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In Canada, ovarian cancer kills about 67% of diagnosed patients, largely due to difficulties in early diagnosis. Current treatment consists of debulking surgery and intermittent chemotherapy every three weeks. This approach leads to insufficient drug concentrations at disease sites, and long treatment-free intervals cause accelerated tumor proliferation and drug resistance, resulting in a 5-year survival rate of only 25-35%. Drug resistance development is the ultimate cause of the majority of patient deaths. Improvements yielding more effective treatment are fundamental for successful management of this disease. This thesis investigated a continuous chemotherapy strategy devoid of treatment-free intervals for ovarian cancer treatment. A biocompatible, biodegradable polymer-lipid injectable formulation PoLigel, was used for continuous DTX delivery. The formulation was well tolerated; no alterations in body weight, behaviour, histology of peritoneal tissues, or interleukin-6 levels were seen in CD-1 mice treated with the PoLigel. Continuous DTX therapy via the PoLigel was considerably more efficacious than intermittent therapy, resulting in significantly less tumor burden and ascites fluid in models of human and murine ovarian cancer. Continuous therapy resulted in less tumor cell proliferation and angiogenesis, and more tumor cell death than intermittent DTX. The presence and length of treatment-free intervals was shown to contribute to the development of drug resistance. Eliminating these intervals by continuous dosing resulted in superior antitumor efficacy in both chemosensitive and chemoresistant xenograft models of human ovarian cancer, and prevented drug resistance increase after a 21-day treatment period. Survival studies revealed that intermittent dosing led to a mild survival prolongation of 36% and 10% in chemosensitive and chemoresistant models, respectively, whereas continuous DTX prolonged survival by a striking 114% and 95%. Although long-term continuous chemotherapy substantially improved survival, increased drug resistance mechanisms were found at the endpoint. Overall, results presented here encourage the clinical implementation of continuous chemotherapy due to greater achievable therapeutic advantages.

In Canada, ovarian cancer kills about 67% of diagnosed patients, largely due to difficulties in early diagnosis. Current treatment consists of debulking surgery and intermittent chemotherapy every three weeks. This approach leads to insufficient drug concentrations at disease sites, and long treatment-free intervals cause accelerated tumor proliferation and drug resistance, resulting in a 5-year survival rate of only 25-35%. Drug resistance development is the ultimate cause of the majority of patient deaths. Improvements yielding more effective treatment are fundamental for successful management of this disease. This thesis investigated a continuous chemotherapy strategy devoid of treatment-free intervals for ovarian cancer treatment. A biocompatible, biodegradable polymer-lipid injectable formulation PoLigel, was used for continuous DTX delivery. The formulation was well tolerated; no alterations in body weight, behaviour, histology of peritoneal tissues, or interleukin-6 levels were seen in CD-1 mice treated with the PoLigel. Continuous DTX therapy via the PoLigel was considerably more efficacious than intermittent therapy, resulting in significantly less tumor burden and ascites fluid in models of human and murine ovarian cancer. Continuous therapy resulted in less tumor cell proliferation and angiogenesis, and more tumor cell death than intermittent DTX. The presence and length of treatment-free intervals was shown to contribute to the development of drug resistance. Eliminating these intervals by continuous dosing resulted in superior antitumor efficacy in both chemosensitive and chemoresistant xenograft models of human ovarian cancer, and prevented drug resistance increase after a 21-day treatment period. Survival studies revealed that intermittent dosing led to a mild survival prolongation of 36% and 10% in chemosensitive and chemoresistant models, respectively, whereas continuous DTX prolonged survival by a striking 114% and 95%. Although long-term continuous chemotherapy substantially improved survival, increased drug resistance mechanisms were found at the endpoint. Overall, results presented here encourage the clinical implementation of continuous chemotherapy due to greater achievable therapeutic advantages.

Being currently the second and potentially becoming the first cause of death in North America, cancer has been the focus of researchers from various areas of science. Chemotherapy is one of the leading treatment options for treating various types of cancer, particularly advanced cancers. Among different chemotherapeutic drugs currently used against cancer, cisplatin (CDDP) is considered as one of the most effective and widely used. Despite being the most successful drug in cancer chemotherapy, cisplatin has some shortcomings that restrict it from being more widely used. More than three decades of intensive research has not yet clearly explained why these shortcomings are associated with cisplatin treatment. Using the advanced “Pump-Probe Femtosecond Time-Resolved Transient Absorption Laser Spectroscopy” technique to study the reaction dynamics of cisplatin at the molecular level, we discovered new findings that make a profound contribution to our understanding of the mechanism of activity of CDDP as a very widely used and effective anticancer drug. By observing the reaction dynamics of cisplatin both in its reaction with electrons in water, and with all four DNA bases, in real time, we shed new light on the issues that have long been elusive for the last three decades. In addition to these two main research goals, we utilized the same methodology to examine the reaction dynamics of transplatin, which currently is not a clinically effective drug, despite being an isomer of cisplatin. In this part we mainly focused on examining the molecular reaction dynamics of transplatin photoactivation caused by UV irradiation. Here, we studied the transplatin reaction with electrons in water as well as with four DNA bases. Results obtained in this thesis work clearly reveal the mechanism underlying the cytotoxicity enhancement of this molecule after it is irradiated by UV radiation. The data obtained by our experiments provide a mechanistic understanding of this cytotoxicity enhancement at the molecular level. As the last goal in our research, we compared the explored reaction dynamics of cisplatin with its clinically ineffective trans isomer, transplatin. We believe that our understanding of one of these isomers, would also contribute to understanding of the other. The methodology we used to examine transplatin was the same as what we used for cisplatin. First, we monitored the possible reactions of transplatin with prehydrated electrons in water. After this, the dynamics of transplatin’s reactions with DNA bases were examined. For the first time, we directly observed the reactions of cisplatin and discovered that its extremely high reactivity with prehydrated electrons happens in an ultrafast process. We also showed the order of reactivity of all four DNA bases with cisplatin and transplatin to be G > A > C > T. Finally, in comparing cis and trans isomers of DDP, we discovered cisplatin to be about 50% more reactive, suggesting why it is much more cytotoxic. In all of these investigations we obtained promising results that revolutionize our understanding of the mechanism of action of cisplatin as a very important drug in current cancer chemotherapy.

Being currently the second and potentially becoming the first cause of death in North America, cancer has been the focus of researchers from various areas of science. Chemotherapy is one of the leading treatment options for treating various types of cancer, particularly advanced cancers. Among different chemotherapeutic drugs currently used against cancer, cisplatin (CDDP) is considered as one of the most effective and widely used. Despite being the most successful drug in cancer chemotherapy, cisplatin has some shortcomings that restrict it from being more widely used. More than three decades of intensive research has not yet clearly explained why these shortcomings are associated with cisplatin treatment. Using the advanced “Pump-Probe Femtosecond Time-Resolved Transient Absorption Laser Spectroscopy” technique to study the reaction dynamics of cisplatin at the molecular level, we discovered new findings that make a profound contribution to our understanding of the mechanism of activity of CDDP as a very widely used and effective anticancer drug. By observing the reaction dynamics of cisplatin both in its reaction with electrons in water, and with all four DNA bases, in real time, we shed new light on the issues that have long been elusive for the last three decades. In addition to these two main research goals, we utilized the same methodology to examine the reaction dynamics of transplatin, which currently is not a clinically effective drug, despite being an isomer of cisplatin. In this part we mainly focused on examining the molecular reaction dynamics of transplatin photoactivation caused by UV irradiation. Here, we studied the transplatin reaction with electrons in water as well as with four DNA bases. Results obtained in this thesis work clearly reveal the mechanism underlying the cytotoxicity enhancement of this molecule after it is irradiated by UV radiation. The data obtained by our experiments provide a mechanistic understanding of this cytotoxicity enhancement at the molecular level. As the last goal in our research, we compared the explored reaction dynamics of cisplatin with its clinically ineffective trans isomer, transplatin. We believe that our understanding of one of these isomers, would also contribute to understanding of the other. The methodology we used to examine transplatin was the same as what we used for cisplatin. First, we monitored the possible reactions of transplatin with prehydrated electrons in water. After this, the dynamics of transplatin’s reactions with DNA bases were examined. For the first time, we directly observed the reactions of cisplatin and discovered that its extremely high reactivity with prehydrated electrons happens in an ultrafast process. We also showed the order of reactivity of all four DNA bases with cisplatin and transplatin to be G > A > C > T. Finally, in comparing cis and trans isomers of DDP, we discovered cisplatin to be about 50% more reactive, suggesting why it is much more cytotoxic. In all of these investigations we obtained promising results that revolutionize our understanding of the mechanism of action of cisplatin as a very important drug in current cancer chemotherapy.

Thesis (Ph. D.) -- California Institute of Technology, 2010. / Title from home page (03/01/2010). Advisor and committee chair names found in the thesis' metadata record in the digital repository. Includes bibliographical references.

Thesis (Ph. D.)--Ohio State University, 2004. / Title from first page of PDF file. Document formatted into pages; contains xxxiii, 278 p.; also includes graphics. Includes abstract and vita. Advisor: Kenneth Chan, Dept. of Pharmacy. Includes bibliographical references (p. 266-278).

Thesis (M.Sc. (Pharmacology))--University of Pretoria, 2008. / Summary in English. Includes bibliographical references.

Nucleosides possess many physiological and pharmacological properties. Among nucleosides, adenosine is a particularly important as it regulates many physiological functions in cardiovascular system. For instance, adenosine possesses anti-inflammatory effect through its action on endothelial cells. The functions of adenosine are indirectly controlled by the human equilibrative nucleoside transporters (hENTs). These transporters mediate the uptake of adenosine, thereby reducing the amount of extracellular adenosine available for the adenosine receptors and hence reducing its vascular protective effects. Nucleoside analogs such as gemcitabine, are commonly used as anti-cancer drugs in chemotherapy. Most of the anti-cancer nucleoside drugs require human concentrative nucleoside transporters (hCNTs) for their transport into cancer cells. On the other hand, hENTs is supposed to be responsible for the efflux of anti-cancer nucleoside drugs out of the cancer cells. In theory, hENT inhibitors should reduce the removal of adenosine from extracellular compartment by endothelial cells and hence increase and prolong the cardioprotective effect of adenosine. hENT inhibitors should also inhibit the efflux of anti-cancer nucleoside drugs, that in turn increases the drug accumulation in the cancer cells, resulting in a higher efficacy. Some typical and clinically used hENT inhibitors have side effects which limit their uses. Emodin, an active ingredient in many herbs, has been proven to have cardioprotective and anti-tumor properties. However, the mechanisms are not fully understood. We hypothesized that these properties may relate to its interaction with nucleoside transporters. The aims of this study were to investigate the pharmacological effects of emodin on hENTs and its implications on vascular functions and anti-cancer therapy. Our result showed that emodin inhibited both hENT-1 and hENT-2 dose-dependently with no priority to any subtypes of hENTs. The inhibitory effect of emodin on hENTs was reversible and non-competitive, indicating that emodin may interact with the allosteric sites on hENTs. 1,8-dihdroxy-3-methyl anthraquinone, which is similar to emodin in terms of chemical structure but it lacks hydroxyl group at position 3,did not inhibit hENTs. It implied that the presence of 3-hydroxyl group was critical for the inhibitory effect of emodin. Our result also demonstrated that emodin reduced the lipopolysaccharide-induced expression of adhesion molecule in human umbilical vein endothelial cells, reflecting its anti-inflammatory effect. Emodin also enhanced the cytotoxic effect of gemcitabine in HepG2, a liver cancer cell line. Nevertheless, these effects may not be due to the inhibitory effect of emodin on hENTs and further investigation is required. / published_or_final_version / Pharmacology and Pharmacy / Master / Master of Philosophy