| Acknowledgement | 第7-13页 |
| Abstract | 第13-14页 |
| Abstract in Chinese(摘要) | 第15-19页 |
| Chapter 1 Arsenic metabolism and thioarsenicals | 第19-41页 |
| Abstract | 第20页 |
| 1.1 Introduction | 第20-23页 |
| 1.2 Arsenic metabolism in animals | 第23-31页 |
| 1.2.1 Challenger's reductive/oxidative methylation pathway of arsenic metabolism | 第24-28页 |
| 1.2.2 Hayakawa's pathway of arsenic metabolism involving arsenic-GSH complexes | 第28-30页 |
| 1.2.3 New pathway of arsenic metabolism | 第30-31页 |
| 1.3 AS3MT activity and excretion of arsenicals | 第31-32页 |
| 1.4 Generation of thioarsenicals | 第32-34页 |
| 1.5 Perspective | 第34-35页 |
| References | 第35-41页 |
| Chapter 2 Double-edged effects of arsenic compounds:anticancer and carcinogenic effects | 第41-73页 |
| Abstract | 第42页 |
| 2.1 Introduction | 第42-44页 |
| 2.2 Arsenic toxicity | 第44-46页 |
| 2.3 Clinical uses of arsenic | 第46-47页 |
| 2.4 Arsenic as chemotherapeutic agent | 第47-51页 |
| 2.5 Mechanism of action of As_2O_3-differentiation or apoptosis | 第51-52页 |
| 2.6 Speciation of arsenicals in APL patients on As_2O_3 therapy | 第52-53页 |
| 2.7 Carcinogenic or chemotherapeutic an enigma for arsenic species | 第53-54页 |
| 2.8 Target mechanism for reactivity of arsenic | 第54-60页 |
| 2.8.1 Arsenic metabolites-induced apoptosis | 第54-56页 |
| 2.8.2 Other sensitive intracellular targets for arsenic | 第56-57页 |
| 2.8.3 Generation of ROS by arsenic | 第57-59页 |
| 2.8.4 DNA damage by arsenic | 第59页 |
| 2.8.5 Effect of arsenic on proteome and genes | 第59-60页 |
| 2.9 Conclusion and perspective | 第60-61页 |
| References | 第61-73页 |
| Chapter 3 Arsenic anticancer drugs | 第73-123页 |
| Abstract | 第74页 |
| 3.1 Introduction | 第74-76页 |
| 3.2 Rekindling of an old drug | 第76-77页 |
| 3.3 Basic information of APL and its history | 第77-78页 |
| 3.4 Wild-type PML and RARa proteins | 第78-81页 |
| 3.4.1 Function of PML and its isoforms | 第78-79页 |
| 3.4.2 Function of RARa in cells | 第79-81页 |
| 3.5 Leukemogenesis of APL:formation of PML-RARa fusion oncoprotein | 第81-82页 |
| 3.6 Treatment of APL | 第82-84页 |
| 3.6.1 Effect of all-trans retinoic acid (ATRA) | 第82-83页 |
| 3.6.2 Mechanistic role of As_2O_3 in APL treatment | 第83-84页 |
| 3.7 Application of As_2O_3 for treatments of non-APL and solid tumors | 第84-91页 |
| 3.7.1 Treatments of non-APL leukemia | 第84-88页 |
| 3.7.1.1 Myelodysplastic syndromes(MDS) | 第85-86页 |
| 3.7.1.2 Myeloid and lymphoid leukemia | 第86页 |
| 3.7.1.3 Chronic myeloid leukemia(CML) | 第86页 |
| 3.7.1.4 Non-M3 AML leukemia | 第86-87页 |
| 3.7.1.5 Lymphoma and lymphocytic leukemia | 第87-88页 |
| 3.7.1.6 Multiple myeloma | 第88页 |
| 3.7.2 Effect of arsenic trioxide on solid tumors | 第88-91页 |
| 3.7.2.1 Hepatocellular carcinoma(HCC) | 第88-89页 |
| 3.7.2.2 Esophageal carcinoma | 第89-90页 |
| 3.7.2.3 Gastric and pancreatic carcinomas | 第90-91页 |
| 3.7.2.4 Ovarian and prostrate carcinoma | 第91页 |
| 3.8 Additional information for molecular mechanism of anticancer effects by As_2O_3 in solidcancers | 第91-92页 |
| 3.9 Organic arsenicals as anti-cancer drugs | 第92-95页 |
| 3.9.1 Melarsoprol | 第93页 |
| 3.9.2 Realgar | 第93-94页 |
| 3.9.3 Darinaparsin | 第94-95页 |
| 3.10 Determinants of arsenic potential as anticancer drug | 第95-103页 |
| 3.10.1 Metabolism of arsenic | 第95-97页 |
| 3.10.2 Arsenic uptake and transport by cells | 第97-103页 |
| 3.10.2.1 Role of aquaglyceroporins for transport of arsenicals | 第99页 |
| 3.10.2.2 Multidrug resistant protein transporters | 第99-101页 |
| 3.10.2.3 Accumulation and intracellular binding affinity of arsenicals | 第101-103页 |
| 3.11 Rationale for arsenic interme diate methylated metabolites as anticancer | 第103-107页 |
| 3.12 Conclusion | 第107-108页 |
| References | 第108-123页 |
| Chapter 4 Mechanisms underlying the inhibitory effects of arsenic compounds on protein tyrosine phosphatase(PTP) | 第123-137页 |
| Abstract | 第124页 |
| 4.1 Introduction | 第124-126页 |
| 4.2 Material and methods | 第126-128页 |
| 4.2.1 Reagents | 第126页 |
| 4.2.2 Preparation of trivalent monomethylarsonous acid (MMA~Ⅲ)and dimethylarsinous acid (DMA~Ⅲ) | 第126-127页 |
| 4.2.3 HPLC-ICP-MS analysis | 第127页 |
| 4.2.4 Culture of HePG2 cells | 第127页 |
| 4.2.5 Determination of PTP activity in cell lysates | 第127-128页 |
| 4.2.6 Determination of recombinant PTP1B activity | 第128页 |
| 4.2.7 Statistical analysis | 第128页 |
| 4.3 Results | 第128-131页 |
| 4.3.1 Inhibitory effects of iAs~Ⅲ, MMA~Ⅲ and DMA~Ⅲ on PTPIB activity | 第128-129页 |
| 4.3.2 Effect of sulfhydryl reducing agent dithiothreitol (DTT) on PTP1B activity after exposure to MMA~Ⅲ and DMA~Ⅲ | 第129页 |
| 4.3.3 Interaction of recombinant protein PTP1B with three arsenic compounds | 第129-130页 |
| 4.3.4 Determination of PTP activity in HepG2 cells after exposure to iAs~Ⅲ MMA~Ⅲ and DMA~Ⅲ | 第130-131页 |
| 4.4 Discussion | 第131-134页 |
| 4.5 Conclusion | 第134页 |
| References | 第134-137页 |
| Chapter 5 Effect of arsenic and its intermediate methylated metabolites on human myeloid leukemia HL-60cells | 第137-152页 |
| Abstract | 第138页 |
| 5.1 Introduction | 第138-140页 |
| 5.2 Materials and methods | 第140-143页 |
| 5.2.1 Reagents | 第140页 |
| 5.2.2 Preparation of MMA~Ⅲ and DMA~Ⅲ | 第140-141页 |
| 5.2.3 Cell and culture condition | 第141页 |
| 5.2.4 Cell viability by MTT assay | 第141页 |
| 5.2.5 Assessment of cellular apoptosis | 第141-142页 |
| 5.2.6 Cellular uptake of iAs~Ⅲ and its methylated trivalent metabolites | 第142页 |
| 5.2.7 Western blot analysis | 第142页 |
| 5.2.8 Measurement of cellular caspase-3 activity | 第142-143页 |
| 5.2.9 Statistics | 第143页 |
| 5.3 Results | 第143-146页 |
| 5.3.1 Effect of iAs~Ⅲ,MMA~Ⅲ and DMA~Ⅲ on viability of leukemic cells | 第143页 |
| 5.3.2 Effect of iAs~Ⅲ,MMA~Ⅲ and DMA~Ⅲ on cellular apoptosis | 第143-145页 |
| 5.3.3 Cellular Uptake of iAsm and its methylated trivalent metabolites | 第145页 |
| 5.3.4 MMAm and DMAminduce activation of apoptosis-related proteins | 第145-146页 |
| 5.3.5 Time-course and concentration dependent effect of iAs~Ⅲ,MMA~Ⅲ and DMA~Ⅲ on cellular caspase-3 activity | 第146页 |
| 5.4 Discussion | 第146-149页 |
| 5.5 Conclusion | 第149页 |
| References | 第149-152页 |
| Chapter 6 Trivalent methylated arsenic metabolites affect human myeloid leukemia HL-60 cells through generation of reactive oxygen species, DNA damage andmitochondrial pathi^y | 第152-166页 |
| Abstract | 第153页 |
| 6.1 Introduction | 第153-155页 |
| 6.2 Materials and methods | 第155-158页 |
| 6.2.1 Reagents | 第155页 |
| 6.2.2 Preparation of monomethylarsonous acid (MMA~Ⅲ) and dimethylarsinous acid (DMA~Ⅲ) | 第155-156页 |
| 6.2.3 Cell and culture condition | 第156页 |
| 6.2.4 Measurement of intracellular ROS | 第156页 |
| 6.2.5 Apoptotic DNA ladder determination | 第156页 |
| 6.2.6 Detection of γ-H2AX by immunofluorescence | 第156-157页 |
| 6.2.7 Detection of mitochondrial membrane potential | 第157页 |
| 6.2.8 Western blot analysis | 第157-158页 |
| 6.2.9 Statistics | 第158页 |
| 6.3 Results | 第158-160页 |
| 6.3.1 Effect of iAs~Ⅲ, MMA~Ⅲ and DMA~Ⅲ on intracellular ROS generation | 第158-159页 |
| 6.3.2 MMA~Ⅲ and DMA~Ⅲ can induces loss of mitochondrial membrane potential | 第159页 |
| 6.3.3 Effect of iAs~Ⅲ,MMA~Ⅲ and DMA~Ⅲ on DNA ladder | 第159-160页 |
| 6.3.4 Effect of iAs~Ⅲ,MMA~Ⅲ and DMA~Ⅲ on γ-H2AX generation | 第160页 |
| 6.4 Discussion | 第160-163页 |
| 6.5 Conclusion | 第163页 |
| References | 第163-166页 |
| Chapter 7 Summary and future perspectives | 第166-169页 |
| 7.1 Summary | 第167-168页 |
| 7.2 Future perspectives | 第168-169页 |
| Author biography | 第169-173页 |
| Author introduction | 第169页 |
| Honors and awards | 第169页 |
| List of publications | 第169页 |
| Publications from dissertation | 第169-170页 |
| Other publications | 第170-173页 |
