|ognizant Communication Corporation|
AN INTERNATIONAL JOURNAL
INCORPORATING ANTI-CANCER DRUG DESIGN
VOLUME 16, NUMBER 9
Oncology Research, Vol. 16, pp. 405-413
0965-0407/07 $90.00 + .00
Copyright © 2007 Cognizant Comm. Corp.
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Functional Evidence for a Nasopharyngeal Carcinoma-Related Gene BCAT1 Located at 12p12
Wen Zhou,1* Xiangling Feng,1* Hong Li,1 Lei Wang,1 Hui Li,1 Bin Zhu,1 Hejun Zhang,1 Kaitai Yao,1,2 and Caiping Ren1
1Cancer Research Institute, Xiang-Ya School of Medicine,
Central South University, Hunan 410078, P. R. China
2Cancer Research Institute, Southern Medical University, Guangdong 510515, P. R. China
Nasopharyngeal carcinoma (NPC) is a malignancy that is prevalent among populations from Southeast Asia. The carcinogenesis of NPC is thought to be a multistep process involving several genetic changes. Our previous study based on distance and branching-tree models for NPC carcinogenesis indicated +12p11-p12 was an early event and should play an important role in NPC development. To understand the role of +12p11-p12 as the tree model predicted and evaluate which gene located at 12p11-p12 might be involved in NPC development, semiquantitative RT-PCR was applied to examine the expression status of 18 genes selected from 12p11-p12 in 36 NPC and 8 normal nasopharynx (NP) biopsies. The results revealed that BCAT1, KCNJ8, PTX1, and KRAS2 genes were overexpressed in NPC tissues and BCAT1 was of particular interest based on its function reported in other tumors. To further elucidate the function of BCAT1 gene in NPC, BCAT1 expression was specifically suppressed in 5-8F NPC cell line by RNA interference (RNAi), confirmed by RT-PCR and Western blotting. As expected, the depletion of BCAT1 could effectively block the proliferation of NPC cells. The BCAT1 identified in the amplified 12p11-p12 region may play a certain role in NPC development.
Key words: Nasopharyngeal carcinoma; +12p11-p12; BCAT1; Gene expression; RNA interference
Address correspondence to Caiping Ren, M.D., Cancer Research Institute, Xiang-Ya School of Medicine, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, P. R. China. Tel: 86-731-2355066; Fax: 86-731-4360094; E-mail: firstname.lastname@example.org or to Kaitai Yao, Professor, Cancer Research Institute, Xiang-Ya School of Medicine, Central South University, 110 Xiangya Rd., Changsha, Hunan 410078, P. R. China; Cancer Research Institute, Southern Medical University, 1838 Guangzhou N. Rd., Guangzhou, Guangdong 510515, P. R. China. Tel: 86-731-4805451; Fax: 86-731-4360094; E-mail: email@example.com
Antitumor Activity of Mannan-Methotrexate Conjugate In Vitro and In Vivo
Renata Budzynska,1 Dmitry Nevozhay,2,3 Urszula Kanska,1 Monika Jagiello,1 Adam Opolski,2,4 Joanna Wietrzyk,2 and Janusz Boratynski1,4
1Laboratory of Biomedical Chemistry, Institute of Immunology
and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
2Laboratory of Experimental Anticancer Therapy, Department of Experimental Oncology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
3Kopvillem Institute of Medical Physics, 690068 Vladivostok, Russia
4Jan Dlugosz Academy, 42-201 Czestochowa, Poland
Conjugation of anticancer drugs with different carriers has been extensively studied recently as a potential method of obtaining improved drug forms. The conjugation often results in the increase of the therapeutic effect, alteration of a toxicity profile, and/or selective targeting of therapeutic agent to the tissue of interest. We have synthesized mannan-methotrexate conjugate by means of methotrexate anhydride and studied its antitumor properties both in vitro and in vivo in comparison with free methotrexate. Mannan-methotrexate conjugate showed significantly improved antitumor activity compared to free methotrexate in the model of P388 mouse leukemia disseminated in the peritoneal cavity treated with intraperitoneally injected chemotherapy. Conversely, the antitumor effects of free methotrexate and mannan-methotrexate conjugate were comparable when leukemia was implanted subcutaneously and chemotherapy agents were administered intravenously. These results suggest that mannan-methotrexate conjugate should be further investigated as a potential therapeutic agent for intraperitoneally disseminated tumors.
Key words: Mannan; Methotrexate; Conjugates; Leukemia; Cancer; Antitumor
Address correspondence to Janusz Boratynski, Ph.D., Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigl St, 12, 53-114, Wroclaw, Poland. Tel: +48 (71) 3371172, ext. 333; Fax: +48 (71) 3371382; E-mail: firstname.lastname@example.org
The Role of GSTM1 and GSTT1 Polymorphisms in Head and Neck Cancer Risk
Halit Sinan Suzen,1 Gulçin Guvenc,1 Mehmet Turanli,2 Ela Comert,2 Yaliçin Duydu,1 and Atilla Elhan3
1Faculty of Pharmacy, Department of Toxicology, Ankara University,
Tandogan-06100, Ankara, Turkey
2Department of Otolaryngology/Head and Neck Surgery, Ankara Oncology Education and Research Hospital, Demetevler, Ankara, Turkey
3Faculty of Medicine, Department of Biostatistics, Ankara University, Turkey
Head and neck cancer (HNC) is a serious health problem worldwide and tobacco smoke is a main causative factor for this malignancy. Interindividual genetic differences in enzymes involved in the metabolism of tobacco smoke carcinogens are one of the most important risk factors in the development of HNC. GSTM1 and GSTT1 enzymes participate in detoxifying of tobacco smoke carcinogens and have deletion polymorphisms. We performed a case control study to investigate a possible association between GSTM1 and GSTT1 variants and HNC risk. A total of 98 HNC cases, all of which were squamous cell carcinoma, and 120 healthy controls were investigated. GSTM1 and GSTT1 polymorphisms were genotyped using PCR. There was a significant association between HNC and GSTM1-null genotype (adjusted OR: 2.36, 95% CI: 1.303-4.26, p = 0.005). The frequency overall of GSTT1-null genotypes was not significant in HNC patients compared with that of GSTT1-positive genotypes (adjusted OR: 1.16, 95% CI: 0.563-2.397, p = 0.686). No combined effect was observed for GSTM1 and GSTT1 genotypes. When data were stratified by smoking status, cases having GSTM1-null genotype who were smokers conferred the highest risk (adjusted OR: 4.06, 95% CI: 1.3-12.63). Thus, our results suggest that GSTM1 polymorphism may significantly increase the risk of HNC and there is an additive interaction between GSTM1-null genotype and smoking on HNC risk.
Key words: GSTM1; GSTT1; Polymorphism; Head and neck cancer
Address correspondence to H. Sinan Suzen, B.Pharm., M.Sc., Ph.D., Professor, Faculty of Pharmacy, Department of Toxicology, Ankara University, Tandogan-06100, Ankara, Turkey. Tel: +90 312 2126805, ext. 2331; Fax: +90 312 2131081; E-mail: email@example.com
Loss of Hugl-1 Expression Associates With Lymph Node Metastasis in Endometrial Cancer
Tetsushi Tsuruga, Shunsuke Nakagawa, Michiko Watanabe, Shin Takizawa, Yoko Matsumoto, Kazunori Nagasaka, Kenbun Sone, Haruko Hiraike, Yuichiro Miyamoto, Osamu Hiraike, Takeo Minaguchi, Katsutoshi Oda, Toshiharu Yasugi, Tetsu Yano, and Yuji Taketani
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
Mutation of neoplastic tumor suppressor genes, scribble, discs large, and lethal giant larvae (lgl), causes disruption of cell polarity and overproliferation of Drosophila epithelial cells and neuroblasts. Reduced expression of human homologue of lgl, Hugl-1, has been reported to be involved in development and progression of human colon cancer and malignant melanoma. To explore the association between Hugl-1 expression and clinical character in endometrial cancer, we examined the expression of Hugl-1 in primary endometrial cancer tissues. The expression of Hugl-1 mRNA in 86 primary endometrial cancer tissues was examined using semiquantitative reverse transcription polymerase chain reaction (RT-PCR). All samples were categorized into two groups: Hugl-1 positive and Hugl-1 negative. Clinical data of each group were analyzed by Fisher's exact probability test and survival rates of each group were compared by Kaplan-Meier method and Log-rank test. Loss of Hugl-1 expression had correlation with the higher incidence of lymph node metastasis, but not to the patient's age at onset, distant metastasis, clinical stage, lymph or venous vessel invasion, or histopathological grade of differentiation. The Hugl-1-positive group had poorer prognosis compared with the Hugl-1-negative group. These results indicate that loss of Hugl-1 expression in endometrial cancer may contribute to lymph node metastasis and it can be a factor of poor prognosis.
Key words: Hugl-1; Endometrial cancer; Lymph node metastasis; Lethal giant larvae; Neoplastic tumor suppressor genes; Cell polarity
Address correspondence to Dr. Shunsuke Nakagawa, Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel: +81-3-3815-5411, ext. 37358; Fax: +81-3-3816-2017; E-mail: firstname.lastname@example.org
CYP1A1 Msp1 T/C Polymorphism in Esophageal Cancer: No Association and Risk Modulation
Meenu Jain,1 Shaleen Kumar,2 Uday C. Ghoshal,3 and Balraj Mittal1
1Department of Medical Genetics, Sanjay Gandhi Post Graduate
Institute of Medical Sciences, Lucknow-226014, India
2Department of Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow-226014, India
3Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow-226014, India
Phase I enzyme CYP1A1 metabolizes environmental carcinogens and a Msp1 T/C functional polymorphism in 3´UTR in its gene has been reported to influence the inducibilty of the enzyme. There are controversies regarding association of the polymorphism with risk of esophageal cancer in Chinese and Caucasian populations. Moreover, no study has been done in Indian populations. The present study was aimed to explore the associations of CYP1A1 3´UTR polymorphism with clinical phenotypes and environmental interaction in esophageal cancer from North Indian population. A total of age- and gender-matched 161 cases and 201 healthy controls were used to genotype the CYP1A1 3´UTR polymorphism by PCR-EFLP methodology. None of the CYP1A1 genotypes and alleles was significantly associated with risk of esophageal cancer, even after adjusting for age and sex. After stratifying the genotypes according to disease characteristics such as tumor histology, location, and lymph nodes, individuals with TT genotype were at high risk for developing tumor in the upper third location (OR: 2.2, 95% CI: 0.81-6.2, p = 0.11). Interaction of tobacco usage (smoking or nonsmoking) and presence of occupational exposure in esophageal cancer patients did not show significant increase in cancer risk with CYP1A1 genotypes. However, in patients with alcohol habits, TT genotype showed a higher risk, which was not significant (OR: 2.5, 95% CI: 0.61-10.6, p = 0.19). In conclusion, CYP1A1 genotype did not influence the susceptibility of developing esophageal cancer. The presence of variant CYP1A1 genotypes together with environmental exposures also did not modulate the cancer risk.
Key words: CYP1A1; Esophageal cancer; Polymorphisms; Risk
Address correspondence to Prof. Balraj Mittal, Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareilly Road, Lucknow-226014, India. Tel: +91-522-2668973, 004-8, Ext: 2322; Fax: +91-522-2668017, 2668074; E-mail: email@example.com or firstname.lastname@example.org
Serum Levels of VEGF-C, VEGF-D, and sVEGF-R2 in Patients With Lung Cancer During Chemotherapy
Wojciech Naumnik, Tomasz Izycki, Ewa Swidzinska, Maria Ossolinska, and Elzbieta Chyczewska
Department of Lung Diseases and Tuberculosis, Medical University of Bialystok, Bialystok, Poland
The aim of this study was to assess serum levels of vascular endothelial growth factor C and D (VEGF-C, VEGF-D) and soluble VEGF receptor 2 (sVEGFR-2) in patients with lung cancer during chemotherapy. The study included 80 patients (64 men and 16 women; mean age 61.1) diagnosed histologically with lung cancer. Forty-four (55%) had non-small cell lung cancer (NSCLC) and 36 (45%) had small cell lung cancer (SCLC). Squamous cell carcinoma was established in 56% (25 patients) of all patients with NSCLC, adenocarcinoma in 20% (9 patients), and non-small cell lung cancer in 23% (10 patients). The control group consisted of 20 healthy volunteers. Peripheral blood samples were taken before and after four cycles of chemotherapy. VEGF-C, VEGF-D, and sVEGFR-2 levels were assessed by ELISA method. Serum levels of VEGF-C and VEGF-D were significantly higher in both NSCLC and SCLC groups in comparison with controls. VEGF-C concentration decreased after chemotherapy, whereas VEGF-D concentration was at the same level. No correlation was found between VEGF-C and VEGF-D concentrations and the effect of treatment. Patients with lung cancer and progression after chemotherapy (PD) had the higher concentration of sVEGFR-2 than patients with partial remission (PR). The levels of sVEGFR-2 were lower before and after treatment than in controls. No relation was found between VEGF-C, VEGF-D, and sVEGFR-2 concentrations and the histological type and staging of lung cancer. Summing up, serum concentrations of VEGFC and VEGF-D were higher in patients with lung cancer both before and after chemotherapy than in healthy controls, whereas sVEGFR-2 concentration was lower than in healthy controls. An increase in concentration of sVEGFR-2 during chemotherapy may suggest progression of the disease. However, it requires further examination.
Key words: Lung cancer; VEGF-C; VEGF-D; Soluble VEGF receptor 2 (sVEGFR-2); Chemotherapy
Address correspondence to Wojciech Naumnik, Department of Lung Diseases
and Tuberculosis, Medical University of Bialystok, 14 Zurawia St., PL 15-540,
Bialystok, Poland. Tel/fax: +48 85 7324149; E-mail: email@example.com