Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Cigarette smoke; Cervical cancer; HPV; DNA damage; Comet assay; Vaginal cells
Cervix uteri--Cancer; Cigarette smoke--Health aspects; Tobacco use--Health aspects; Papillomaviruses
Among gynecological malignancies, carcinoma of the cervix is the leading cancer type worldwide. Conversely, vaginal tumors account for an incidence of approximately 1-2% of lower genital tract malignancies. Interestingly, the major shared risk factor among women with cervical and vaginal tumors is infection with cancer-associated human papillomaviruses (HPVs). In fact, HPV infection is the necessary causative factor in the development and progression of cervical and vaginal neoplasia in the majority of cases. Epidemiological studies support that cervical and vaginal pre-cancerous lesions that are initiated by HPV infection generally regress in the absence of known risk factors such as cigarette smoking. Further, female smokers have two times higher risk of developing cervical cancer from premalignant lesions than non-smokers, although the association between cigarette smoking and vaginal tumors has been controversial. Cigarette smoking exerts its cytogenetic effects in various forms such as DNA strand breaks and oxidative DNA damage. However, previous studies on cervical and vaginal abnormalities failed to investigate the effects of cigarette smoking on cervical and vaginal cells from a biological standpoint. Therefore, the goal of this work was to investigate cigarette smoke-induced DNA strand breaks, oxidative damage and DNA repair in human cervical cancer cells (in vitro studies, Chapters II and III); we also examined DNA strand breaks in human vaginal cells in light of cigarette smoking and HPV status (an ex vivo study, Chapter IV). It was determined that cigarette smoke induces both DNA single- (SSBs) and double-strand breaks (DSBs) that are highly persistent, in addition to oxidative DNA damage, which is more pronounced in HPV infected human cervical cancer cells. Though, CSC-induced oxidative DNA damage was eventually removed in the cells, the possibility of error-prone DNA repair, however, cannot be ruled out. Lastly, our data derived from the ex-vivo study clearly showed an inverse relationship between the interaction of cigarette smoking and HPV infection in the induction of DNA strand breaks in vaginal cells of the studied population, regardless of age. Further, we have clearly showed that the extent of DNA DSBs increases as a function of age, which corroborates with the fact that vaginal cancers occur at a much older age, as compared to cervical cancers. In summary, the findings of this research project shed light on the role of cigarette smoke in cervical/vaginal carcinogenesis. Moreover, comet assay might serve as an early biomarker in identifying susceptible populations that are at risk for developing cervical/vaginal abnormalities.
Moktar, Afsoon, "Cigarette smoke, DNA damage and repair in human cervical and vaginal cells in vitro and ex vivo." (2010). Electronic Theses and Dissertations. Paper 999.