A Novel Combination Therapy of Cisplatin with a Molecular Promoter for Cancer Treatment
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Date
2017-01-25
Authors
Zhang, Qinrong
Journal Title
Journal ISSN
Volume Title
Publisher
University of Waterloo
Abstract
Cisplatin is the first and most widely used platinum-based chemotherapy drug and is the cornerstone agent in treating a broad spectrum of cancers, including ovarian cancer, testicular cancer, cervical cancer, bladder cancer, lung cancer, head and neck cancer, lymphoma, and brain tumors. It is one of the few curative anti-cancer agents; however, its clinical application is often limited by severe toxic side effects and resistance possessed by some cancers.
Our group has recently, through the femtomedicine approach, unraveled a new molecular mechanism of Cisplatin. It has been found that Cisplatin is extremely effective for the dissociative electron transfer (DET) reaction with weakly-bound electrons to produce reactive radicals that cause DNA strand breaks, apoptosis, and final clonogenic cell kill.
Based on this DET mechanism, it is proposed that Cisplatin may be administered in combination with a biological electron donor to enhance its chemotherapeutic efficacy. We have tried a few combinations of Cisplatin and electron-donating compounds. In this thesis, we show results of the combination: Cisplatin and Rhodamine-B, the one with the greatest potential as demonstrated in both in vitro assays and in vivo xenograft mouse cancer models. This thesis begins with an introduction to cancer and cancer therapies in Chapter 1, where the theory, objective, and scope of this thesis are introduced. Chapter 2 focuses on some new understandings of Cisplatin-induced DNA damage. In vitro and in vivo experiment results on the effectiveness of the combination of Cisplatin and Rhodamine-B are presented in Chapter 3 and Chapter 4, respectively. In Chapter 5, time-resolved femtosecond laser spectroscopic studies on the reaction between Cisplatin and Rhodamine-B are shown. Chapter 6 as the last Chapter summarizes results obtained in this project and proposes some possible future research.
In vitro experiments confirm the potential of this proposed combination of Cisplatin and Rhodamine-B to treat cancer. From cell survival tests, by applying MTT assays and clonogenic assays, it has been shown that our proposed combination significantly enhances the cell-killing efficacy in cancer cells; but surprisingly, not in normal cells. Besides, plasmid DNA gel electrophoresis and γ-H2AX staining in treated cells indicate that more double-strand breaks can be induced using our combination, compared to Cisplatin only. In addition, measurements on Caspase 3/7 activation and Annexin V-FITC labeling flow cytometry experiments clearly show a significant enhancement in the population of apoptotic cells using our combination. To further verify the effectiveness of the combination of Cisplatin and Rhodamine-B, in vivo xenograft mouse models have been developed. Our combination greatly enhances the tumor growth inhibition and even tumor shrinkage in three different mouse models. Acute toxicity analysis and body weight measurements do not show additional side effects induced by the addition of Rhodamine-B. Lastly, spectroscopic measurements have confirmed that Cisplatin and Rhodamine-B can react, and the reaction is an electron transfer reaction.
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Keywords
Cancer, Combination Therapy, Cisplatin