmatkesh

Department of Biology, Faculty of sciences, University of Guilan, Rasht, Iran

Colonization of the human stomach with Helicobacter pylori induces chronic gastritis and is associated with the development of gastric and duodenal ulcers, gastric carcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Infection with an H. pylori strain containing the cytotoxin-associated (cagA) gene (a marker for a pathogenicity island) may increase the risk of atrophic gastritis and gastric cancer. The exact role of H. pylori in gastric carcinogenesis is still being investigated. Hence, we assessed whether H. pylori infection is associated with the development of gastric adenocarcinoma in northern Iran. Gastric biopsy specimens from 168 patients suffering from gastric adenocarcinoma, gastric ulcer, and non-ulcer dyspepsia were analyzed by means of the polymerase chain reaction. H. pylori was detected in the gastric mucosa of 34 (75.5%) gastric adenocarcinoma, 56 (88.8%) gastric ulcer, and 36(60%) non-ulcer dyspepsia. In patients with gastric adenocarcinoma, the cagA was less commonly found than those in noncancer patients (4/34 vs. 58/92, p < 0.05). Our work suggests that although H. pylori infection is significantly associated with gastric adenocarcinoma in northern Iran, the cagA is not the dominant virulence in development of gastric adenocarcinoma.

Key words: Helicobacter pylori; Gastric adenocarcinoma; cagA

Address correspondence to Dr. Zivar Salehi, Department of Biology, Faculty of sciences, University of Guilan, Rasht, Iran. Tel: 0098-9113337003; Fax: 0098-131-3233647; E-mail: geneticzs@yahoo.co.uk




Oncology Research, Vol. 18, pp. 329-335
0965-0407/09 $90.00 + .00
DOI: 10.3727/096504010X12626118080028
E-ISSN 1555-3906
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Genetic Variants of DNA Repair Gene XPC Modulating Susceptibility to Cervical Cancer in North India

Ruchika Gangwar,1 Balraj Mittal,2 Shruti Srivastava,2 Hariom Singh,2 and Rama Devi Mittal1

1Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
2Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

The objective of the study was to investigate the association of Xeroderma Pigmentoum group C (XPC) Lys939Gln (A>C) and poly (AT) insertion deletion (PAT -/+) gene polymorphism with the risk of cervical cancer. We enrolled 220 cervical cancer patients and 237 healthy individuals. Polymorphism for <i>XPC gene (Lys939Gln, PAT -/+) was genotyped by polymerase chain reaction and restriction fragment length polymorphism method. XPC Lys939Gln CC genotype was associated with elevated risk of cervical cancer (OR = 2.15, p = 0.036). CC genotype of Lys939Gln (OR = 3.68; p = 0.02) and +/+ genotype of PAT (OR = 7.99; p = 0.01) were observed to have statistically significant elevated risk in stage IV of cervical cancer. Among tobacco users, carriers of the +/+ genotype of PAT showed a borderline significance (OR = 3.72, p = 0.032). Haplotypes A+ and C- (A>C of Lys939Gln, ->+ of PAT) were significantly associated with higher susceptibility to cervical cancer (OR = 2.01, p = 0.005 and OR = 1.76, p = 0.002, respectively). Polymorphisms and haplotypes in XPC appear to influence cervical cancer risk and may modify risk attributable to tobacco usage.

Key words: Cervical cancer; DNA repair capacity; Genetic susceptibility; Polymorphism; XPC

Address correspondence to Dr. Rama Devi Mittal, Additional Professor (Biochemistry), Department of Urology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow-226014, India. Tel: 091-522-2668004-8, ext. 2116; Fax: 091-522-2668 017; E-mail: ramamittal@gmail.com or remittal@sgpgi.ac.in




Oncology Research, Vol. 18, pp. 337-342
0965-0407/09 $90.00 + .00
DOI: 10.3727/096504010X12626118079822
E-ISSN 1555-3906
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

The UGT1A1*28 Genotype and the Toxicity of Low-Dose Irinotecan in Patients With Advanced Lung Cancer

Tomohide Sugiyama,1 Takashi Hirose,1 Sojiro Kusumoto,1 Takao Shirai,1 Toshimitsu Yamaoka,1 Kentaro Okuda,1 Tsukasa Ohnishi,1 Tohru Ohmori,2 and Mitsuru Adachi1

1Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Showa University School of Medicine, Tokyo 142-8666, Japan
2Institute of Molecular Oncology, Showa University School of Medicine, Tokyo 142-8666, Japan

The association between the UGT1A1*28 genotype and the severe toxicity of low-dose irinotecan has been controversial, and few studies have examined this association in patients with lung cancer. The aim of this study was to assess the association between the UGT1A1*28 genotype and the severe toxicity of low-dose irinotecan in Japanese patients with lung cancer. From December 2005 through July 2008, 53 Japanese patients with advanced lung cancer who underwent chemotherapy that included low-dose irinotecan (50 or 60 mg/m2) as a single agent or in combination chemotherapy were retrospectively analyzed. Genomic DNA was extracted from peripheral blood. Genotypes for the UGT1A1*28 were denoted as wild-type for 6/6, heterozygous for 6/7, or homozygous for 7/7 depending on the number of TA repeats found in each allele. Of the 53 patients, 42 (79.2%) were wild-type, 9 (17.0%) were heterozygous, and 2 (3.7%) were homozygous for theUGT1A1*28 genotype. The UGT1A1*28 genotype was not associated with grade 3 or 4 neutropenia, thrombocytopia, diarrhea, or febrile neutropenia. The frequency of dose reduction of irinotecan did not differ between wild-type and heterozygous or homozygous for the UGT1A1*28 genotype. In addition, there were no significant differences in response rates and survival between wild-type and heterozygous or homozygous for the UGT1A1*28 genotype. In conclusion, the UGT1A1*28 genotype did not predict the severe toxicity of low-dose irinotecan in patients with lung cancer. Therefore, low-dose irinotecan could be administered without reducing starting dose in patients with UGT1A1*28 genotype.

Key words: UGT1A1*28 genotype; Low-dose irinotecan; Lung cancer; Toxicity

Address correspondence to Takashi Hirose, M.D., Ph.D., Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8666, Japan. Tel: +81-3-3784-8532; Fax: +81-3-3784-8742; E-mail: thirose-shw@umin.ac.jp




Oncology Research, Vol. 18, pp. 343-347
0965-0407/09 $90.00 + .00
DOI: 10.3727/096504010X12626118079903
E-ISSN 1555-3906
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

The CYP1A1 Ile462Val Polymorphism and Platinum Resistance of Epithelial Ovarian Neoplasms

Martin Heubner,1,2 Pauline Wimberger,2 Kathrin Riemann,1 Sabine Kasimir-Bauer,2 Friedrich Otterbach,3 Rainer Kimmig,2 and Winfried Siffert1

1Institute of Pharmacogenetics, Medical Faculty, University of Duisburg-Essen, Essen, Germany
2Clinic of Obstetrics and Gynaecology, Medical Faculty, University of Duisburg-Essen, Essen, Germany
3Institute of Pathology, Medical Faculty, University of Duisburg-Essen, Essen, Germany

The role of estrogens in ovarian carcinogenesis and progression of ovarian cancer is unclear. Cytochrome P450 is involved in estrogen metabolism, and polymorphisms have been associated with functional changes and risk for ovarian cancer. In this study, we investigated the impact of the CYP1A1 Ile462Val polymorphism upon tumor risk and disease progression in ovarian cancer patients. One hundred and eleven ovarian cancer patients who had been treated at the University Hospital of Essen between 1999 and 2007 and 119 age-matched healthy female controls were enrolled in this study. Genotyping was performed using PCRRFLP. The distribution of genotypes was statistically significant different between ovarian cancer patients and healthy controls. We observed a significant association of the Ile allele with ovarian cancer (OR 2.6, 95% CI 1.5-4.7, p = 0.001). Clinical parameters such as overall survival, FIGO stage, grading, and age at diagnosis did not differ significantly. We observed a statistically significant association between the 462Val allele and platinum resistance, which was defined as a time interval <6 months to disease progression after administration of a platinum-based primary chemotherapy (OR 5.9, 95% CI 1.5-23.2, p = 0.005). We observed a significant association between the presence of the 462Ile allele with ovarian cancer. While there is uncertainty about the potential involvement of CYP1A1 in the metabolism of platinum-containing agents, our findings suggest an association between the 462Val allele and the development of platinum resistance in ovarian tumors. If confirmed in a larger, independent collective, our findings would have important relevance with respect to the clinical consequences for the primary chemotherapy of ovarian cancer patients.

Key words: Ovarian cancer; Polymorphism; CYP1A1; Platinum resistance

Address correspondence to Dr. med. Martin Heubner, Institute of Pharmacogenetics, University of Duisburg-Essen Hufelandstr. 55, 45147 Essen, Germany. Tel: 49-201-723-3459; Fax: 049-201-723-5968; E-mail: martin.heubner@uk-essen.de




Oncology Research, Vol. 18, pp. 343-347
0965-0407/09 $90.00 + .00
DOI: 10.3727/096504010X12626118080064
E-ISSN 1555-3906
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Genetic Polymorphisms in GSTA1, GSTP1, GSTT1, and GSTM1 and Gastric Cancer Risk in a Vietnamese Population

Thai V. Nguyen,1 Marcel J. R. Janssen,2 Martijn G. H. van Oijen,2 Saskia M. Bergevoet,2 Rene H. M. te Morsche,2 Henri van Asten,3 Robert J. F. Laheij,2 Wilbert H. M. Peters,2 and Jan B. M. J. Jansen2

1Department of Gastroenterology, Can Tho University of Medicine and Pharmacy, Can Tho, Vietnam
2Department of Gastroenterology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
3Nijmegen Institute for International Health, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Glutathione S-transferases (GSTs) are a family of enzymes involved in the detoxification of noxious agents. Genes encoding for GSTA1, GSTP1, GSTT1, and GSTM1 proteins are polymorphic in humans, which can result in (partial) loss of enzyme activity. Previous epidemiologic studies have associated dysfunction of these GST genes with a higher risk of cancer, but this is still controversial. The aim of this study was to investigate the susceptibility to gastric cancer in relation to the above-mentioned GST polymorphisms. Patients visiting the Can Tho General Hospital in Vietnam between January 2004 and August 2004 for upper gastrointestinal endoscopy, who were diagnosed with gastric cancer, were compared with a control group of endoscoped dyspepsia patients with no history of malignancy. Genotypes of the GSTs mentioned above were assessed by multiplex PCR. Fifty-nine patients with gastric cancer (mean age: 63 years, 80% males), and 109 dyspeptic controls (mean age: 46 years, 69% males) were included in this study. The frequencies of the combined heterozygote and homozygote mutant GSTA1 and GSTP1 genotypes were 10% and 48% in patients with gastric cancer versus 28% and 40% in dyspeptic controls, respectively. GSTT1 and GSTM1 were deleted in 42% and 73% of patients with gastric cancer and in 35% and 69% of the controls, respectively. The GSTA1 homozygous wild-type genotype was significantly more often present in patients with gastric cancer compared with controls (odds ratio 4.3, 95% CI 1.2-17), which was even more apparent after adjustment for age, gender, current smoking, current alcohol consumption, and polymorphisms in GSTP1, GSTT1, or GSTM1 (odds ratio 5.0, 95% CI 1.2-25). The present work shows that the homozygous wild-type GSTA1 genotype is associated with gastric cancer in a Vietnamese population, whereas there was no relationship with polymorphisms in GSTP1, GSTT1, or GSTM1.

Key words: Gastric cancer; Dyspepsia; Glutathione S-transferase; Genetic polymorphism

Address correspondence to Dr. Wilbert H. M. Peters, Department of Gastroenterology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: w.peters@mdl.umcn.nl