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Suramin Pharmacokinetics After Regional Or Systemic

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Suramin Pharmacokinetics After Regional Or Systemic TRANSLATIONAL RESEARCH IN CANCER: PRECLINICAL PHARMACODYNAMICS AND CANCER EPIDEMIOLOGY DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jia Ji, M.A.S. Graduate Program in Pharmacy The Ohio State University 2009 Dissertation Committee: Dr. Jessie L.-S. Au, Advisor Dr. M. Guillaume Wientjes Dr. Dennis B. McKay Copyright by Jia Ji 2009 ABSTRACT Translational research bridges preclinical and clinical research and shortens distance between these two areas in biomedical research. In preclinical study, our laboratory has found suramin sensitization at low and non-toxic dose and antagonism at toxic dose in multiple experimental models. The first part of this dissertation, Chapter 2 and 3, aims to evaluate cellular pharmacodynamics (PD) of biphasic effect of suramin and identify potential PD endpoint for future application in clinical practice. In Chapter 2, we first established an in vitro experimental model that illustrated suramin sensitization and antagonism to cisplatin, known as DNA-damaging drug. Addition of low dose suramin enhanced cellular response to cisplatin-induced DNA damage in three aspects, which are cell cycle arrest, cell death and senescence. Chapter 3 documented that persistence of γH2AX, a marker of DNA damage, was sustained by the addition of low dose suramin compared with cisplatin-alone treatment. No significant change of γH2AX kinetics was detected when suramin biphasic effect to taxanes, non-DNA-damaging drugs, was observed under both in vitro and in vivo settings. These preclinical discoveries not only lead us to treatment-dependant mechanism of suramin sensitization effect, but also indicate prospective clinical application of γH2AX as PD endpoint in anti-cancer therapy combined with suramin. ii The second part of this dissertation applied the principle of translational research for the purpose of studying and facilitating the application of research findings to the community. In cancer epidemiology, Chapter 4 investigated prevalence of serological response to human papillomavirus (HPV) 6, 11, 16, and 18, among women in China, as persistent HPV infection is a leading cause of cervical cancer. As the first report of HPV seroprevalence in China, we proposed necessity of primary prevention of HPV infection through application of HPV prophylactic vaccines, when most of Chinese women are not exposed. Chapter 5 focused on causes of breast cancer and ovarian cancer attributable to oral contraceptives use and reproductive factor change. Modest fraction of breast cancer and ovarian cancer is attributable to reproductive factor change, as insignificant percentage of cancer cases and deaths of breast cancer attributable to oral contraceptives use. These clinical findings prompt appropriate adoption of policies suitable and applicable to public health in China. iii DEDICATION Dedicated to my grandmother, a strong woman, and my husband, whose encouragement and love is always with me iv ACKNOWLEDGEMENTS I wish to express my sincere appreciation to my adviser, Dr. Jessie L.-S. Au, who has made this dissertation come true. Her scientific guidance, insightfulness and superior foresight have been inspiring me throughout my graduate study. It was her kind patience and persistent support that saved me from confusion and frustration during my most difficult times. I am always speechless on how to describe my gratefulness for her supervision, encouragement and strong faith on me, because no words can fully express my feeling. It has been my honor and privilege to receive such intact and extensive training on translational research from her. Her huge success in career and life will definitely influence and motivate me to pursue my dream. My deep appreciation also goes to Dr. M. Guillaume Wientjes, for all his invaluable contribution to my overall scientific training and growth. His scientific enthusiasm, integrity and dedication are treasures I will be learning from. I am fortunate to have him as mentor and friend for life. I truly thank Dr. Dennis B. McKay for being my committee member and all his intellectual advices and suggestions on my progress and dissertation. I genuinely appreciate his kindness and patience. I want to express my thankfulness to Dr. Duxin Sun, who had guided me at the beginning of my graduate study and served as committee v member in my oral exam. I will remember his kindness, considerateness and understanding and keep my deep appreciation to him from bottom of my heart. A special recognition is extended to Dr. Myron Cohen and Dr. Jennifer S. Smith, my mentors in the States, when I studied in Beijing as Fogarty scholar. It is their dedication that made my last year productive. Sincere gratefulness goes to Dr. Youlin Qiao, my mentor in China, for his invaluable scientific suggestions, discussions, and input into my dissertation work. His amazing enthusiasm and devotion have greatly inspired me. I appreciate his thoughtfulness and support. Also, everyone in his group deserves my sincere gratitude for their help and care. I am blessed to work with them. Everyone in the lab has played a special role in my training. I am really grateful to have such an enjoyable environment to finish the most important training in my career. I want to thank each of them for the sweet memorable days. In particular, my sincere thanks go to Dr. Yong Wei, Dr. Leijun Hu, Dr. Jie (Jack) Wang, Dr. Yan Xin and Dr. Bei Yu, who walked me through the starting stage in this laboratory. They have earned my undying gratitude for invaluable comments and encouragement. I would also like to recognize the following individuals for their direct experimental contribution and invaluable suggestions to my dissertation: Dr. Zancong Shen for the cooperation of micro-autoradiography, Dr. Mingjie Liu, Dr. Ling (Lucy) Chen, Jianning Yang and Tong Shen for the collaboration in pharmacodynamics study, Dr. Ji-hyun Chung for training on western blotting and running samples, Dr. Ze Lu for providing tumor tissues, Dr. Ling vi Chen for the help of tissue sectioning and Xie (JJ) Zhe for some counting work. In addition, I want to express my thankfulness to the following labmates for their friendship and help: Dr. Xiao (Shelley) Hu, Dr. Greg Lyness, Dr. Dan Lu, Dr. Colin Walsh, Dr. Bin Chen, Dr. Ho-lun Wong, Dr. Peng Guo, Jing Li, Yue Gao. My appreciation also goes to Kathy Brooks, Carol Camm and Emily Noble for their patient help during my study. My dear officemates, Jianning Yang and Jing Li, once again earned my special thankfulness for their friendship and encouragements during the last few years. Thanks to all my other friends for their support during the whole training. I will treasure those touching moments. Last but not the least, my deepest appreciation goes to my grandmother, my husband, my mother, my father, my god-parents, my parents-in-law, my uncle and aunt. Without their endless love and support, I would not be able to go through all the way here. vii VITA August 22, 1979………………………………...Born – Beijing, P.R.China July 2001….…………………………………….B.S., Pharmacy School of Pharmacy Peking University Health Science Center August 2008….………………………………….M.A.S., Statistics The Ohio State University April 2004 to present…………………...……….Graduate Research Associate College of Pharmacy The Ohio State University July 2008 to June 2009………………………….Fogarty International Clinical Research Scholar Fogarty International Center National Institute of Health PUBLICATIONS Papers 1. Hao Cheng, Xianhua Cao, Ming Xian, Lanyan Fang, Tingwei Bill Cai, Jacqueline Jia Ji, Josefino B. Tunac, Duxin Sun, and Peng George Wang. Synthesis and Enzyme- Specific Activation of Carbohydrate-Geldanamycin Coujugates with Potent Anticancer Activity. Journal of Medicinal Chemistry, 48(2): 645-652, 2005. 2. Qin E’de*, He Xionglei*, Tian Wei*, Liu Yong*, Li Wei*, ……Ji Jia, ……Zhu Qingyu, and Yang Huanming. A Genome Sequence of Novel SARS-CoV Isolates: the Genotype, GD-Ins29, Leads to a Hypothesis of Viral Transmission in South China. Genomics, Proteomics & Bioinformatics, 1(2):101-107, 2003. 3. Xu Zuyuan*, Zhang Haiqing*, Tian Xiangjun*, Ji Jia* et al.. The R Protein of SARS- CoV: Analysis of Structure and Function Based on Four Complete Genome viii Sequences of Isolates BJ01-BJ04. Genomics, Proteomics & Bioinformatics, 1(2):155- 165, 2003. 4. Wang Jingqiang*, Ji Jia*, Ye Jia*, Zhao Xiaoqian* et al.. The Structure Analysis and Antigenicity Study of the N Protein of SARS-CoV. Genomics, Proteomics & Bioinformatics, 1(2):145-154, 2003. 5. Wu Qingfa*, Zhang Yilin*, Lv Hong*, Wang Jing*, ……Ji Jia, ……Yang Huanming. The E Protein Is a Multifunctional Membrane Protein of SARS-CoV. Genomics, Proteomics & Bioinformatics, 1(2):131-144, 2003. 6. Li Jingxiang*, Luo Chunqing*, Deng Yajun*, Han Yujun*, ……Ji Jia, ……YANG Huanming. The Structural Characterization and Antigenicity of the S Protein of SARS-CoV. Genomics, Proteomics & Bioinformatics, 1(2):108-117, 2003. 7. Wu Qingfa, Ji Jia, Dong Wei. Recent development in the study of Pharmacogenomics. Biotechnology, 12(2):39-41, 2002. Presentations 1. Jia Ji*, He Wang*, Jennifer S. Smith, Mark Esser, Christine Velicer, Wen Chen, Shangying Hu, Robert G. Pretorius, Jerome L. Belinson, You-Lin Qiao. Population- based Seroprevalence of Human Papillomavirus in Chinese Women. The 25th International Papillomavirus Conference, Malmö, Sweden, May 8-14th, 2009. 2. Jia Ji, Yuli Chang, Jennifer S. Smith. Age-specific Prevalence of Human Papillomavirus DNA and Antibody: Systematic Review. The 25th International Papillomavirus Conference, Malmö, Sweden, May 8-14th, 2009. 3. Jennifer S. Smith , Jerome L. Belinson, Jia Ji, Shangying Hu, Wen Chen, Mark Esser, Frank J. Taddeo, Robert G. Pretorius, You-Lin Qiao. Population-based Human Papillomavirus 16/18/6/11 DNA and Seropositivity in Chinese Women. The 25th International Papillomavirus Conference, Malmö, Sweden, May 8-14th, 2009. 4. Shangying Hu, Jennifer S. Smith , Wen Chen, Jia Ji, Robert G. Pretorius, Mark Esser, Frank J. Taddeo, Jerome L. Belinson , You-Lin Qiao. HPV16/18 High in Precancer, Low in Normal Cytology in China.
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