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Translational Research in Cancer: Preclinical Pharmacodynamics and Cancer Epidemiology

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2009, Doctor of Philosophy, Ohio State University, Pharmacy.

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.

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.

Jessie L.-S. Au, Ph.D., Pharm.D. (Advisor)
M. Guillaume Wientjes, Ph.D. (Committee Member)
Dennis B. McKay, Ph.D. (Committee Member)

Recommended Citations

Citations

  • Ji, J. (2009). Translational Research in Cancer: Preclinical Pharmacodynamics and Cancer Epidemiology [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1250092164

    APA Style (7th edition)

  • Ji, Jia. Translational Research in Cancer: Preclinical Pharmacodynamics and Cancer Epidemiology. 2009. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1250092164.

    MLA Style (8th edition)

  • Ji, Jia. "Translational Research in Cancer: Preclinical Pharmacodynamics and Cancer Epidemiology." Doctoral dissertation, Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1250092164

    Chicago Manual of Style (17th edition)